Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management

Intravenous iron is widely used for the treatment of iron deficiency anemia when oral iron is inappropriate, ineffective or poorly tolerated. Acute hypersensitivity reactions during iron infusions are very rare but can be life-threatening. This paper reviews their frequency, pathogenesis and risk factors, and provides recommendations about their management and prevention. Complement activation-related pseudo-allergy triggered by iron nanoparticles is probably a more frequent pathogenetic mechanism in acute reactions to current formulations of intravenous iron than is an immunological IgE-mediated response. Major risk factors for hypersensitivity reactions include a previous reaction to an iron infusion, a fast iron infusion rate, multiple drug allergies, severe atopy, and possibly systemic inflammatory diseases. Early pregnancy is a contraindication to iron infusions, while old age and serious co-morbidity may worsen the impact of acute reactions if they occur. Management of iron infusions requires meticulous observation, and, in the event of an adverse reaction, prompt recognition and severity-related interventions by well-trained medical and nursing staff.     

Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease

BACKGROUND: Systemic sclerosis (SSc, scleroderma) in either its diffuse or limited skin forms has a high mortality when vital organs are affected. No treatment has been shown to influence the outcome or significantly affect the skin score, though many forms of immunosuppression have been tried. Recent developments in haemopoietic stem cell transplantation (HSCT) have allowed the application of profound immunosuppression followed by HSCT, or rescue, to autoimmune diseases such as SSc. METHODS: Results for 41 patients included in continuing multicentre open phase I/II studies using HSCT in the treatment of poor prognosis SSc are reported. Thirty seven patients had a predominantly diffuse skin form of the disease and four the limited form, with some clinical overlap. Median age was 41 years with a 5:1 female to male ratio. The skin score was >50% of maximum in 20/33 (61%) patients, with some lung disease attributable to SSc in 28/37 (76%), the forced vital capacity being <70% of the predicted value in 18/36 (50%). Pulmonary hypertension was described in 7/37 (19%) patients and renal disease in 5/37 (14%). The Scl-70 antibody was positive in 18/32 (56%) and the anticentromere antibody in 10% of evaluable patients. Peripheral blood stem cell mobilisation was performed with cyclophosphamide or granulocyte colony stimulating factor, alone or in combination. Thirty eight patients had ex vivo CD34 stem cell selection, with additional T cell depletion in seven. Seven conditioning regimens were used, but six of these used haemoimmunoablative doses of cyclophosphamide +/- anti-thymocyte globulin +/- total body irradiation. The median duration of follow up was 12 months (3-55). RESULTS: An improvement in skin score of >25% after transplantation occurred in 20/29 (69%) evaluable patients, and deterioration in 2/29 (7%). Lung function did not change significantly after transplantation. One of five renal cases deteriorated but with no new occurrences of renal disease after HSCT, and the pulmonary hypertension did not progress in the evaluable cases. Disease progression was seen in 7/37 (19%) patients after HSCT with a median period of 67 (range 49-255) days. Eleven (27%) patients had died at census and seven (17%) deaths were considered to be related to the procedure (direct organ toxicity in four, haemorrhage in two, and infection/neutropenic fever in one). The cumulative probability of survival at one year was 73% (95% CI 58 to 88) by Kaplan-Meier analysis. CONCLUSION: Despite a higher procedure related mortality rate from HSCT in SSc compared with patients with breast cancer and non-Hodgkin's lymphoma, the marked impact on skin score, a surrogate marker of mortality, the trend towards stabilisation of lung involvement, and lack of other treatment alternatives justify further carefully designed studies. If future trials incorporate inclusion and exclusion criteria based on this preliminary experience, the predicted procedure related mortality should be around 10%.     

Electroencephalographic coherence analysis in multiple sclerosis: correlation with clinical, neuropsychological, and MRI findings

OBJECTIVE: To explore functional corticocortical connections in multiple sclerosis by means of coherence of the EEG, and to evaluate their correlations with the degree of cognitive impairment and with brain lesion load assessed by MRI. METHODS: EEG coherence was studied from 28 patients with clinically definite multiple sclerosis. Ten minutes of resting EEG were recorded with 20 scalp electrodes, with binaural reference. FFT power and coherence were calculated in artifact free epochs of 1 second and compared with values from 22 control subjects of comparable age and sex distribution. Patients also underwent MRI (n=27) and neuropsychological examination (n=21). RESULTS: Compared with controls, patients with multiple sclerosis showed increased theta power in the frontotemporal-central regions (p<0.005). theta Band coherence was decreased between homologous areas (p<0.02). alpha Band coherence was decreased both in the local and long distance connections (p<0.0005). These findings were most striking both in patients with high MRI subcortical lesion load and in patients with cognitive involvement. A significant correlation was found between interhemispheric theta (p=0.02) and alpha (p=0. 017) and anteroposterior alpha (p=0.013) coherence and subcortical MRI lesion load, but not with exclusively periventricular lesion load. CONCLUSIONS: These findings support the hypothesis that cognitive impairment in multiple sclerosis is mostly dependent on involvement of corticocortical connections related to demyelination and/or axonal loss within the white matter immediately underlying the cortex.     

Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis

CD8 T lymphocytes are important effectors in protective immunity against Mycobacterium tuberculosis. We recently characterized the detour pathway of CD8 T cell activation in tuberculosis mediated by apoptotic vesicles from infected cells that transport mycobacterial antigens to dendritic cells (DCs). Here we demonstrate that apoptotic vesicles from mycobacteria-infected macrophages stimulate CD8 T cells in vivo. Homing of DCs to draining lymph nodes was critically required for effective crosspriming. Subsequent fate of vesicle-associated antigens in recipient DCs was characterized by endosomal mechanisms predominating over proteasomal processing. In addition, vesicle processing depended on the presence of saposins to disintegrate apoptotic membranes. Apoptotic vesicles displayed potent adjuvant activity by stimulating through Toll-like receptors (TLR). Ultimately, vaccination with vesicles from infected cells induced protection against M. tuberculosis infection. Taken together, we propose the detour pathway to represent a genuine immunological mechanism mediating crosspriming of CD8 T cells in vivo and protection against tuberculosis.     

Pentraxin 3 in plasma and vaginal fluid in women with preterm delivery

OBJECTIVE To investigate the role of pentraxin 3 (PTX3), an acute-phase protein produced by cells of innate immunity in response to inflammatory signals, in spontaneous preterm delivery (PTD). DESIGN Cohort study. SETTING Department of Obstetrics and Gynecology of the University of Milano-Bicocca. POPULATION Forty-six pregnant women with preterm rupture of membranes (n=33) or preterm labour with intact membranes (n=13) delivering at <34 weeks of gestation and 34 women with uncomplicated pregnancies (control group). METHODS We compared plasma and vaginal PTX3 levels between study group and controls, and in women with versus women without clinical or histologic evidence of intrauterine infection using statistical analysis. MAIN OUTCOME MEASURES Peak PTX3 concentration. RESULTS Peak PTX3 concentration in plasma samples of study group was significantly higher than that in controls (1175, 0-9630 versus 650, 0-1450 pg/ml; P=0.0003) but not in vaginal swabs (1660, 0-6604 versus 457, 0-4649 pg/ml; P=0.386). PTX3 levels in plasma were significantly higher in women with placenta vasculopathy compared with that in women with no placental lesions (2910, 0-9630 versus 636, 0-5692 pg/ml; P=0.04). Peak plasma and vaginal PTX3 concentrations were not significantly different in women with versus women without intrauterine infection (1168, 0-7110 versus 845, 0-9630 pg/ml, P=0.34 and 1975, 471-6604 versus 1919, 0-4150 pg/ml, P=0.38, respectively). CONCLUSIONS Spontaneous PTD is associated with a significant increase of maternal plasma concentrations of PTX3. PTX3 seems to be a marker of placenta vasculopathy rather than intrauterine infection.     

Unmanipulated donor lymphocytes for EBV-related PTLD after T-cell depleted HLA-haploidentical transplantation

Epstein-Barr virus (EBV)-related post-transplantation lymphoproliferative disorder (PTLD) is a life-threatening complication in patients given T-cell-depleted hematopoietic stem cell transplantation from an HLA-haploidentical relative (haplo-HSCT). We report the case of a child who developed severe EBV-related PTLD after haplo-HSCT from his mother. Despite receiving the anti-CD20 monoclonal antibody, the patient presented with intestinal obstruction due to huge abdominal lymphadenopathy, hematemesis, and nodulary pulmonary lesions. Histology showed that the lesions were due to CD20-/CD19+ large neoplastic B cells. The patient underwent double intestinal resection with partial abdominal lymphadenectomy and then received 3 monthly doses of donor-derived unmanipulated mononuclear cells. The initial dose of CD3+ cells was 3?10(5)/kg recipient body weight. The 2 additional doses consisted of 5?10(5) CD3+ cells/kg. No sign or symptom attributable to graft-versus-host disease was observed, and the patient completely cleared EBV-related lesions. The child was disease-free for 13 months after the first lymphocyte infusion. This case demonstrates that repeated infusions of controlled numbers of donor CD3+ cells cure EBV-related PTLD in haplo-HSCT without inducing graft-versus-host disease.     

On the mechanism of olefin polymerization by titanocene/MAO catalysts: Relationships between metathesis and addition polymerization

Ethylene polymerizations and norbornene oligomerizations catalysed by Cp₂Ti¹³CH₃Cl/MAO (Cp: cyclopentadienyl; MAO: methylaluminoxane) mixtures have been carried out at different temperatures (from -20°C to 20°C), in order to test the validity of carbene mechanisms in α-olefin polymerizations. Depending on the temperature, different ratios of the cationic species [Cp₂Ti¹³CH₃]⁺[Cl · MAO]^? and precursors of the alkylidene Cp₂Ti = ¹³CH₂ exist. The in situ polymerization of ¹³C enriched ethylene was monitored by ¹³C NMR spectroscopy. Moreover, catalytic activity was determined and polyethylene samples were analyzed by ¹³C NMR and gel permeation chromatography (GPC). The following evidence has been provided against the carbene mechanism in the α-olefin polymerization with titanocene based catalysts: (a) in the in situ ethylene polymerization experiments the appearance of polyethylene signals is concurrent with the decrease of cationic [Cp₂Ti¹³CH₃]⁺[Cl · MAO]^? signals and is not related to the intensity of the alkylidene Cp₂Ti = ¹³CH₂ signals; (b) from the ¹³C NMR analysis of polyethylene chain-end groups the ¹³C enrichment of Cp₂Ti¹³CH₃Cl has only been found in the methyl chain-end group and not in the methylene of the propyl chain-end group, as should have been the case if the carbene mechanism had been valid; (c) from norbornene oligomerization (at 0°C) the addition product 2-¹³C enriched methyl-norbornane has been identified. Moreover, the identification of a ¹³C enriched methylidene-norbornane dimer at higher temperatures has revealed the possibility of norbornene addition to titanium carbenes through the formation of titanacyclobutane without the opening of the norbornene ring. However, this process requires higher energies with respect to the Cossee type insertion.     

Human leucocyte antigen diversity: A biological gift to escape infections,no longer a barrier for haploidentical Hemopoietic Stem Cell Transplantation

Since the beginning of life, every multicellular organism appeared to have a complex innate immune system although the adaptive immune system, centred on lymphocytes bearing antigen receptors generated by somatic recombination, arose in jawed fish approximately 500 million years ago. The major histocompatibility complex MHC, named the Human leucocyte antigen (HLA) system in humans, represents a vital function structure in the organism by presenting pathogen‐derived peptides to T cells as the main initial step of the adaptive immune response. The huge level of polymorphism observed in HLA genes definitely reflects selection, favouring heterozygosity at the individual or population level, in a pathogen‐rich environment, although many are located in introns or in exons that do not code for the antigen‐biding site of the HLA. Over the past three decades, the extent of allelic diversity at HLA loci has been well characterized using high‐resolution HLA‐DNA typing and the number of new HLA alleles, produced through next‐generation sequencing methods, is even more rapidly increasing. The level of the HLA system polymorphism represents an obstacle to the search of potential compatible donors for patients affected by haematological disease proposed for a hematopoietic stem cell transplant (HSCT). Data reported in literature clearly show that antigenic and/or allelic mismatches between related or unrelated donors and patients influences the successful HSCT outcome. However, the recent development of the new transplant strategy based on the choice of haploidentical donors for HSCT is questioning the role of HLA compatibility, since the great HLA disparities present do not worsen the overall clinical outcome. Nowadays, NGS has contributed to define at allelic levels the HLA polymorphism and solve potential ambiguities. However, HLA functions and tissue typing probably need to be further investigated in the next future, to understand the reasons why in haploidentical transplants the presence of a whole mismatch haplotype between donors and recipients, both the survival rate and the incidence of acute GvHD or graft rejection are similar to those reported for unrelated HSCTs.