Pentoxifylline therapy: a new adjunct in the treatment of pulmonary hypertension?

Patients with markedly elevated pulmonary vascular resistance, whether caused by primary pulmonary hypertension or by congenital heart disease, have a grave prognosis, regardless of the type of therapy they undergo. This brief report presents our experience in treating 6 patients (4 women and 2 men) having pulmonary vascular obstructive disease, by administrating pentoxifylline (Trental), a drug that has been used in patients with chronic occlusive systemic arterial disease. Our patients underwent treadmill testing before the study and again 1 to 3 months after initiation of the study. Duration of exercise was short in all patients; however, it increased significantly while patients were taking pentoxifylline. These preliminary results are encouraging; however, we were unable to confirm other physiologic improvement with noninvasive study, and placebo effect was not ruled out. Therefore, we believe that use of pentoxifylline in patients with pulmonary vascular obstructive disease warrants further investigation by means of detailed direct hemodynamic measurement.     

Diastolic dysfunction and pulmonary hypertension in sickle cell anemia: is there a role for L-carnitine treatment?

Clinical manifestations of cardiovascular abnormalities in patients with sickle cell (SC) anemia are well documented. Many variables were assessed in our study before and after administration of L-carnitine to randomly selected 37 SC disease (SCD) children for a period of 6 months. Variables such as weight, height, serum ferritin levels, units of blood transfused and the number of veno-occlusive crises all showed significant improvement after the 6 months of therapy with L-carnitine. Our study also showed that cardiac diastolic function and pulmonary hypertension are common in pediatric SCD patients. These two disorders showed some improvement after L-carnitine administration. Therefore, L-carnitine deserves a rigorous large-scale randomized clinical trial to evaluate its potential benefits as treatment for SCD patients with cardiac complications.     

Dendritic cells: a new horizon in cell therapy for inflammatory bowel disease?

Autoimmune diseases, or immune-mediated diseases, are characterized by loss of tolerance to autoantigens and immune system activation causing damage to one or multiple organs. The mechanisms through which this abnormal immune response is started and maintained are not fully established. The therapeutic approach to these diseases is generally based on corticosteroids, immunomodulators, and monoclonal antibodies. Given the exceptional capacity of dendritic cells to induce immunogenicity, early results in humans for the treatment of tumors (melanoma) or infections (HIV) with immunogenic dendritic cells have recently been obtained. Identification of dendritic cells with tolerogenic capacity and the results in experimental models of autoimmune diseases (autoimmune encephalomyelitis, diabetes mellitus, colitis) suggests that treatment with tolerogenic dendritic cells could be a beneficial therapeutic alternative in the treatment of autoimmune diseases or immune-mediated diseases such as Crohn's disease.     

Gene therapy for sickle cell disease: where we are now?

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Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?

Haematopoietic stem cell transplantation (HSCT) is curative in sickle cell disease (SCD); however, the lack of available matched donors makes this therapy out of reach for the majority of patients with SCD. Alternative donor sources such as haploidentical HSCT expand the donor pool to nearly all patients with SCD, with recent data showing high overall survival, limited toxicities, and effective reduction in acute and chronic graft-versus-host disease (GVHD). Simultaneously, multiple gene therapy strategies are entering clinical trials with preliminary data showing their success, theoretically offering all patients yet another curative strategy without the morbidity and mortality of GVHD. As improvements are made for alternative donors in the allogeneic setting and as data emerge from gene therapy trials, the optimal curative strategy for any individual patient with SCD will be determined by many critical factors including efficacy, transplant morbidity and mortality, safety, patient disease status and preference, cost and applicability. Haploidentical may be the preferred choice now based mostly on availability of data; however, gene therapy is closing the gap and may ultimately prove to be the better option. Progress in both strategies, however, makes cure more attainable for the individual with SCD.     

Vaccination in sickle cell disease: Immunocompromised or immunocompetent?

Sickle cell disease (SCD) is an immunocompromised condition and patients with SCD may have a reduced immune response to certain vaccinations. The report by Nakahara et al. demonstrated that SCD patients exhibited elevated and more sustained IgG production following COVID-19 vaccination, when compared to healthy controls. This suggests that the immune response to vaccinations may vary among different types of vaccines in individuals with SCD. Commentary on: Nakahara et al. Enhanced IgG immune response to COVID-19 vaccination in patients with sickle cell disease. Br J Haematol 2023;202:937–941.     

Hemophilia gene therapy: ushering in a new treatment paradigm?

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Has stem cell transplantation come of age in the treatment of sickle cell disease?

Currently, hematopoietic SCT (HCT) is the only intervention that can restore normal hematopoiesis to provide a 'cure' in sickle cell disease. Yet, this treatment modality is used sparsely-a total of less than 400 transplants are reported in the Center for International Blood and Marrow Transplant Research database despite 70,000 afflicted in the United States; 88% of transplants are from HLA-matched sibling donors and 84% are <16 years of age at transplant. Overall survival at 3 years is over 90% after HCT in the young but 62% in adult HCT recipients due to increased disease and transplant-related morbidity. The decision and timing of HCT is a dilemma for physicians and families due to the need to consider HCT before severe organ damage in a disease that is generally not fatal in children with adequate supportive care. From the transplant physician's perspective, however, advances in the ability to identify well-matched donors, supportive care and promising conditioning regimens with low toxicity and transplant complications support the development of new HCT trials for sickle cell disease as the risk/benefit ratio can be balanced better. With the recognition of new predictors of early mortality, the anticipation of extensive and expensive life-long medical support, and the poor quality of life despite medical care, the scales tip in favor of HCT. This is prime time for the development of careful unrelated donor HCT trials for sickle cell disease. Research efforts targeting HCT will need to be directed at seeking safe and effective transplant methods applicable to all patients who might derive benefit.     

Periodic limb movement in sleep and sickle cell disease: a neglected association?

High frequency of periodic limb movements in sleep (PLMS) has been described among children with sickle cell disease (SCD), but there is little information about PLMS among adults with SCD. We aim to determine the frequency of PLMS among adults with SCD and to identify possible associations with iron status and haemolytic parameters. We analysed polysomnography on 99 adults: 74 with sickle cell anaemia (HbSS), 19 with HbSC (double heterozygosis HbS and HbC) and 6 with HbS‐beta thalassaemia. Laboratory data were collected close to the time of the polysomnography examination. The prevalence of PLMS > 5/h was 70% and of PLMS > 15/h 36%, in the total group of patients. No differences were observed regarding gender, use of hydroxyurea and iron parameters. Logistic regression showed an association between PLMS > 15/h and hemolytic parameters: absolute reticulocyte count (p = 0.03) and unconjugated bilirubin (p = 0.01). Our data suggest that PLMS may be associated with manifestations of greater severity in SCD.     

Paediatric haematologists’ attitudes regarding haematopoietic cell transplantation as treatment for sickle cell disease

Beginning early in childhood, patients with sickle cell disease [SCD; a group of genetic haemoglobin disorders characterized by the sickle or HbS mutation (HBB E7V)] are at risk of life-threatening and debilitating health events. Despite the high morbidity and mortality of this disease, haematopoietic cell transplantation (HCT), a curative therapy for SCD, remains underutilized. A variety of factors, including the limited availability of suitable donors, play a role in this trend, but do not fully explain the low frequency with which this therapy is employed. The objective of this study was to identify paediatric haematologists’ attitudes about HCT as a treatment option for SCD, and to describe the impact of these attitudes on their practices of discussing HCT with families of children affected by this disease. A nationwide survey of paediatric haematologists in the United States was conducted between February and May 2016. Two hundred and eighty-seven surveys were included in the final analysis (response rate 20%). On average, respondents reported informing 42% of families about HCT as a treatment option (N = 248, 95% confidence interval: 38–46). Clinician attitudes about the cost and safety of HCT were associated with practices of discussing this therapy with families. These findings suggest that clinician attitudes and referral practices may play a role in the underutilization of this therapy in the SCD population.