Coagulation parameters and venous thromboembolism in patients with and without COVID-19 admitted to the Emergency Department for acute respiratory insufficiency.

BACKGROUND: In the recent outbreak of COVID-19 pandemic, increased D-dimer levels and high rates of venous thromboembolic events were reported. We aimed to compare coagulation parameters on admission between COVID-19 patients and non-COVID-19 patients with acute respiratory insufficiency and to describe VTE diagnosed at entry. METHODS: In this single-centre, observational retrospective study consecutive patients admitted for fever and acute respiratory failure were included. Patients underwent laboratory tests, arterial blood gas, chest X-ray, point of care ultrasound (POCUS), limited compression ultrasonography of the lower limbs (L-CUS), chest CT-scan if necessary, and swab test for COVID-19. RESULTS: Of 324 patients, 50% had COVID-19. COVID19 patients had significantly lower mean white blood cells, neutrophils, platelet count, and pCT values, and significantly higher CRP, LDH, and ferritin levels than non-COVID19 patients. D-dimer was increased in 86.5% COVID19 patients and in 84.9% non-COVID19 patients; mean values were similar (2185 ng/mL and 2814 ng/mL, respectively, p = n.s.). After multivariate analysis, results were unchanged (Odds Ratio 1.00 95%CI: 0.99-1.00, p = 0.21). PT and aPTT values were also similar between the two groups, fibrinogen levels were higher in COVID19 than in non-COVID19 patients (684 and 496 mg/dL, respectively, p < 0.0001). Five patients had asymptomatic proximal deep vein thrombosis detected by L-CUS (3 COVID19) and 2 patients had symptomatic pulmonary embolism (both non-COVID19). CONCLUSIONS: D-dimer levels were similarly increased in patients with and without SARS-CoV 2 related disease. There were few cases of asymptomatic deep vein thrombosis or symptomatic pulmonary embolism at first day of admission, similarly distributed between COVID19 patients and non-COVID19 patients.

PREVALENCE AND CORRELATES OF ADHERENCE IN CHILDREN AND ADOLESCENTS TREATED WITH GROWTH HORMONE: A MULTICENTER ITALIAN STUDY.

OBJECTIVE: To evaluate the self-reported prevalence of poor adherence to recombinant human growth hormone (rhGH) therapy in a large, representative sample of Italian children and adolescents and to assess treatment and patient level correlates of poor adherence. METHODS: The study was conducted in 46 pediatric centers throughout Italy. A questionnaire was administered to consecutive children/adolescents treated with rhGH or their parents. Eligible patients were represented by subjects aged between 6 and 16 years, of both sexes, on rhGH treatment for at least 6 months. The questionnaire was administered to the person in charge of preparing the injection. Multivariable logistic regression analysis was performed to identify factors independently associated with adherence. RESULTS: Overall, 1,007 children/adolescents were involved, of whom 24.4% missed 1 or more injections during a typical week and were thus considered as nonadherent. The most frequently reported reasons for missing a dose were being away from home (33.3%), forgetfulness (24.7%), not feeling well (12.9%), and pain (10.3%). Multivariable analysis indicated association between poor adherence and adolescence, low level of parent education, longer duration of treatment, need to convince the child to inject, and low level of awareness of the consequences of not properly following treatment. The likelihood of adherence markedly increased with higher levels of perceived device convenience. CONCLUSION: Poor adherence is still a major problem in the treatment of growth disorders. Increasing awareness and reassessment of treatment adherence on an annual basis should be part of clinical practice of pediatric endocrinologists involved with rhGH treatment. ABBREVIATIONS: CI = confidence interval GH = growth hormone rhGH = recombinant human growth hormone.

Cardiovascular autonomic alterations in hospitalized patients with community-acquired pneumonia.

BACKGROUND: Alterations of cardiac autonomic control (CAC) are associated with poor outcomes in patients with infectious and non-infectious diseases. No evaluation of CAC in patients with community-acquired pneumonia (CAP) has been performed so far. The aim of the study was to assess CAC in patients with CAP and evaluate the impact of its alterations on disease severity and clinical outcomes in a multicenter, prospective, observational study. METHODS: Consecutive patients hospitalized for CAP were enrolled between 2011 and 2013 two university hospitals in Italy. CAC was assessed by linear spectral and non-linear symbolic analysis of heart rate variability. The presence of severe CAP was evaluated on hospital admission. The primary study outcome was time to clinical stability (TCS) during hospitalization. RESULTS: Among the 75 patients enrolled (median age: 75 years; 57 % males), a significantly lower total variability and reduction of sympathetic rhythmical component with predominant respiratory modulation was detected in comparison to controls. Among CAP patients affected by a severe CAP on admission, CAC showed a lower sympathetic modulation and predominant parasympathetic oscillatory rhythm. At the multivariate analysis, variables independently correlated with a TCS >7 days were total power, as marker of total variability, [OR (95 % CI): 0.997 (0.994-1.000), p = 0.0454] and sympathetic modulation [OR (95 % CI): 0.964 (0.932-0.998), p = 0.0367]. CONCLUSIONS: Loss of sympathetic rhythmical oscillation is associated with a more severe disease and worse early clinical outcome in hospitalized patients with CAP.

Haematopoietic stem cell transplantation in Nigerian sickle cell anaemia children patients.

BACKGROUND: Sickle cell anaemia (SCA) remains associated with high risks of morbidity and early death. Children with SCA are at high risk for ischaemic stroke and transient ischaemic attacks, secondary to intracranial arteriopathy involving carotid and cerebral arteries. Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative treatment for SCA. We report our experience with transplantation in a group of patients with the Black African variant of SCA. PATIENTS AND METHODS: This study included 31 consecutive SCA patients who underwent bone marrow transplantation from human leukocyte antigen (HLA)-identical sibling donors between 2010 and 2014 following a myeloablative-conditioning regimen. RESULTS: The median patient age was 10 years (range 2-17 years). Before transplantation, 14 patients had recurrent, painful, vaso-occlusive crisis; ten patients had recurrent painful crisis in association with acute chest syndrome; three patients experienced ischaemic stroke and recurrent vaso-occlusive crisis; two patients experienced ischaemic stroke; one patient exhibited leukocytosis; and one patient exhibited priapism. Of the 31 patients, 28 survived without sickle cell disease, with Lansky/Karnofsky scores of 100. All surviving patients remained free of any SCA-related events after transplantation. CONCLUSION: The protocols used for the preparation to the transplant in thalassaemia are very effective also in the other severe haemoglobinopathy as in the sickle cell anaemia with 90% disease free survival. Today, if a SCA patient has a HLA identical family member, the cellular gene therapy through the transplantation of the allogeneic haemopoietic cell should be performed. Tomorrow, hopefully, the autologous genetically corrected stem cell will break down the wall of the immunological incompatibility.

Invasive pulmonary aspergillosis in a haematopoietic stem cell transplant recipient with sickle cell disease: a successful treatment.

Sickle Cell Anaemia (SCA) is the most common inherited blood disorder and is associated with severe morbidity and decreased survival. Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) is the only curative approach. Nevertheless the decision to perform a bone marrow transplant includes the risk of major complications and transplant-related mortality. Infections represent the leading cause of death in SCA patients undergoing HSCT. Invasive Pulmonary Aspergillosis (IPA) is a devastating opportunistic infection and remains a significant cause of morbidity and mortality in HSCT recipients. Data regarding IPA in the setting of SCA are lacking. In the present report, we describe a patient with SCA, who developed IPA after allogeneic bone marrow transplant. The fungal infection was treated by systemic antifungal therapy in addition to surgery, despite mild chronic graft versus host disease (GVHD) and continuing immunosuppressive therapy. This case shows that IPA occurring in bone marrow recipients with SCA can be successfully treated.

Peripheral red blood cell split chimerism as a consequence of intramedullary selective apoptosis of recipient red blood cells in a case of sickle cell disease.

Allogeneic cellular gene therapy through hematopoietic stem cell transplantation is the only radical cure for congenital hemoglobinopathies like thalassemia and sickle cell anemia. Persistent mixed hematopoietic chimerism (PMC) has been described in thalassemia and sickle cell anemia. Here, we describe the clinical course of a 6-year-old girl who had received bone marrow transplant for sickle cell anemia. After the transplant, the patient showed 36% donor hematopoietic stem cells in the bone marrow, whereas in the peripheral blood there was evidence of 80% circulating donor red blood cells (RBC). The analysis of apoptosis at the Bone Marrow level suggests that Fas might contribute to the cell death of host erythroid precursors. The increase in NK cells and the regulatory T cell population observed in this patient suggests that these cells might contribute to the condition of mixed chimerism.

Reduction of intramedullary apoptosis after stem cell transplantation in black african variant of pediatric sickle cell anemia.

BACKGROUND AND PURPOSE: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for sickle cell anemia (SCA). We report our experience with transplantation in children with the Black African variant of SCA and the effects of transplant on erythroid compartment in bone marrow (BM). PATIENTS AND METHODS: Twenty-seven consecutive patients who underwent BM transplantation from HLA-identical donors following a myeloablative conditioning regimen were included. Using both CD71 and FSC parameters, we obtained three erythroid populations: EryA-C. Ery A (CD71(high) FSC(high)) are basophilic; Ery B (CD71(high) FSC(low)) are late basophilic and polychromatic; and Ery C (CD71(low) FSC(low)) are orthochromatic erythroblasts and reticulocytes. To analyze the effect of transplantation on intramedullary apoptosis, we studied Fas (CD95+) and caspase-3 expression in erythroblast subpopulations. RESULTS: All patients experienced sustained engraftment, and all surviving patients remained free of SCA-related events after transplantation. The erythroid population showed expansion in the BM at baseline. After transplant, levels decreased, especially of Ery C, in parallel to reduced Fas expression and an initial caspase 3 increase in erythroid population, similar to reported later steps of "normal" erythroid maturation. CONCLUSIONS: The results suggest a good chance of cure for children with SCA, with an excellent survival rate. We also observed "normalization" of erythroid populations in parallel with a decreased intramedullary apoptosis rate, suggesting normal erythroid maturation in ex-SCA patients after HSCT.

Immunohematologic reconstitution in pediatric patients after T cell-depleted HLA-haploidentical stem cell transplantation for thalassemia.

To analyze immunohematologic reconstitution, particularly of natural killer (NK) cells, we evaluated 13 ß-thalassemia patients after 20 and 60 days and 1 year posttransplantation with T cell-depleted HLA-haploidentical stem cells. We assessed lymphocyte and bone marrow (BM) progenitor cell phenotype and differentiation capacity, spontaneous BM cytokine production, stromal cells, and stromal cell interleukin (IL)-7 production. A reduced clonogenic capability manifested at day +20. Patients had significantly lower CD4(+) T cells versus controls, mainly in the CD45RA(+)CD62L(+) subset. NKs were among the first lymphocytes to repopulate the peripheral blood. At day +60, an increase in primitive BM progenitor cells paralleled small increases in CD4(+), naïve CD4(+), and thymic naïve Th cells. A significant increase in CD4(+) and CD8(+) markers paralleled an increase in CD3⁻CD16(+) NKs, especially with full engraftment. In patients with stable mixed chimerism we observed very low levels of CD3(+) donor chimerism early after transplant that increased over time, but a stable population of high donor NK cells, suggesting a role of these cells on donor engraftment. Stromal cells secreted less IL-7 and displayed "macrophage-like" morphology. Patients initially manifested impaired stem/progenitor cell growth and differentiation capacity in parallel with altered T cell homeostasis and a reduced T cell naïve compartment. We hypothesize that T cell compartment damage partly arises from altered new T cell production from the hematopoietic stem/progenitor cells under stromal cytokine influence. NNK subset analysis might be useful for determining transplant outcome.

Purified T-depleted, CD34+ peripheral blood and bone marrow cell transplantation from haploidentical mother to child with thalassemia.

Fetomaternal microchimerism suggests immunological tolerance between mother and fetus. Thus, we performed primary hematopoietic stem cell transplantation from a mismatched mother to thalassemic patient without an human leukocyte antigen-identical donor. Twenty-two patients with thalassemia major were conditioned with 60 mg/kg hydroxyurea and 3 mg/kg azathioprine from day -59 to -11; 30 mg/m(2) fludarabine from day -17 to -11; 14 mg/kg busulfan starting on day -10; and 200 mg/kg cyclophosphamide, 10 mg/kg thiotepa, and 12.5 mg/kg antithymocyte globulin daily from day -5 to -2. Fourteen patients received CD34(+)-mobilized peripheral blood and bone marrow progenitor cells; 8 patients received marrow graft-selected peripheral blood stem cells CD34(+) and bone marrow CD3/CD19-depleted cells. T-cell dose was adjusted to 2 x 10(5)/kg by fresh marrow cell addback at the time of transplantation. Both groups received cyclosporine for graft-versus-host disease prophylaxis for 2 months after transplantation. Two patients died (cerebral Epstein-Barr virus lymphoma or cytomegalovirus pneumonia), 6 patients reject their grafts, and 14 showed full chimerism with functioning grafts at a median follow-up of 40 months. None of the 14 patients who showed full chimerism developed acute or chronic graft-versus-host disease. These results suggest that maternal haploidentical hematopoietic stem cell transplantation is feasible in patients with thalassemia who lack a matched related donor.

Late-onset hemorrhagic cystitis in children after hematopoietic stem cell transplantation for thalassemia and sickle cell anemia: a prospective evaluation of polyoma (BK) virus infection and treatment with cidofovir.

Little is known about late-onset hemorrhagic cystitis (HC) in children, its relationship to BK virus, and treatment with cidofovir (CDV) following hematopoietic stem cell transplantation (HSCT). We prospectively investigated BK virus reactivation in children who underwent HSCT from a matched related donor for thalassemia or sickle cell anemia following busulfan-cyclophosphamide-based conditioning regimens and analyzed risk factors for development of HC and its treatment with CDV. Grade 2-4 HC occurred in 30 patients with a cumulative incidence of 26% (95% confidence interval [CI] = 18%-34%). The cumulative incidences of BK viruria and viremia were 81% (95% CI = 69%-89%) and 28% (95% CI = 18%-40%), respectively. Multivariate analysis revealed that use of antithymocyte globulin (ATG) (hazard ratio [HR] = 10.5; P = .001), peak BK viruria >100,000 copies/mL (HR = 6.2; P = .004), and grade II-IV acute graft-versus-host disease (HR = 5.3; P = .007) were predictive factors for HC. Nineteen patients with HC were given CDV at 1.5 mg/kg/day 3 times a week, or 5 mg/kg/week. The median duration of therapy was 27 days (range, 21-180 days), and a median of 9 doses were given (range, 6-22). All patients had a complete clinical response (CCR), and 69% had a microbiological response at 4 weeks. Eleven patients with BK virus-related HC receiving supportive care also had CCR. The median duration of HC in these patients was similar to that in patients treated with CDV. None of the patients with HC cleared BK viruria when CCR was achieved. We conclude that late-onset HC is more prevalent in children with sustained high BK viruria who are treated with ATG or who develop graft-versus-host disease. Randomized clinical trials are urgently needed to better define the role of CDV in treating BK virus-related HC.

Sustained and full fetal hemoglobin production after failure of bone marrow transplant in a patient homozygous for beta 0-thalassemia: a clinical remission despite genetic disease and transplant rejection.

An adult patient affected by beta(0)-thalassemia major underwent allogeneic bone marrow transplant (BMT) from a matched related donor. Forty days after transplant, allogeneic engraftment failure and autologous beta(0)-thalassemic bone marrow recovery were documented. Red blood cell transfusions were required until 118 days post-transplant. Thereafter, the haemoglobin (Hb) levels stabilized over 11.8 gr/dl throughout the ongoing 34-month follow-up, abolishing the need for transfusion support. The Hb electrophoresis showed 100% Hb Fetal (HbF). This unexplained case suggests full HbF production may occur in an adult patient with beta(0)-thalassemia major.

Risk of thromboembolism in patients with idiopathic autoimmune hemolytic disease and antiphospholipid antibodies: results from a prospective, case-control study.

During a period of 4 years, 21 consecutive patients with newly diagnosed idiopathic autoimmune hemolytic disease (IAHD) and 42 healthy, sex- and age-matched subjects, were tested for the presence of antiphospholipid antibodies (APA). At diagnosis, APA were detected in 10/21 (47.6%) patients and in 2/42 (4.76%) controls (p< 0.01). No thromboembolic events were registered during the follow-up period.