Basic science research opportunities in thrombosis and hemostasis: Communication from the SSC of the ISTH.

Bleeding and thrombosis are major clinical problems with high morbidity and mortality. Treatment modalities for these diseases have improved in recent years, but there are many clinical questions remaining and a need to advance diagnosis, management, and therapeutic options. Basic research plays a fundamental role in understanding normal and disease processes, yet this sector has observed a steady decline in funding prospects thereby hindering support for studies of mechanisms of disease and therapeutic development opportunities. With the financial constraints faced by basic scientists, the ISTH organized a basic science task force (BSTF), comprising Scientific and Standardization Committee subcommittee chairs and co-chairs, to identify research opportunities for basic science in hemostasis and thrombosis. The goal of the BSTF was to develop a set of recommended priorities to build support in the thrombosis and hemostasis community and to inform ISTH basic science programs and policy making. The BSTF identified three principal opportunity areas that were of significant overarching relevance: mechanisms causing bleeding, innate immunity and thrombosis, and venous thrombosis. Within these, five fundamental research areas were highlighted: blood rheology, platelet biogenesis, cellular contributions to thrombosis and hemostasis, structure-function protein analyses, and visualization of hemostasis. This position paper discusses the importance and relevance of these opportunities and research areas, and the rationale for their inclusion. These findings have implications for the future of fundamental research in thrombosis and hemostasis to make transformative scientific discoveries and tackle key clinical questions. This will permit better understanding, prevention, diagnosis, and treatment of hemostatic and thrombotic conditions.

ASH Research Collaborative: a real-world data infrastructure to support real-world evidence development and learning healthcare systems in hematology.

The ASH Research Collaborative is a nonprofit organization established through the American Society of Hematology's commitment to patients with hematologic conditions and the science that informs clinical care and future therapies. The ASH Research Collaborative houses 2 major initiatives: (1) the Data Hub and (2) the Clinical Trials Network (CTN). The Data Hub is a program for hematologic diseases in which networks of clinical care delivery sites are developed in specific disease areas, with individual patient data contributed through electronic health record (EHR) integration, direct data entry through electronic data capture, and external data sources. Disease-specific data models are constructed so that data can be assembled into analytic datasets and used to enhance clinical care through dashboards and other mechanisms. Initial models have been built in multiple myeloma (MM) and sickle cell disease (SCD) using the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) and Fast Healthcare Interoperability Resources (FHIR) standards. The Data Hub also provides a framework for development of disease-specific learning communities (LC) and testing of health care delivery strategies. The ASH Research Collaborative SCD CTN is a clinical trials accelerator that creates efficiencies in the execution of multicenter clinical trials and has been initially developed for SCD. Both components are operational, with the Data Hub actively aggregating source data and the SCD CTN reviewing study candidates. This manuscript describes processes involved in developing core features of the ASH Research Collaborative to inform the stakeholder community in preparation for expansion to additional disease areas.

Development and implementation of common data elements for venous thromboembolism research: on behalf of SSC Subcommittee on official Communication from the SSC of the ISTH.

Clinical research in venous thromboembolism (VTE) is hindered by variability in the collection and reporting of data and outcomes. A consistent data language facilitates efficiencies, leads to higher quality data, and permits between-study comparisons and evidence synthesis. The International Society on Thrombosis and Haemostasis (ISTH) launched an international task force of more than 50 researchers to develop common data elements for clinical research in venous thromboembolism. The project was organized in seven working groups, each focusing on a topic area: General Core Data Elements; Anticoagulation and Other Therapies; Chronic VTE and Functional Outcomes; Diagnosis of VTE; Malignancy; Perioperative; and Predictors of VTE. The groups met via teleconference to collaboratively identify key data elements and develop definitions and data standards that were structured in a project-specific taxonomy. A Steering Committee met by teleconference and in-person to determine the overall scope of the project and resolve questions arising from the working groups. ISTH held an open public comment period to enable broader stakeholder involvement and feedback. The common data elements were then refined by the working groups to create a set of 512 unique data elements that are publicly available at http://isth.breakthrough.healthcare. The ISTH VTE Common Data Elements are intended to be a living project with ongoing curation, future expansion, and adaptation to meet the needs of the thrombosis and hemostasis research community.

Incidence, spectrum and outcome of immune reconstitution syndrome in HIV-infected children after initiation of antiretroviral therapy.

BACKGROUND: Immune reconstitution syndrome (IRS) is a relatively common complication in HIV-infected adults starting combination antiretroviral therapy (cART). Data on IRS in HIV-infected children remain limited and are largely restricted to resource-limited settings. This study investigated the incidence, spectrum and outcome of IRS in a pediatric cohort in the United Kingdom. METHODS: Retrospective analysis of clinical events during the first 12 months after initiation of cART in 135 treatment-naïve, HIV-infected children in the United Kingdom over a 5-year period. Demographic and laboratory data were provided by the Collaborative HIV Paediatric Study. RESULTS: The median age at cART initiation was 6.6 years (interquartile range: 2.3-10.2). The median CD4 lymphocyte percentage (CD4%) at baseline was 15% (median CD4 lymphocyte count: 390 cells/µL). Eight patients (5.9%) developed IRS (incidence: 5.7/100 person years). The IRS events comprised: Bacillus Calmette-Guerin-related complications (local ulceration/lymphadenitis; n = 4), pulmonary tuberculosis (n = 1), Mycobacterium avium intracellulare infection (n = 1), combined tuberculosis/Mycobacterium avium intracellulare infection (n = 1) and cutaneous herpes simplex (n = 1). The mortality was significantly higher in children with IRS than in those without (P < 0.0001). The only statistically significant risk factor for IRS identified was increment in CD4 count at 12 months after starting cART (P = 0.03). CONCLUSIONS: The incidence of IRS was significantly lower than previously reported from resource-limited settings, likely reflecting less profound immunodeficiency at cART initiation and fewer coexisting opportunistic infections in our cohort. However, IRS events were associated with considerable morbidity and mortality. Therefore, preventive strategies that can reduce the risk of IRS in children need to be identified.

Factors influencing T cell activation and programmed death 1 expression in HIV-infected children.

Immune activation is the best marker of HIV disease progression in both adults and children. However, the factors that drive immune activation in HIV-infected children remain incompletely understood and may differ from those in adults. Immune activation was investigated in a cohort of 93 untreated HIV-infected children, of median age 10.8 years, and 37 HIV-uninfected children. CD8(+) T cell activation, which was higher in HIV-infected than HIV-uninfected children (p<0.001), did not correlate with viral load (R=-0.03, p=0.838). Similarly, programmed death 1 (PD-1) expression on CD8(+) T cells, which was higher in HIV-infected children than HIV-uninfected children (p<0.001), was not associated with viral load (R=0.11, p=0.40), but correlated with CD8 activation (R=0.41, p=0.002). Both CD8 activation and PD-1 expression were partially driven by the magnitude of the HIV-specific CD8(+) T cell response. CD3(+)CD4(+)CD25(hi)FoxP3(+) regulatory T cells (Tregs) were depleted in HIV-infected, compared to HIV-uninfected, children [median 1.0% (IQR 0.6, 1.9) vs. 2.6% (IQR 1.7, 3.2) CD3 cells; p<0.001]. Depletion was associated with increased CD8 activation (R=-0.27, p=0.068), suggesting that the decline in Tregs may allow immune activation to increase. Taken together, immune activation and PD-1 upregulation in children are not directly driven by viral load but may be influenced by the magnitude of the immune response to HIV itself, and to the depletion of Tregs that occurs during HIV infection. Further understanding of the factors that drive immune activation in children is critical to developing future therapeutic strategies in this population.

Percutaneous endoscopic gastrostomy placement in a human immunodeficiency virus-positive pediatric population leads to an increase in minor complications.

AIM: The development of effective multiple drug regimens for treating human immunodeficiency virus (HIV) are associated with nonadherence in children. HIV-positive children also have a higher incidence of malnutrition. Placement of a percutaneous endoscopic gastrostomy (PEG) is a potential solution. Primary outcome was to determine the complications of PEG placement in a pediatric HIV-positive population. MATERIALS AND METHODS: A 10 year retrospective data analysis was carried out on all HIV-positive children undergoing insertion of a PEG at two institutions. Parameters examined included infections, leakage, displacement, reasons for removal, total time in situ, HIV stage, CD4 count, and serological investigation. Data were compared against published data for PEG insertion in pediatric oncology patients and other comparable pediatric series using Fisher's exact test. RESULTS: Eighteen children were identified, with a median age 35 months and follow-up of 62 months. The majority of patients had advanced disease (Stage C; 65%). Fifty percent of PEGs were inserted for feeding supplementation and all were used for the administration of medications. Sixty-one percent experienced a minor complication; 5/18 (27.7%) experienced peristomal infection; 2/18 (11.1%) experienced either bleeding, leakage, or excessive granulation; and 1/18 (5.6%) experienced dislodgement. Stage of HIV did not affect the incidence of bleeding or infection: 5/11(Stage C) versus 2/7(Stage B) (P = .3). There was no significant difference for major complications when compared with any series though comparison with a large pediatric series revealed a significant difference for minor complications 11/18 versus 27/120 (P = .0003). CONCLUSIONS: There is a low rate of serious complications with PEG insertion in our patients, and the rate is comparable to that seen in pediatric oncology patients. The minor complication rate is, however, higher than a nonimmune compromised population; and careful follow-up for these patients is recommended so that the appropriate therapy can be promptly initiated.

Comparison of interferon-gamma release assays and tuberculin skin test in predicting active tuberculosis (TB) in children in the UK: a paediatric TB network study.

BACKGROUND: The value of interferon-gamma release assays (IGRA) to diagnose active tuberculosis (TB) in children is not established, but these assays are being widely used for this purpose. The authors examined the sensitivity of commercially available IGRA to diagnose active TB in children in the UK compared with the tuberculin skin test (TST). METHODS: The authors established a paediatric tuberculosis network and conducted a retrospective analysis of data from children investigated for active TB at six large UK paediatric centres. All centres had used TST and at least one of the commercially available IGRA (T-Spot.TB or Quantiferon-Gold in Tube) in the diagnostic work-up for active TB. Data were available from 333 children aged 2 months to 16 years. The authors measured the sensitivity of TST and IGRA in definite (culture confirmed) and probable TB in children, agreement between TST and either IGRA, and their combined sensitivity. RESULTS: Of 333 children, 49 fulfilled the criteria of definite TB, and 146 had probable TB. Within the definite cohort, TST had a sensitivity of 82%, Quantiferon-Gold in tube (QFT-IT) had a sensitivity of 78% and T-Spot.TB of 66%. Neither IGRA performed significantly better than a TST with a cut-off of 15 mm. Combining the results of TST and IGRA increased the sensitivity to 96% for TST plus T-Spot.TB and 91% for TST plus QFG-IT in the definite TB cohort. CONCLUSIONS: A negative IGRA does not exclude active TB disease, but a combination of TST and IGRA increases the sensitivity for identifying children with active TB.

Bacterial tracheitis: a multi-centre perspective.

The published literature on bacterial tracheitis is limited. We report the first multi-centre study of bacterial tracheitis together with a concise review of the literature. We conducted a retrospective study of cases admitted during the period 1993-2007 to 3 tertiary paediatric centres in the United Kingdom and 1 in Australia. A total of 34 cases were identified. 31 patients (91%) required intubation. Complications included cardiorespiratory arrest in 1, ARDS in 1, hypotension in 10, toxic shock syndrome in 1 and renal failure in 1 patient(s). Staphylococcus aureus was the most commonly implicated bacterial organism, isolated from the respiratory tract in 55.8% of the cases overall. Other pathogens commonly isolated from the respiratory tract included Streptococcus pyogenes (5.9%), Streptococcus pneumoniae (11.8%) and Haemophilus influenzae (11.8%). Viral coinfection was identified in 9 (31%) of the 29 cases in whom immunofluorescence testing was performed (influenza A in 4 cases; parainfluenza 1 in 2 cases; parainfluenza 3 in 2 cases; adenovirus in 1 case). The combined experience from 4 major paediatric intensive care units suggests that bacterial tracheitis remains a rare condition with an estimated incidence of approximately 0.1/100,000 children per year. Short-term complications were common but long-term sequelae were rare. There were no fatal outcomes, which contrasts with the high historical mortality rates and likely reflects improvements in intensive care management.

Chalk and cheese: symptomatic hypocalcaemia during paediatric anti-tuberculous therapy.

Standard anti-tuberculosis therapy may disrupt normal vitamin D metabolism and consequently calcium homeostasis, but this is previously unreported in paediatric patients. We describe two children developed symptomatic hypocalcaemia secondary to hypovitaminosis D, which had been precipitated by rifampicin and isoniazid. The complex relationship between tuberculosis, anti-tuberculosis therapy, vitamin D metabolism and calcium, together with the clinical implications, are discussed.

Children with human immunodeficiency virus admitted to a paediatric intensive care unit in the United Kingdom over a 10-year period.

OBJECTIVE: There is little published experience regarding the outcome of children with human immunodeficiency virus (HIV) infection treated on a paediatric intensive care unit (PICU). We describe the outcome of children with HIV infection in our hospital over a 10-year period. METHOD: We performed a retrospective analysis of all children with HIV infection admitted to our PICU between August 1992 and July 2002. Their ages ranged from 2 months to 11 years (median 4 months). Information collected included demographic data, clinical presentation, investigations, treatment and outcome. RESULTS: There were 42 children with HIV infection admitted to PICU during the study period, with 66 admission episodes. Sixteen (38%) children died in PICU, and 26 (62%) survived their last PICU admission. Of these, 5 died at a later date (between 1 and 32 months after discharge from PICU) and 21 survived to the time of reporting. The most frequent reason for PICU admission was respiratory failure, due either to Pneumocystis carinii pneumonia (45% of admissions) or to other respiratory pathogens (32%). Over 80% of current survivors had good outcomes in terms of growth and development; 6 children had evidence of spastic diplegia. CONCLUSIONS: Although there is significant mortality among children with HIV infection admitted to PICU, many of them survive their admission, and over 80% of the survivors have good outcomes with the currently available highly active anti-retroviral therapy. This provides evidence that intensive care treatment is appropriate for this group of patients in the United Kingdom.

Nevirapine use in HIV-1-infected children.

OBJECTIVES: To evaluate the safety, efficacy, and clinical, virological, and immunological responses in HIV-1-infected children receiving nevirapine as part of combination antiretroviral therapy (ART). METHODS: A review of case notes of all HIV-1-infected children 96 weeks after starting nevirapine, under a national compassionate access scheme between August 1997 and March 1999 in the UK. Nevirapine was dosed according to the manufacturer's guidelines. RESULTS: Seventy-four children (36 boys, 28 naive to ART) were enrolled, with a median age of 5.2 years, viral load of 5.1 log copies/ml and CD4 lymphocyte count of 13.5%. The liquid formulation and tablets of nevirapine were well tolerated. The proportions of patients achieving undetectable viral load levels at weeks 12, 24, 48 and 96 were 30, 40, 36 and 33%, respectively (intention-to-treat analysis). Of children not on a protease inhibitor who received more than 300 mg/m2/day of nevirapine, 60% had undetectable viral loads at week 96, compared with 17% on recommended doses. Outcomes were similar for patients receiving nevirapine once or twice daily. CD4 cell count percentages increased significantly, with median values sustained above 25% by week 48 onwards. Z-scores for weight and height increased significantly during 96 weeks of treatment. Rash occurred in 20%, of which four (5%) were severe. There were no cases of Stevens-Johnson syndrome. CONCLUSION: Nevirapine was mostly well tolerated, and was associated with encouraging clinical and immunological responses. Virological responses in this cohort support the use of nevirapine doses greater than 300 mg/m2/day, which is higher than currently recommended by the manufacturers.