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- Roifman, Chaim M2
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- OPEN ACCESSA diagnosis of immunodeficiency can be challenging for families as they navigate the emotional impact of this diagnosis, as well the potential financial burden of treatment. As is the case with many rare diseases, there existed a paucity of information for families looking for appropriate resources related to their diagnosis. The Primary Immunodeficiency Social Work Network was established in 2011 by Immunodeficiency Canada to develop a network of social workers across Canada who work with patients diagnosed with primary immunodeficiency. This network has had a focus on support programs, education, and research. Resource guides were created by the network with the goal of providing comprehensive support and information on resources available for families and individuals affected by primary immunodeficiency in each province as well as those available nationally.Statement of Novelty: National and provincial resources guides, reviewed and updated yearly, have been created for families and individuals affected by primary immunodeficiency.
- OPEN ACCESSThe continued demand for immunoglobulin treatment for multiple indications has placed considerable strain on the supply of immunoglobulin product. Reliance on a few manufacturers can significantly impact the availability of product. In addition, patient tolerability may vary from one product to another necessitating a choice of products to find the best treatment for an individual patient. Therefore, it is important to conduct clinical trials with new immunoglobulin products to ensure that there is adequate supply and choice of products available on the market. This is particularly important for immunodeficient patients who require treatment with immunoglobulins for life. A requirement for licensing by the Federal Food and Drug Administration and Health Canada is that every immunoglobulin licensing study includes some paediatric patients. Enrolling paediatric subjects in immunoglobulin clinical trials can be challenging due to the need for both consent and assent for enrolment, as well as the increased demands that the study protocol places on the child and family over their usual clinical care. Therefore, it is necessary to utilize strategies that make the demands of the protocol more tolerable for children, and to ensure that the study documentation reflects the unique needs of paediatric patients (Denhoff et al. 2015).Statement of novelty: This paper discusses strategies to facilitate enrolment and adherence to immunoglobulin study protocols that are unique to paediatric patients.
- OPEN ACCESSThis protocol is excerpted from recent clinical trials used to study the pharmacokinetics, safety, and tolerability of subcutaneously administered immunoglobulin (SCIG) in subjects with primary immunodeficiency. The primary objective is to determine the weekly dose of SCIG product that produces a steady-state area under the concentration-time curve of total immunoglobulin G level that is non-inferior to that of regularly administered intravenous immunoglobulin (IVIG). We include details of the target population, eligibility criteria, treatment phases, key assessments and procedures, and study analyses. Given that IVIG may be problematic in patients with poor venous access or those who develop systemic adverse effects, among others, the development of SCIG for use in the home setting provides an alternative treatment technique for adults and children with primary immunodeficiency.Statement of novelty: This protocol describes the main topics found in prospective clinical studies evaluating the safety and pharmacokinetics of SCIG in subjects with primary immunodeficiency.
- OPEN ACCESSIntroduction: The evaluation of lymphocyte proliferation responses is a critical component of the clinical work up for patients with suspected immunodeficiencies. Those with severe combined immunodeficiency (SCID) have consistently low to absent responses (stimulation index, SI) to the mitogen phytohemagglutinin (PHA). However, patients with combined immunodeficiency (CID) have more varied proliferative responses, and are open to a wide range of interpretations.Aims: To establish lymphocyte proliferation response reference ranges for patients with T cell defects, especially those with CID as well as healthy controls.Methods: Data was collected retrospectively from charts of patients with a diagnosis of SCID (n = 39), CID (n = 52), or from healthy controls (n = 440). Reference percentiles were calculated using the 95% of the distribution of the test results.Results: The reference ranges for the control group ranged from 134 to 2220.5, whereas those with CID were distributed between 0.81 and 169.1. Patients with typical SCID had profound low proliferative responses, with SI <5.Conclusion: Our results highlight the variability of lymphocyte proliferation responses to PHA in patients with CID as well as healthy controls. These reference ranges will assist with the critical interpretation of assay results, particularly when values fall on the extreme end of the range.Statement of novelty: We provide reference ranges for lymphocyte proliferation responses to PHA from patients with CID and healthy controls.
- OPEN ACCESS
- Stephen Betschel,
- Rae Brager,
- Alison Haynes,
- Thomas Issekutz,
- Vy Hong-Diep Kim,
- Bruce Mazer,
- Christine McCusker,
- Chaim M. Roifman,
- Tamar Rubin,
- Gordon Sussman,
- Stuart Turvey, and
- Susan Waserman
Immunoglobulin replacement therapy is a mainstay in the treatment of immune deficiencies characterized by antibody failure. Whether the cause is primary or secondary, affected patients frequently present with a history recurrent and complicated infections of the upper and (or) lower respiratory tract. Such replacement therapy has been available since the 1980s, although treatment modalities have since been refined to provide improved protection against infections resulting in reduced morbidity and mortality. Here, we describe an algorithm for diagnosing patients with suspected primary or secondary immunodeficiency, including assessment of clinical, laboratory, and genetic information, when considering initiating immunoglobulin replacement. The increasing availability of molecular genetic techniques will likely result in decreased diagnostic delay for these patients.Statement of novelty: We describe here an algorithm for diagnosing patients with immunodeficiency requiring immunoglobulin replacement therapy. - OPEN ACCESSPurine nucleoside phosphorylase (PNP) is a key enzyme required for the degradation of purine nucleosides into uric acid or their salvage into nucleic acids. Patients who are deficient in PNP suffer from progressive T cell immunodeficiency, with increased susceptibility to infections, autoimmunity, and neurologic abnormalities. In the absence of successful treatment to restore immune function, these patients rarely survive to adulthood. Hematopoietic stem cell transplantation is the only known cure for PNP deficiency. Use of an HLA-matched donor is preferable as the outcome with alternative donors have been variable; however, this option is rarely available.Gene therapy represents a therapeutic option that bypasses the need for a donor, and thus associated complications. Although first generation γ-retroviral vectors have been successful in some immunodeficiencies, in others, evidence of insertional mutagenesis prompted a halt in their use. More recently, the introduction of safer lentiviral vectors holds promise in offering a viable option to treat immunodeficiency.Here, we present a clinical trial protocol utilizing self-inactivating lentiviral vectors to treat PNP deficiency. Patients will be evaluated up to 3 years post-transplantation to determine the safety of lentiviral-treated stem cell infusion, as well as the extent of immune reconstitution.Statement of novelty: This protocol describes the novel treatment of PNP deficiency using lentiviral-based gene therapy.
- OPEN ACCESSThe identification of the genetic causes of Common Variable Immune Deficiency (CVID) has led to recognition of the need for biological medications to treat the autoimmune manifestations that CVID patients with LRBA and CTLA4 deficiency experience. Immunologists have not traditionally used biological medications as treatment in CVID patients and may not be familiar with the use of them. We present the process and protocol as well as a nursing checklist used by the Division of Rheumatology for the use of Abatacept.Statement of novelty: The methodology used to develop the order set and nursing checklist may be applied to other biologic medications as they become available.
- OPEN ACCESS
- Stephen Betschel,
- Peter Dent,
- Elie Haddad,
- Alison Haynes,
- Thomas Issekutz,
- Bruce Mazer,
- Brenda Reid,
- Chaim M. Roifman,
- Bob Schellenberg,
- Gordon Sussman,
- Stuart Turvey, and
- Susan Waserman
The use of immunoglobulin therapy has grown steadily over the past 3 decades, mainly due to the increased awareness and expansion of indications. This limited resource is now shared between patients with immunodeficiency disorders who need it as replacement therapy, and individuals who suffer a variety of autoimmune or inflammatory disorders. While alternative therapies exist for the latter diseases, immunodeficient patients are dependent upon this treatment for life. Due to the long-term cost burden of this treatment on healthcare systems, healthcare providers have attempted to moderate its use but are frequently seeking evidence from experts in the field. This raised the critical need for recommendations from experts. To this end, a group a Canadian immunologists representing all regions of the country have formed a panel, the National Immunoglobulin replacement Expert Committee (NIGEC), and formulated a set of unanimously agreed upon recommendations for the use of immunoglobulin replacement in primary immunodeficiency. - OPEN ACCESSNewborn screening for severe combined immunodeficiency was implemented in Ontario in August 2013. Infants identified by a positive newborn screen are referred in an orderly fashion for evaluation by an expert immunologist and, when appropriate, for immune function studies and treatment.Statement of novelty: We demonstrate a novel flow chart for assessing and referring newborn screen-positive cases.
- OPEN ACCESS
- OPEN ACCESSHematopoietic stem cell transplantation using HLA-mismatched related donors for the treatment of severe combined immunodeficiency has led to disappointing outcomes at our institution. This created an impetus to consider other donor sources when an HLA-matched related donor was not available. In 1988, a new protocol using HLA-matched unrelated donors was developed at our institution and continues to be used to date. This has contributed to improved outcomes and change in practice for patients with severe combined immunodeficiency.Statement of novelty: This report describes in detail the protocol for hematopoietic stem cell transplantations using HLA-matched unrelated donors for patients with severe combined immunodeficiency at our institution. This protocol is published for those centres wishing for guidance in setting up procedures for hematopoietic stem cell transplantation.
- OPEN ACCESSInfants with severe combined immune deficiency (SCID) typically present in the first few months of life with severe, recurrent, opportunistic infections, and without definitive treatment the condition is invariably fatal (Gaspar et al. 2013). Many centres believe that protective isolation is required for treatment of SCID patients once diagnosed, and the isolation protocol varies across institutions. This paper describes the isolation protocol for SCID requiring hematopoietic stem cell transplant (HSCT) that has been utilized at our institution for over the last 25 years. We believe that the profound immunodeficiency in SCID patients warrants a more restrictive treatment to limit the morbidity and mortality associated with HSCT. With this protocol, we have seen a very low infection rate in and have a very good survival rate for our SCID population.
- OPEN ACCESS
- Carsten Speckmann MD,
- Annette Uhlmann PhD,
- Sam Doerken MSc,
- Martin Wolkewitz PhD,
- Annette Pohl, and
- Stephan Ehl MD
This is a prospective outcome study of patients with profound combined immunodeficiency (P-CID) (study number DRKS00000497).Combined immunodeficiencies (CID) are a heterogeneous group of inherited immune disorders with impaired T-cell development and (or) function manifesting through increased susceptibility to infections and (or) immune dysregulation. They can be delineated from severe CID (SCID) by their manifestation beyond the first year of life. Profound CID (P-CID) is a potentially life-threatening form of CID, in which stem cell transplant (SCT) is a relevant consideration at diagnosis.The primary objective of the study is to provide natural history data on patients with P-CID, irrespective of whether they undergo hematopoietic stem cell transplant (HSCT) or not. The goals are to determine survival, the frequency of severe events, and quality of life (QOL) 5 years after study inclusion.The secondary objective is to develop a risk model for P-CID patients. The model is developed from a set of clinical and laboratory parameters obtained at diagnosis, at study inclusion, and yearly thereafter.The tertiary objectives of this study are to determine the effects of donor, recipient, and treatment factors on the outcome of HSCT. The goal is to determine the quality of engraftment and immunological reconstitution and to determine the effects of these parameters on clinical outcome.The main hypothesis is that P-CID patients undergoing early HSCT have a better 5-year survival rate than patients who undergo late HSCT or are not transplanted.This is a prospective multi-centre international cohort study (observational study).Enrolled patients will be evaluated and treated according to local institutional protocols. They will receive comparable baseline and follow-up evaluations across all participating centres, irrespective of the therapeutic strategy at the individual site.There will be at least 6 study visits (scheduled yearly) for all patients. Because of the variable history prior to study inclusion, a morbidity score is determined for each patient at study visit 1. For those patients undergoing HSCT, an additional 6 month post-HSCT visit will be scheduled. The study visits will document immunological parameters, severe events including major infections, and major manifestations of immune dysregulation, severe transplant-related events, and QOL. - OPEN ACCESSPatients with severe combined immunodeficiency (SCID) typically present with profoundly reduced T cells. In some cases, however, T cells may be affected by defects that allow some T-cell development but compromise T-cell function such as in Omenn syndrome (OS), which is characterized by impaired T cell differentiation in the presence of abnormal self-reactive cells. One distinctive feature of SCID patients, which can sometimes resemble the clinical picture of OS, is the presence of alloreactive cells that originated from transplacentally acquired maternal T lymphocytes. The traditional view is that self-reactive cells and transplacentally acquired maternal T cells cannot occur concomitantly in the same OS patient. This review provides an updated functional characterization of transplacentally acquired maternal T cells and compares them with the T cells of an OS patient. An unusual case of an immunodeficient SCID patient with a mild OS phenotype is also presented. This patient had both self-reactive cells and transplacentally acquired maternal T cells, allowing us to simultaneously evaluate the function and tolerance capacities of both cell types. We propose that coexistence of autologous and maternal T cells in patients exhibiting mild OS symptoms was rejected because it had not been studied before and not because the cells are mutually exclusive. Moreover, taking into consideration the milder clinical phenotype associated with transplacentally acquired maternal T cells in SCID patients, we believe that these cells may provide some degree of immunity and prevent autoimmunity, even though they do not actually function to protect against infections.Statement of novelty: Autologous and transplacental-acquired maternal T cells can coexist in the same SCID patient. Although both cell types are nonfunctional for protecting against infections, maternal cells provide some degree of immunity and therefore are associated with only mild GVHD symptoms.
