Vanessa Howard

Primary B Cell Immunodeficiencies: Comparisons and Contrasts

Sophisticated genetic tools have made possible the identification of the genes responsible for most well-described immunodeficiencies in the past 15 years. Mutations in Btk, components of the pre-B cell and B cell receptor (lambda5, Igalpha, Igbeta), or the scaffold protein BLNK account for approximately 90% of patients with defects in early B cell development. Hyper-IgM syndromes result from mutations in CD40 ligand, CD40, AID, or UNG in 70-80% of affected patients. Rare defects in ICOS or CD19 can result in a clinical picture that is consistent with common variable immunodeficiency, and as many as 10% of patients with this disorder have heterozygous amino acid substitutions in TACI. For all these disorders, there is considerable clinical heterogeneity in patients with the same mutation. Identifying the genetic and environmental factors that influence the clinical phenotype may enhance patient care and our understanding of normal B cell development.

Genetic analysis of patients with defects in early B‐cell development

Summary:  Approximately 85% of patients with defects in early B‐cell development have X‐linked agammaglobulinemia (XLA), a disorder caused by mutations in the cytoplasmic Brutons tyrosine kinase (Btk). Although Btk is activated by cross‐linking of a variety of cell‐surface receptors, the most critical signal transduction pathway is the one initiated by the pre‐B cell and B‐cell antigen receptor complex. Mutations in Btk are highly diverse, and no single mutation accounts for more than 3% of patients. Although there is no strong genotype/phenotype correlation in XLA, the specific mutation in Btk is one of the factors that influences the severity of disease. Mutations in the components of the pre‐B cell and B‐cell antigen receptor complex account for an additional 5–7% of patients with defects in early B‐cell development. Patients with defects in these proteins are clinically indistinguishable from those with XLA. However, they tend to be younger at the time of diagnosis, and whereas most patients with XLA have a small number of B cells in the peripheral circulation, these cells are not found in patients with defects in µ heavy chain or Igα. Polymorphic variants in the components of the pre‐B cell and B‐cell receptor complex, particularly µ heavy chain and λ5, may contribute to the severity of XLA.

Developing a conceptual model for fatigue in children

The purpose of this research study was to define fatigue experienced by children with cancer and to begin development of a conceptual model.Two major Paediatric Cancer Centers in the Southern USA participated in this study. Children who participated in this study were in the out-patient clinic or in the hospital. Five focus groups with a total of 14 children between 7 and 12 years-of-age were held over a 2-month period of time. Focus groups were used to first assess the contextual understanding and essential attributes of fatigue in 7 to 12-year-old children. Each focus group session lasted 30 to 45 minutes, was audiotaped and transcribed verbatim.A team of four researchers used content analysis to evaluate the transcripts. Codes and definitions were developed for the characteristics of fatigue, causes of fatigue and what alleviates fatigue. Concept analysis was completed as a basis for developing the conceptual framework. Eight codes emerged to define fatigue. Seven codes were used to describe the causes of fatigue.An additional three codes were used to describe what alleviated fatigue.A conceptual definition for fatigue experienced by children with cancer emerged from the data, and a conceptual model was developed to demonstrate relationships between fatigue and contributory and alleviating factors.The conceptual work for model development contributes to understanding fatigue in children with cancer and serves as a basis for establishing operational definitions

Description of Posterior Fossa Syndrome in Children After Posterior Fossa Brain Tumor Surgery

Brain tumors are the second most common malignancy in children less than 15 years of age and the most common solid tumor of childhood. Approximately 60% to 70% of pediatric brain tumors originate in the posterior fossa. Since 1989, the two hospitals that comprise the setting for this study have treated 121 children with posterior fossa brain tumors. A postoperative syndrome, labeled posterior fossa syndrome, has been identified in certain children. This syndrome involves a variety of signs and symptoms including mutism or speech disturbances, dysphagia, decreased motor movement, cranial nerve palsies and, emotional lability. These signs and symptoms develop from an average range of 24 to 107 hours after surgery and may take weeks to months to resolve. The exact etiology of the syndrome is unknown. The purpose of this retrospective medical records review of 19 children diagnosed with posterior fossa syndrome is to describe the symptoms of the syndrome. Early recognition of this syndrome could facilitate preventive and restorative patient care, prevent subsequent complications, decrease length of hospital stays, and promote patient and family understanding of and coping with the syndrome.

Stem cell transplants for patients with X-linked agammaglobulinemia

Six young patients with X-linked agammaglobulinemia and proven mutations in Btk were treated with cord blood or bone marrow transplants from HLA-matched siblings. Complete blood counts, serum chemistries, serum immunoglobulin concentrations, lymphocyte cell surface markers, and physical findings were evaluated at 3- to 5-day intervals for the first 2 weeks after transplant and then every 3 to 6 months. The first three patients were not given any preparative regimen or antirejection drugs and at 24 to 42 months posttransplant these patients have shown no benefit or harm related to the transplants. The second three patients were not given a preparative regimen but were treated with cyclosporine A (70 days) and mycophenolate mophetil (28 days) after transplant. Two of these patients have developed normal sized, nontender cervical lymph nodes 3 to 12 months after transplant but none of the three patients have shown an increase in serum IgM or an increase in the number of peripheral blood B cells. It is likely that successful engraftment will require more aggressive immunosupressive medications.

Adults with X-linked agammaglobulinemia: impact of disease on daily lives, quality of life, educational and socioeconomic status, knowledge of inheritance, and reproductive attitudes.

Since many children with X-linked agammaglobulinemia (XLA) can now be expected to reach adulthood, knowledge of the status of adults with XLA would be of importance to the patients, their families, and the physicians caring for these patients. We performed the current study in adults with XLA to examine the impact of XLA on their daily lives and quality of life, their educational and socioeconomic status, their knowledge of the inheritance of their disorder, and their reproductive attitudes. Physicians who had entered adult patients with XLA in a national registry were asked to pass on a survey instrument to their patients. The patients then filled out the survey instrument and returned it directly to the investigators. Adults with XLA were hospitalized more frequently and missed more work and/or school than did the general United States population. However, their quality of life was comparable to that of the general United States population. They achieved a higher level of education and had a higher income than did the general United States population. Their knowledge of the inheritance of their disease was excellent. Sixty percent of them would not exercise any reproductive planning options as a result of their disease. The results of the current study suggest that although the disease impacts the daily lives of adults with XLA, they still become productive members of society and excel in many areas. Abbreviations: IVIG = intravenous immunoglobulin, XLA = X-linked agammaglobulinemia.

The Natural Connection: The Clinical Nurse Specialist and Bedside Nursing Research

THE EDUCATIONAL PREPARATION and consistent clinical focus of CNSs position them ideally for conducting research at the bedside and helping staff nurses see the relevance of such research. Our research studies have identified a new category of clinical nursing research termed bedside nursing research. Like its parent category of clinical nursing research, the function of bedside nursing research is to generate new knowledge or validate and expand previously generated knowledge. Characteristics that distinguish bedside nursing research from other forms of clinical nursing research are: focus, idea stimulus and setting, originator of the research question, relationship with theory, sensitivity to changing technology in health care, and impact on nursing practice. To illustrate to nature and outcome of this type of research, we describe three bedside nursing research studies conducted by CNSs in a pediatric oncology setting. These studies assessed:(1) the effects of chest tube stripping on the incidence of pain, fever, and pulmonary complication; (2)the relative safety and efficacy of techniques for blood sampling from Hickman catheters; and (3)the effects of infusion method on quality and survival of transfused platelets. The impact of these studies of hospital practices is reviewed.

Effects of conditioning regimens and T cell depletion in hematopoietic cell transplantation for primary immune deficiency.

This study analyzes the hematopoietic cell transplantation experience in patients with immune deficiency at a single institution. The objective is to comprehensively evaluate the short-term and long-term outcomes with various preparative regimens, donor grafts, and ex vivo manipulations to identify transplantation approaches that most likely favor early donor immune competency without generating excessive toxicity. Clinical outcomes were evaluated in 52 consecutive patients with immune deficiencies. Thirty-seven of the 52 patients (71%) survived with attenuation of their underlying disease. The use of a melphalan-based reduced-intensity conditioning preparative regimen and immunomagnetic CD3(+) T cell depletion techniques (when T cell depletion was indicated) were associated with improved event-free survival. Survivors who received a preparative regimen other than a melphalan-based reduced-intensity regimen suffered from therapy-related morbidities or chronic/recurrent infections. Our findings indicate that melphalan-based reduced-intensity conditioning regimens and immunomagnetic CD3(+) T cell depletion limit therapy-related toxicity, and demonstrate promising results for the early establishment of donor immune competency.

A possible bichromatid mutation in a male gamete giving rise to a female mosaic for two different mutations in the X-linked gene WAS

In genetic disorders caused by point mutations or small frameshift mutations, affected members of the same family are expected to have the same mutation in the causative gene. We have recently evaluated a family in which this was not the case. Maternal cousins with Wiskott–Aldrich syndrome (WAS; MIM 301000) had two different but contiguous single base pair deletions in WAS. The proband had an A deletion in codon 242 in exon 7 of WAS; his two cousins had a C deletion in codon 241. The mother of the proband was heterozygous for the A deletion allele, but her three sisters, including the mother of the affected cousins, were heterozygous for the C deletion. Both deletions occurred on the haplotype from the unaffected maternal great‐grandfather. The maternal grandmother, who was a carrier of WAS, based on a non‐random pattern of X chromosome inactivation in T cells, was mosaic for both deletions. These findings are most consistent with the mutations originating in a male gamete with different mutations on the two strands of DNA, a bichromatid mutation.