Theodore B. Moore

Newborn Screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States

IMPORTANCE Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births. OBJECTIVES To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments. DESIGN Epidemiological and retrospective observational study. SETTING Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test. MAIN OUTCOMES AND MEASURES Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked. RESULTS Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia. CONCLUSIONS AND RELEVANCE Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.

Transplantation Outcomes for Severe Combined Immunodeficiency, 2000–2009

BACKGROUND The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. METHODS We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). RESULTS Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival. CONCLUSIONS Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: Results of the first 2 years

BACKGROUND Assay of T-cell receptor excision circles (TRECs) in dried blood spots obtained at birth permits population-based newborn screening (NBS) for severe combined immunodeficiency (SCID). OBJECTIVE We sought to report the first 2 years of TREC NBS in California. METHODS Since August 2010, California has conducted SCID NBS. A high-throughput TREC quantitative PCR assay with DNA isolated from routine dried blood spots was developed. Samples with initial low TREC numbers had repeat DNA isolation with quantitative PCR for TRECs and a genomic control, and immunophenotyping was performed within the screening program for infants with incomplete or abnormal results. Outcomes were tracked. RESULTS Of 993,724 infants screened, 50 (1/19,900 [0.005%]) had significant T-cell lymphopenia. Fifteen (1/66,250) required hematopoietic cell or thymus transplantation or gene therapy; these infants had typical SCID (n = 11), leaky SCID or Omenn syndrome (n = 3), or complete DiGeorge syndrome (n = 1). Survival to date in this group is 93%. Other T-cell lymphopenic infants had variant SCID or combined immunodeficiency (n = 6), genetic syndromes associated with T-cell impairment (n = 12), secondary T-cell lymphopenia (n = 9), or preterm birth (n = 8). All T-cell lymphopenic infants avoided live vaccines and received appropriate interventions to prevent infections. TREC test specificity was excellent: only 0.08% of infants required a second test, and 0.016% required lymphocyte phenotyping by using flow cytometry. CONCLUSIONS TREC NBS in California has achieved early diagnosis of SCID and other conditions with T-cell lymphopenia, facilitating management and optimizing outcomes. Furthermore, NBS has revealed the incidence, causes, and follow-up of T-cell lymphopenia in a large diverse population.

Invasive fungal infections in pediatric oncology patients: 11-year experience at a single institution.

The purpose of this study was to determine the incidence of fungal infections in pediatric hematology and oncology (PHO) patients and to describe variations regarding site of infection, organisms, and mortality. The records of 1,052 patients presenting to the UCLA PHO service with various malignancies from 1991 to 2001 were retrospectively reviewed. No patient received invasive antifungal prophylaxis. Transplant patients were excluded. The 11-year incidence of fungal infections in this pediatric oncology cohort was 4.9%. There was a linear increase in the incidence of fungal infections from 2.9% to 7.8% between 1996 and 2001 (P = 0.001). Patients with acute leukemia represented 36% of the population but had a disproportionate incidence (67%) of fungal infections. Adolescents had twice the expected incidence of infection (P < 0.0001). Overall, Candida sp. was the major pathogen. Over time, a trend of fewer infections caused by Candida and more due to Aspergillus was noted. Blood-borne infections decreased over time, while those in the urinary and respiratory tracts increased (P = 0.04). Sixty-two percent of infections occurred in neutropenic patients. PHO patients had an overall mortality of 21%, but those with fungal infections experienced a 2.6-fold higher mortality that was not attributable to infections alone. Empiric antifungal therapy had no effect on mortality rates. Concurrent nonfungal infections did not increase mortality rates. The incidence of fungal infections increased over time, possibly as a result of advances in antibacterial and chemotherapeutic regimens. Adolescents and patients with leukemia were especially at risk. Fungal infections are a poor prognostic factor, independent of fungal-related mortality. New diagnostic methods allowing for early detection and treatment as well as more effective therapies are needed.

FMS‐Like Tyrosine Kinase 3 in Normal Hematopoiesis and Acute Myeloid Leukemia

Ligand‐mediated activation of the FMS‐like tyrosine kinase 3 (FLT3) receptor is important for normal proliferation of primitive hematopoietic cells. However, activating mutations in FLT3 induce ligand‐independent downstream signaling that promotes oncogenesis through pathways involved in proliferation, differentiation, and survival. FLT3 mutations are identified as the most frequent genetic abnormality in acute myeloid leukemia and are also observed in other leukemias. Multiple small‐molecule inhibitors are under development to target aberrant FLT3 activity that confers a poor prognosis in patients.

Frequency of fungemia in hospitalized pediatric inpatients over 11 years at a tertiary care institution.

Objectives. To determine the frequency of bloodstream fungal infections in children who were admitted to our tertiary institution over an 11-year period. Methods. We conducted a retrospective cohort study of patients who were aged 0 to 21 years, had bloodstream fungal infections, and were admitted to the University of California, Los Angeles from 1991 through 2001. Patients were identified through the microbiology laboratory database. All positive fungal cultures for pediatric inpatients were reviewed. For each fungemic patient, a review of clinical course, cause, and outcome was performed. Results. Over 11 years, 1124 pediatric inpatients with 3633 positive cultures had evidence of fungal colonization or infection. The mean incidence of positive fungal cultures increased from 105 between 1991 and 1996 to 129 patients per year between 1997 and 2001. Fungal isolates were mainly Candida species (85%) obtained primarily from respiratory (41%) and urine (27%) cultures. Only 7.5% of positive fungal cultures were from blood, although 24490 pediatric admissions prompted 72960 bacterial and fungal blood cultures, at charges of

Cell Surface Antigen and Molecular Targeting in the Treatment of Hematologic Malignancies

2.52 million. Of 14592 fungal blood cultures, <2% (n = 272) were positive, involving <1% (n = 97) of patients. The mean rise in number of children with fungemia was significant, from 6.8 between 1991 and 1996 to 13.0 patients per year between 1997 and 2001. Fungemia was associated with a high all-cause mortality rate (46%), particularly in immunocompromised patients (57%). Organisms recovered were primarily Candida species (91%). There was a decline in C albicans and C glabrata fungemia and an increase in C parapsilosis organisms. In 84% of patients, fungal organisms were isolated from both bacterial and fungal blood cultures, and in 74%, the same organism was isolated from additional body sites. Conclusions. Episodes of fungemia increased significantly over 11 years as compared with a moderate increase in positive fungal cultures and were associated with high all-cause mortality rates. More sensitive assays for early identification of fungal bloodstream infections are warranted.

Changing outcomes for children requiring intensive care following hematopoietic stem cell transplantation

Conventional cytotoxic therapy of hematologic malignancies is often associated with significant morbidity. This morbidity is often due to the lack of specificity for hematopoietic cells. Therefore, the concept of targeted therapy for patients with hematologic malignancies has received attention for many years. The goal of monoclonal antibody therapy is to target specific cell surface antigens on malignant hematopoietic cells, while sparing normal cells and tissues. Currently, monoclonal antibodies are being evaluated for their cytotoxic effects as well as their ability to deliver toxic agents or radiation. Rituximab, a chimeric anti‐CD20 antibody, has shown response rates of approximately 50% with minimal toxicity in patients with refractory indolent lymphoma. Campath‐1H (anti‐CD52) has shown encouraging results in patients previously treated for chronic lymphocytic leukemia, with response rates up to 33%, although with significant toxicity. Anti‐CD33 antibodies are being used to deliver cytotoxic agents, such as calicheamicin to patients with acute myeloid leukemia with response rates up to 30%. In addition, anti‐CD33 and anti‐CD45 antibodies have been used to deliver radiation directly to leukemic cells. 131I‐labeled anti‐CD45 antibodies are being studied in combination with conventional preparative regimens in patients receiving bone marrow transplantation. Lastly, the therapeutic agent STI571 (signal transduction inhibitor 571) has demonstrated the capability of targeting specific molecular abnormalities seen in hematologic malignancies. STI571 targets the tyrosine kinase activity of the bcr‐abl fusion protein seen in chronic myeloid leukemia. STI571 has induced complete hematologic responses in up to 98% of patients evaluated in clinical trials.

One year follow-up of children and adolescents with chronic immune thrombocytopenic purpura (ITP) treated with rituximab

Abstract: Past literature has shown that respiratory failure following hematopoietic stem cell transplant is associated with a universally poor outcome with mortality rates approaching 100%. More recent studies have suggested that patient survival is improving. We report our experience with the patients from our institution, a large childrens hospital, who were admitted to the intensive care unit (ICU). Medical records of 183 patients, who received a bone marrow transplant between 1992 and early 2004, who were <20 yr of age, were retrospectively reviewed. Various factors that might influence mortality were examined. Over the course of the study, the ICU survival increased from 18% during the period 1992–1999 to 59% between 2000 and early 2004. In the latter period, 54% of the patients discharged from the ICU were alive at 100 days post‐transplant. Factors that were significant predictors of poor outcome were malignancy as the reason for transplant, dialysis during the ICU stay, or extreme respiratory failure with a ratio of arterial oxygen tension (PaO2)/inspired oxygen concentration (FiO2) <300. Analysis of patients who required a high positive end‐expiratory pressure or were ventilated with permissive hypercapnia showed that they also had a higher mortality. The impact on survival of factors such as age at time of transplant, graft‐vs.‐host disease, pneumonia, bacteremia, sepsis, post‐transplant days, Pediatric Risk of Mortality III score, engraftment status, or veno‐occlusive disease did not reach statistical significance in this cohort. Survival has improved for children who require intensive care following a bone marrow transplant, even for those who require mechanical ventilation. Patients with extreme respiratory failure and those requiring dialysis continue to have poor outcome. Because of an overall improvement in survival, children whose condition following transplant requires intensive care should be treated aggressively.

Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi‐passageable neurosphere formation

We previously showed in a prospective study that rituximab appears to be effective in some children and adolescents with severe chronic immune thrombocytopenia. Eleven of 36 patients achieved and maintained platelet counts over 50,000/mm3 within the first 12 weeks. These patients were followed for the next year.