Brett Loechelt

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.).

Eradication of disseminated adenovirus infection in a pediatric hematopoietic stem cell transplantation recipient using the novel antiviral agent CMX001.

Adenovirus infection is a serious and often fatal complication in hematopoietic stem cell transplant patients. There are currently no FDA-approved therapies for adenovirus infection, with only anecdotal, off-label uses described for a variety of anti-viral agents or immune therapies. We report the first case of successful eradication of disseminated adenovirus infection by the novel antiviral agent CMX001 in a severely immunocompromised pediatric stem cell transplant recipient following failure to respond to intravenous cidofovir. Complete clinical and virologic response was documented; virologic and pharmacokinetic data are reported. CMX001 is a promising new oral antiviral agent under development for the prophylaxis and treatment of severe infections caused by double-stranded DNA viruses including adenovirus in immunocompromised patients.

Outcome for children <4 years of age with malignant central nervous system tumors treated with high‐dose chemotherapy and autologous stem cell rescue

Children <4 years of age (yo) with malignant central nervous system (CNS) tumors have a dismal prognosis. In an attempt to delay or obviate radiation therapy (XRT) and improve outcome, our institution has treated children <4 yo with newly diagnosed malignant CNS tumors with high‐dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) followed by selective XRT.

Low risk of graft-versus-host disease with transplantation of CD34 selected peripheral blood progenitor cells from alternative donors for Fanconi anemia.

Objectives Transplant results for Fanconi anemia with alternative-donor bone marrow transplantation currently entail a high incidence of graft failure and graft-versus-host disease (GVHD). The authors sought to improve outcome in this disease category with alternative donors with a 5-6/6 antigen match by transplantation of highly purified peripheral blood progenitor cells (PBPC) using the Isolex 300i v2.5 device as a means of T-cell depletion to lessen the risk of GVHD. Methods All Fanconi anemia patients (n = 8) received the same preparative regimen that included total body irradiation (450 cGy), Cytoxan (20 mg/kg), ATGAM, and fludarabine (120 mg/m2). The cell dose of CD34+ cells was a median of 11.4 × 106/kg; the cell dose of CD3+ cells was a median of 1.9 × 104/kg. Primary engraftment was rapid in all patients, with neutrophil recovery occurring at a median of day 10 and platelet count more than 50,000 on day 27. Two patients subsequently had secondary graft failure. Despite lack of cyclosporine GVHD prophylaxis, only two patients developed acute GVHD (both grade I), and no patients developed chronic GVHD. Three patients died: one at day 59 secondary to disseminated fungal infection, the second at day 196 during a second transplant, and the third at day 202 due to graft failure. With a median follow-up of 12 months, the overall survival was 58 ± 18%. Conclusions Transplantation of CD34-selected PBPCs from alternative donors results in a very low risk of GVHD in patients with Fanconi anemia.

AMEBIC OSTEOMYELITIS IN a CHILD WITH ACQUIRED IMMUNODEFICIENCY SYNDROME: A Case Report

Disseminated Acanthamoeba infection has been described in immunocompromised or debilitated patients. The usual sites of involvement are skin, sinus, and brain. Sporadic reports of Acanthamoeba infection in patients infected with the human immunodeficiency virus are present in recent literature, predominantly in adults, and one case involving an 8-year-old child. We describe a case of amebic osteomyelitis, seen in a 6-year-old child with vertically acquired human immunodeficiency virus and a 6-month history of cutaneous Acanthamoeba infection.

Epstein-Barr and Other Herpesvirus Infections in Patients With Early Onset Type 1 Diabetes Treated With Daclizumab and Mycophenolate Mofetil

BACKGROUND We assessed the morbidity of herpesviruses in patients with type 1 diabetes mellitus (T1D) enrolled in immunosuppressive treatment studies. METHODS Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV) infections were monitored in 126 participants of a randomized, double-blind, placebo-controlled study of daclizumab (DZB) and mycophenolate mofetil (MMF) including DZB(+)MMF(+), DZB(-)MMF(+), DZB(+)MMF(-), and DZB(-)MMF(-). During the 2-year follow-up, herpesviral infections were monitored clinically, by serology and blood DNA polymerase chain reaction. RESULTS Among 57 baseline EBV-seronegative participants, 9 developed EBV primary infections, including 2 with infectious mononucleosis syndrome. There were no appreciable differences in the course of the primary EBV infections across treatment groups. Among 69 baseline EBV-seropositive participants, 22 had virologic reactivations, including 1 symptomatic DZB(-)MMF(+) subject. Compared with 7 DZB(-)MMF(-) EBV reactivators, the 9 DZB(+)MMF(+) reactivators tended to have more prolonged viremia (11.4 vs 4.4 months; P = .06) and higher cumulative viral burden (14.2 vs 12.5 log EBV copies/mL; P = .06). Four of 85 baseline CMV-seronegative subjects developed asymptomatic primary CMV infections. There were no CMV reactivations. Of 30 baseline HSV-seropositive subjects, 8 developed ≥1 episode of herpes labialis; 1 subject had a primary HSV infection; and 1 subject without baseline serology information had a new diagnosis of genital HSV. There were no significant differences in the incidence of HSV recurrences across treatment groups. Of 100 baseline VZV-seropositive subjects, 1 DZB(-)MMF(-) subject developed herpes zoster and 1 DZB(-)MMF(+) subject had Bells palsy possibly related to VZV. CONCLUSIONS The use of DZB alone or in combination with MMF was not associated with increased morbidity due to herpesviruses. CLINICAL TRIALS REGISTRATION NCT00100178.

Thrombopoietin levels in HIV-associated thrombocytopenia in children.

OBJECTIVES To determine the mechanism of human immunodeficiency virus (HIV)-associated thrombocytopenia by using thrombopoietin (TPO) levels. STUDY DESIGN TPO levels were measured in 14 HIV+ children with thrombocytopenia (TCP+), 28 HIV+ children without thrombocytopenia (TCP-), and 15 matched control subjects. RESULTS For the patients with moderate symptoms, TPO levels were similar for the TCP+ and TCP- groups (251 pg/mL vs 263 pg/mL; P =.98) and similar to those of control subjects. For the patients with severe symptoms, TPO levels were significantly higher for the TCP+ group versus the TCP- group (1172 pg/mL vs 222 pg/mL; P =.03). Patients with severe symptoms and thrombocytopenia had significantly higher TPO levels than those with moderate symptoms and thrombocytopenia (P <.005), were more likely to require growth factors, and did not respond to treatment with intravenous immunoglobulin. CONCLUSIONS TPO levels can distinguish 2 groups of patients with HIV-associated thrombocytopenia. Patients with severe disease had elevated TPO levels, did not respond to treatment with intravenous immunoglobulin, and were more likely to be growth factor-dependent, suggesting marrow failure.

CD34+ collection efficiency as a function of blood volumes processed in pediatric autologous peripheral blood stem cell collection

To characterize the relationship between CD34+ collection efficiency and blood volumes processed in pediatric patients undergoing autologous peripheral blood stem cell (PBSC) collection.

Screening and Monitoring for Infectious Complications When Immunosuppressive Agents Are Studied in the Treatment of Autoimmune Disorders

Significant progress has been made in the development, investigation, and clinical application of immunosuppressive agents to treat a variety of autoimmune disorders. The expansion of clinical applications of these new agents requires the performance of large multicenter clinical trials. These large clinical trials are particularly important as one considers these agents for the treatment of type 1 diabetes, which although autoimmune in its pathogenesis, is not classically treated as an autoimmune disorder. Although these agents hold promise for amelioration or cure of this disease, they have the potential to facilitate infectious complications. There are limited data regarding the prospective assessment of infectious risks with these agents in trials of this nature. Pediatric subjects may be at greater risk due to the higher likelihood of primary infection. A subgroup of experts associated with TrialNet (a National Institutes of Health [NIH]-funded Type 1 diabetes mellitus research network) with expertise in infectious diseases, immunology, and diagnostics developed an approach for screening and monitoring of immunosuppression-associated infections for prospective use in clinical trials. The goals of these recommendations are to provide a structured approach to monitor for infections, to identify specific laboratory testing and surveillance methods, and to consider therapies for treatment of these potential complications. Prospective evaluations of these infectious risks allow for greater scientific rigor in the evaluation of risk, which must be balanced with the potential benefits of these therapies. Our experience supports an important role for investigators with expertise in infections in immunocompromised individuals in protocol development of immunosuppressive trials in type 1diabetes and potentially other autoimmune diseases.

Alemtuzumab based reduced intensity transplantation for pediatric severe aplastic anemia

Hematopoietic cell transplantation (HCT) is curative in patients with severe aplastic anemia (SAA). HCT is considered at presentation when a HLA‐matched related donor (MRD) is available and has a high success rate. Unrelated donor (URD) transplants are typically undertaken if immunosuppressive therapy fails. Increased toxicity and graft rejection are often encountered in this setting.