Publications by authors named "Howard M Rosenblatt"

21 Publications

  • Page 1 of 1

Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.

Blood 2012 Nov 11;120(18):3635-46. Epub 2012 Sep 11.

Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD, USA.

We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency.
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http://dx.doi.org/10.1182/blood-2012-02-400937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488882PMC
November 2012

Immunogenicity, immunologic memory, and safety following measles revaccination in HIV-infected children receiving highly active antiretroviral therapy.

J Infect Dis 2012 Aug 12;206(4):512-22. Epub 2012 Jun 12.

Pediatric Infectious Diseases, Box B055, Children’s Hospital Colorado, 13123 East 16th Ave, Aurora, CO 80045, USA.

Background: Response rates and immunologic memory following measles vaccination are reduced in human immunodeficiency virus (HIV)-infected children in the absence of highly active antiretroviral therapy (HAART).

Methods: HIV-infected children 2 to <19 years old receiving HAART and with HIV loads <30,000 copies/mL, CD4% ≥15, and ≥1 prior measles-mumps-rubella vaccination (MMR) were given another MMR. Measles antibody concentrations before and 8, 32, and 80 weeks postvaccination were determined by plaque reduction neutralization (PRN). A subset was given another MMR 4-5 years later, and PRN antibody was measured before and 7 and 28 days later.

Results: At entry, 52% of 193 subjects were seroprotected (PRN ≥120 mIU/mL). Seroprotection increased to 89% 8 weeks postvaccination, and remained at 80% 80 weeks postvaccination. Of 65 subjects revaccinated 4-5 years later, 85% demonstrated memory based on seroprotection before or 7 days after vaccination. HIV load ≤400 copies/mL at initial study vaccination was associated with higher seroprotection rates, greater antibody concentrations, and memory. Grade 3 fever or fatigue occurred in 2% of subjects.

Conclusions: Measles revaccination induced high rates of seroprotection and memory in children receiving HAART. Both endpoints were associated with HIV viral load suppression.

Clinical Trials Registration: NCT00013871 (www.clinicaltrials.gov).
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http://dx.doi.org/10.1093/infdis/jis386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491735PMC
August 2012

Excellent survival after sibling or unrelated donor stem cell transplantation for chronic granulomatous disease.

J Allergy Clin Immunol 2012 Jan 12;129(1):176-83. Epub 2011 Nov 12.

Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital, and Texas Children's Hospital, Houston, Tex 77030, USA.

Background: Matched related donor (MRD) hematopoietic stem cell transplantation (HSCT) is a successful treatment for chronic granulomatous disease (CGD), but the safety and efficacy of HSCT from unrelated donors is less certain.

Objective: We evaluated the outcomes and overall survival in patients with CGD after HSCT.

Methods: We report the outcomes for 11 children undergoing HSCT from an MRD (n = 4) or an HLA-matched unrelated donor (MUD) (n = 7); 9 children were boys, and the median age was 3.8 years (range, 1-13 years). We treated both X-linked (n = 9) and autosomal recessive (n = 2) disease. Nine children had serious clinical infections before transplantation. The conditioning regimens contained busulfan, cyclophosphamide, cytarabine, or fludarabine according to the donor used. All patients received alemtuzumab (anti-CD52 antibody). Additional graft-versus-host disease (GvHD) prophylaxis included cyclosporine and methotrexate for MUD recipients and cyclosporine and prednisone for MRD recipients.

Results: Neutrophil recovery took a median of 16 days (range, 12-40 days) and 18 days (range, 13-24 days) for MRD and MUD recipients, respectively. Full donor neutrophil engraftment occurred in 9 patients, and 2 had stable mixed chimerism; all patients had sustained correction of neutrophil oxidative burst defect. Four patients had grade I skin acute GVHD responding to topical treatment. No patient had grade II to IV acute GvHD or chronic GvHD. All patients are alive between 1 and 8 years after HSCT.

Conclusion: For CGD, equivalent outcomes can be obtained with MRD or MUD stem cells, and HSCT should be considered an early treatment option.
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http://dx.doi.org/10.1016/j.jaci.2011.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173521PMC
January 2012

Vaccine-acquired rotavirus in infants with severe combined immunodeficiency.

N Engl J Med 2010 Jan;362(4):314-9

Department of Pediatrics, Section of Allergy and Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.

Live pentavalent human-bovine reassortant rotavirus vaccine is recommended in the United States for routine immunization of infants. We describe three infants, two with failure to thrive, who had dehydration and diarrhea within 1 month after their first or second rotavirus immunization and subsequently received a diagnosis of severe combined immunodeficiency. Rotavirus was detected, by means of reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay, in stool specimens obtained from all three infants, and gene-sequence analysis revealed the presence of vaccine rotavirus. These infections raise concerns regarding the safety of rotavirus vaccine in severely immunocompromised patients.
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http://dx.doi.org/10.1056/NEJMoa0904485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103739PMC
January 2010

Outcomes of patients with severe combined immunodeficiency treated with hematopoietic stem cell transplantation with and without preconditioning.

J Allergy Clin Immunol 2009 Nov;124(5):1062-9.e1-4

Department of Pediatrics, Section of Allergy and Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, Tex 77039, USA.

Background: The effect of pretransplantation conditioning on the long-term outcomes of patients receiving hematopoietic stem cell transplantation for severe combined immunodeficiency (SCID) has not been completely determined.

Objective: We sought to assess the outcomes of 23 mostly conditioned patients with SCID and compare their outcomes with those of 25 previously reported nonconditioned patients with SCID who underwent transplantation.

Methods: In the present study we reviewed the medical records of these 23 consecutive, mostly conditioned patients with SCID who underwent transplantation between 1998 and 2007.

Results: Eighteen patients (median age at transplantation, 10 months; range, 0.8-108 months) received haploidentical mismatched related donor, matched unrelated donor, or mismatched unrelated donor transplants, 17 of whom received pretransplantation conditioning (with 1 not conditioned); 13 (72%) patients engrafted with donor cells and survive at a median of 3.8 years (range, 1.8-9.8 year); 5 (38%) of 13 patients require intravenous immunoglobulin; and 6 of 6 age-eligible children attend school. Of 5 recipients (median age at transplantation, 7 months; range, 2-23 months) of matched related donor transplants, all 5 engrafted and survive at a median of 7.5 years (range, 1.5-9.5 year), 1 recipient requires intravenous immunoglobulin, and 3 of 3 age-eligible children attend school. Gene mutations were known in 16 cases: mutation in the common gamma chain of the IL-2 receptor (IL2RG) in 7 patients, mutation in the alpha chain of the IL-7 receptor (IL7RA) in 4 patients, mutation in the recombinase-activating gene (RAG1) in 2 patients, adenosine deaminase deficiency (ADA) in 2 patients, and adenylate kinase 2 (AK2) in 1 patient. Early outcomes and quality of life of the previous nonconditioned versus the present conditioned cohorts were not statistically different, but longer-term follow-up is necessary for confirmation.

Conclusions: Hematopoietic stem cell transplantation in patients with SCID results in engraftment, long-term survival, and a good quality of life for the majority of patients with or without pretransplantation conditioning.
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http://dx.doi.org/10.1016/j.jaci.2009.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271026PMC
November 2009

Hemophagocytic lymphohistiocytosis in a patient with x-linked lymphoproliferative disease.

Allergy Asthma Proc 2009 Jul-Aug;30(4):458-62

Allergy and Immunology Section, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas 77030, USA.

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency affecting approximately 1 to 3 per million live male births. Patients are generally healthy until facing a viral infection such as Epstein-Barr Virus and then may develop fulminant infectious mononucleosis and die. XLP patients are also at increased risk of hemophagocytic lymphohistiocytosis (HLH), which may be triggered by assorted viruses. Here we report a novel case of HLH in a patient with XLP. Significant to his presentation is a paradoxical increase in natural killer (NK) cell activity. We hypothesize that this indicates that Parvovirus B19 activates NK cells via a signaling lymphocytic activation molecule-associated protein (SAP)-independent mechanism. Our case demonstrates an important etiology to consider in the differential diagnosis of XLP patients with nonfocal findings and febrile illnesses.
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http://dx.doi.org/10.2500/aap.2009.30.3259DOI Listing
May 2010

Immunogenicity and immunologic memory after hepatitis B virus booster vaccination in HIV-infected children receiving highly active antiretroviral therapy.

J Infect Dis 2009 Sep;200(6):935-46

University of Colorado Denver School of Medicine and The Children's Hospital, 13123 E. 16th Avenue, Aurora, CO 80045, USA.

Background: Hepatitis B virus (HBV) is an important cause of comorbidity in human immunodeficiency virus (HIV)-infected individuals. The immunogenicity of HBV vaccination in children receiving highly active antiretroviral therapy (HAART) was investigated.

Methods: HIV-infected children receiving HAART who had low to moderate HIV loads and who had previously received 3 doses of HBV vaccine were given an HBV vaccine booster. Concentrations of antibody to hepatitis B surface antigen (anti-HBs) were determined before vaccination and at weeks 8, 48, and 96. A subset of subjects was administered a subsequent dose, and anti-HBs was measured before and 1 and 4 weeks later.

Results: At entry, 24% of 204 subjects were seropositive. Vaccine response occurred in 46% on the basis of seropositivity 8 weeks after vaccination and in 37% on the basis of a 4-fold rise in antibody concentration. Of 69 subjects given another vaccination 4-5 years later, immunologic memory was exhibited by 45% on the basis of seropositivity 1 week after vaccination and by 29% on the basis of a 4-fold rise in antibody concentration at 1 week. Predictors of response and memory included higher nadir and current CD4 cell percentage, higher CD19 cell percentage, and undetectable HIV load.

Conclusions: HIV-infected children frequently lack protective levels of anti-HBs after previous HBV vaccination, and a significant proportion of them do not respond to booster vaccination or demonstrate memory despite receiving HAART, leaving this population insufficiently protected from infection with HBV.
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http://dx.doi.org/10.1086/605448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814776PMC
September 2009

Long-term outcomes of nonconditioned patients with severe combined immunodeficiency transplanted with HLA-identical or haploidentical bone marrow depleted of T cells with anti-CD6 mAb.

J Allergy Clin Immunol 2008 Dec;122(6):1185-93

Department of Pediatrics, Section of Allergy and Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77039, USA.

Background: Between 1981 and 1995, 20 children with severe combined immunodeficiency (SCID; median age at transplant, 6.5 [range, 0.5-145] mo, 12 with serious infection) were treated with haploidentical T cell-depleted (anti-CD6 antibody) bone marrow (median number of 5.7 [0.8-18.8] x 10(8) nucleated cells/kg) from mismatched related donors (MMRDs), and 5 children with SCID (median age at transplant, 1.8 [0.5-5.0] mo, 1 with serious infection) were given unmanipulated bone marrow from matched related donors (MRDs). No conditioning or graft-versus-host disease (GvHD) prophylaxis was used.

Objective: To assess the outcomes of patients with SCID who received bone marrow from MMRDs or MRDs.

Methods: We reviewed the medical records of these 25 consecutive patients with SCID (4 with Omenn syndrome).

Results: Of the 20 patients who received bone marrow from MMRDs, 12 engrafted, 10 survived at a median age of 15.2 [10.0-19.1] years, 4 had chronic GvHD (lung, intestine, skin), 5 required intravenous immunoglobulin, and 8 attended school or college. Two of 5 patients who died had chronic GvHD, and 2 developed lymphoproliferative disease. Of the 5 patients who received bone marrow from MRDs, 5 engrafted, 5 survived at a median age of 23.3 [18.5-26] years, 1 had chronic GvHD (lung, skin), 2 required intravenous immunoglobulin, and 4 attended school or college.

Conclusions: Treatment of critically ill patients with SCID with anti-CD6 antibody T cell-depleted MMRD marrow resulted in an overall 50% long-term survival of patients (83% survival of those engrafted). The principal barriers to long-term survival were delay in diagnosis, life-threatening infection, failure to engraft, and chronic GvHD. Educational goals were achieved in most of the survivors.
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http://dx.doi.org/10.1016/j.jaci.2008.10.030DOI Listing
December 2008

Pertussis booster vaccination in HIV-infected children receiving highly active antiretroviral therapy.

Pediatrics 2007 Nov 15;120(5):e1190-202. Epub 2007 Oct 15.

School of Medicine, University of Colorado and Children's Hospital, Denver, Colorado, USA.

Objective: Our goal was to evaluate the immunogenicity and safety of pertussis booster vaccination in children infected with HIV on highly active antiretroviral therapy (HAART).

Patients And Methods: HIV-infected children on stable HAART for > or = 3 months with plasma HIV-RNA concentrations of < 30,000 to 60,000 copies per mL who previously received > or = 4 doses of diphtheria-tetanus-pertussis (DTP)-containing vaccine were eligible. Diphtheria-tetanus-acellular pertussis (DTaP) vaccine was administered to subjects 2 to < 7 years old who had 4 previous DTP-containing vaccines, subjects 2 to < 7 years old who had > or = 5 previous DTP-containing vaccines and negative tetanus antibody, and subjects > or = 7 to < or = 13 years old who had negative tetanus antibody. Pertussis toxin and filamentous hemagglutinin antibodies were measured before and 8, 24, and 72 weeks after DTaP vaccine.

Results: Ninety-two subjects received DTaP vaccine and met criteria for analysis. Antibody concentrations were low at entry: pertussis toxin geometric mean concentration at 4.8 enzyme-linked immunosorbent assay units (EU) per mL and filamentous hemagglutinin geometric mean concentration at 4.1 EU/mL. Pertussis toxin and filamentous hemagglutinin geometric mean concentrations rose to 22.3 and 77.0 EU/mL, respectively, 8 weeks after the study DTaP vaccine. Antibody concentrations fell by 24 weeks after vaccination but remained higher than before vaccination. Predictors of response 8 weeks after DTaP vaccine included the concentration of homologous antibody, lower HIV-RNA level, and higher CD4 percentage at entry. One vaccinated subject experienced erythema and induration of > or = 25 mm.

Conclusions: A DTaP vaccine booster was well tolerated by children on HAART and induced increases in antibodies. Antibody concentrations after vaccination were lower than those reported in populations uninfected by HIV. Although comparison among studies must be made with caution, these data suggest that children infected with HIV may be deficient in immunologic memory from previous DTP-containing vaccination and/or that immune reconstitution with HAART may be incomplete for pertussis antigens.
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http://dx.doi.org/10.1542/peds.2007-0729DOI Listing
November 2007

Basidiomycetous fungal Inonotus tropicalis sacral osteomyelitis in X-linked chronic granulomatous disease.

Pediatr Infect Dis J 2007 Jul;26(7):655-6

Division of Allergy and Immunology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.

Osteomyelitis is a common clinical manifestation of chronic granulomatous disease, a disorder of phagocytic function. Fungal organisms account for a significant proportion of these infections. We describe the clinical presentation and subsequent destructive sacral osteomyelitis with a basidiomycetous mold, Inonotus tropicalis, in a patient with an X-linked chronic granulomatous disease.
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http://dx.doi.org/10.1097/INF.0b013e3180616cd0DOI Listing
July 2007

Immunogenicity, safety, and predictors of response after a pneumococcal conjugate and pneumococcal polysaccharide vaccine series in human immunodeficiency virus-infected children receiving highly active antiretroviral therapy.

Pediatr Infect Dis J 2006 Oct;25(10):920-9

University of Colorado School of Medicine, Pediatric Infectious Disease, The Children's Hospital, Denver, CO 80218, USA.

Background: The immunogenicity and safety of 2 doses of pneumococcal conjugate vaccine (PCV) and 1 dose of pneumococcal polysaccharide vaccine (PPV) were evaluated in human immunodeficiency virus (HIV)-infected children receiving highly active antiretroviral therapy (HAART).

Methods: Children 2 to <19 years, receiving stable HAART for > or =3-6 months, with HIV RNA PCR <30,000-60,000 copies/mL, received 2 doses of PCV and 1 dose of PPV at sequential 8-week intervals. Antibodies to pneumococcal serotypes (STs) 1 (PPV only) and 6B, 14, 19F, and 23F (PCV and PPV) were measured by ELISA.

Results: Two hundred sixty-three subjects were enrolled, of whom 225 met criteria for inclusion in the primary dataset. Antibody concentrations were low at entry, despite previous PPV in 75%. After vaccination, 76%-96% had concentrations > or =0.5 microg/mL and 62-88% > or =1.0 microg/mL to the 5 STs (geometric mean concentrations [GMCs] = 1.44-4.25 microg/mL). Incremental gains in antibody concentration occurred with each vaccine dose. Predictors of response included higher antibody concentration at entry, higher immune stratum (based on nadir CD4% before HAART and CD4% at screening), lower entry viral RNA, longer duration of the entry HAART regimen, and age <7 years. Response was more consistently related to screening CD4% than nadir CD4%. Seven percent had vaccine-related grade 3 events, most of which were local reactions.

Conclusions: Two PCVs and 1 PPV were immunogenic and safe in HIV-infected children 2 to <19 years who were receiving HAART. Responses were suggestive of functional immune reconstitution. Immunologic status based on nadir and, especially, current CD4% and control of HIV viremia were independent determinants of response.
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http://dx.doi.org/10.1097/01.inf.0000237830.33228.c3DOI Listing
October 2006

Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report.

Blood 2007 Jan 14;109(2):503-6. Epub 2006 Sep 14.

Division of Research Immunology/Bone Marrow Transplantation, General Clinical Research Center, Department of Pathology, Children's Hospital Los Angeles, CA 90027, and Baylor College of Medicine, Houston, TX, USA.

A patient with adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) was enrolled in a study of retroviral-mediated ADA gene transfer to bone marrow hematopoietic stem cells. After the discontinuation of ADA enzyme replacement, busulfan (75 mg/m2) was administered for bone marrow cytoreduction, followed by infusion of autologous, gene-modified CD34+ cells. The expected myelosuppression developed after busulfan but then persisted, necessitating the administration of untransduced autologous bone marrow back-up at day 40. Because of sustained pancytopenia and negligible gene marking, diagnostic bone marrow biopsy and aspirate were performed at day 88. Analyses revealed hypocellular marrow and, unexpectedly, evidence of trisomy 8 in 21.6% of cells. Trisomy 8 mosaicism (T8M) was subsequently diagnosed by retrospective analysis of a pretreatment marrow sample that might have caused the lack of hematopoietic reconstitution. The confounding effects of this preexisting marrow cytogenetic abnormality on the response to gene transfer highlights another challenge of gene therapy with the use of autologous hematopoietic stem cells.
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http://dx.doi.org/10.1182/blood-2006-06-031476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785101PMC
January 2007

Symptom complex is associated with transplant coronary artery disease and sudden death/resuscitated sudden death in pediatric heart transplant recipients.

J Heart Lung Transplant 2005 Nov 20;24(11):1798-803. Epub 2005 Jun 20.

Division of Pediatric Cardiology, Baylor College of Medicine, Houston, Texas 77030, USA.

Background: Transplant coronary artery disease (TCAD) is a common sequela of heart transplantation. Symptom complexes associated with TCAD have not been well described. The purpose of this study was to determine if somatic complaints are associated with TCAD in pediatric heart transplant recipients.

Methods: We reviewed the medical records of all patients who underwent heart transplantation at our institution from November 1984 to December 2000. TCAD was defined as any interval narrowing of coronary arteries by angiography since the previous study or at least 50% luminal obstruction of 1 or more coronary arteries by histologic examination of explanted or autopsied hearts.

Results: Ninety-nine patients received heart transplants, and follow-up data were available in 80. Sixty-six patients met study criteria. Complaints of abdominal (82%), chest (45%), abdominal and chest (27%), and arm (9%) pain were made by 22 (33%) of 66 patients, and TCAD was present in 27 (41%). Of the 22 patients with pain, TCAD was present in 18, for a positive predictive value of 82% (95% confidence interval [CI] 60%-95%). The relative risk of TCAD being present in patients with a history of pain was 4 times that of patients without pain (p < 0.001). Sudden death or resuscitated sudden death occurred in 15 (68%) of 22 patients with pain vs 4 (9%) of 44 without pain (p < 0.001).

Conclusions: The symptom complex of abdominal, chest and/or arm pain is strongly associated with the presence of TCAD and sudden death or resuscitated sudden death in pediatric heart transplant recipients.
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http://dx.doi.org/10.1016/j.healun.2005.03.013DOI Listing
November 2005

Tetanus immunity after diphtheria, tetanus toxoids, and acellular pertussis vaccination in children with clinically stable HIV infection.

J Allergy Clin Immunol 2005 Sep;116(3):698-703

Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

Background: HIV infection often impairs the immune response to childhood vaccines.

Objective: We sought to study the ability of HIV-infected children receiving highly active antiretroviral therapy (HAART) to generate a booster response to immunization with a recall antigen to which they had lost humoral immunity.

Methods: Diphtheria, tetanus toxoids, and acellular pertussis (DTaP) vaccination was given at either 16 or 36 weeks after initiation of HAART to 37 HIV-infected children 2 to 9 years of age with a history of DTaP or diphtheria-tetanus-pertussis receipt who had negative tetanus antibody titers (
Results: There was a clear increase in tetanus titers after vaccination, with an increase of 27-fold over the baseline values at weeks 4 and 8. The effect on tetanus titers faded to a 9-fold and 3-fold increase over baseline values at weeks 18 and 32, respectively. DTaP vaccination did not affect HIV-1 RNA viral load or CD4 percentage or cell count. There was no increase in either acute or long-term adverse events associated with the DTaP vaccination.

Conclusion: Although children with stable HIV infection receiving HAART can mount antigen-specific responses to tetanus immunization, the durability of these responses might be limited. Long-term monitoring of specific immune function in such children is indicated.
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http://dx.doi.org/10.1016/j.jaci.2005.05.016DOI Listing
September 2005

Immunological response to highly active antiretroviral therapy in children with clinically stable HIV-1 infection.

J Infect Dis 2005 Aug 29;192(3):445-55. Epub 2005 Jun 29.

Allergy and Immunology Section, Texas Children's Hospital, Houston 77030, USA.

We studied changes in 60 immunological parameters after the administration of highly active antiretroviral therapy (HAART) in 192 clinically stable antiretroviral drug-experienced HIV-1-infected children 4 months-17 years old. The studied immunological parameters included standard lymphocyte subsets and lymphocyte surface markers of maturation and activation. The most significant changes during the 48-week study period were seen for CD8(+), CD8(+)CD62L(+)CD45RA(+), CD8(+)CD38(+)HLA-DR(+), and CD4(+) T cell percentages (P < .0001 for all parameters). These changes suggest that significant decreases in the expression of activation markers and increases in the expression of naive markers in the CD8(+) T cell population may be related to better virologic control in these HIV-1-infected children, who had relatively stable immune function at the initiation of HAART. At week 44 of HAART, the major immunological parameters in these HIV-1-infected children moved from baseline values to about halfway to two-thirds of the way toward the values in healthy, uninfected children.
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http://dx.doi.org/10.1086/431597DOI Listing
August 2005

Antigen-specific T-cell memory is preserved in children treated for acute lymphoblastic leukemia.

Blood 2005 Sep 26;106(5):1749-54. Epub 2005 May 26.

Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.

Despite profound T-cell immunodeficiency, most patients treated with chemotherapy do not succumb to infection. The basis for residual protective immunity in lymphopenic patients is not known. We prospectively measured T-cell numbers, thymopoiesis, and T-cell memory in 73 children undergoing a 2-year chemotherapy regimen for acute lymphoblastic leukemia (ALL) and compared them to an age-matched cohort of 805 healthy children. Most patients had profound defects in CD4 and CD8 T-cell numbers at diagnosis that did not recover during the 2 years of therapy. Thymic output and the fraction of naive T cells were significantly lower than in healthy controls. However, the remaining T-cell compartment was enriched for antigen-experienced, memory T cells defined both by phenotype and by function. This relative sparing of T-cell memory may, in part, account for the maintenance of protective immunity in lymphopenic patients treated for ALL. Moreover, because the memory T-cell compartment is least affected by ALL and its treatment, strategies to induce immunity to pathogens or tumor antigens in cancer patients may be most successful if they seek to expand pre-existing memory T cells.
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http://dx.doi.org/10.1182/blood-2005-03-1082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895221PMC
September 2005

Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.

J Allergy Clin Immunol 2003 Nov;112(5):973-80

Baylor College of Medicine, Houston, Tex, USA.

Background: Peripheral blood lymphocyte subsets need to be determined in a large, urban, minority-predominant cohort of healthy children to serve as suitable control subjects for the interpretation of the appearance of these cells in several disease conditions, notably pediatric HIV-1 infection.

Objective: We sought to determine the distribution of lymphocyte subsets in healthy urban-dwelling infants, children, and adolescents in the United States.

Methods: Lymphocyte subsets were determined by means of 3-color flow cytometry in a cross-sectional study of 807 HIV-unexposed children from birth through 18 years of age.

Results: Cell-surface marker analysis demonstrated that age was an extremely important variable in 24 lymphocyte subset distributions measured as percentages or absolute counts--eg, the CD4 (helper) T cell, CD8 (cytotoxic) T cell, CD19 B cell, CD4CD45RACD62L (naive helper) T cell, CD3CD4CD45RO (memory helper) T cell, CD8HLA-DRCD38 (activated cytotoxic) T cell, and CD8CD28 (activation primed cytotoxic) T cell. The testing laboratory proved to be an important variable, indicating the need for using the same laboratory or group of laboratories to assay an individual's blood over time and to assay control and ill or treated populations. Sex and race-ethnicity were much less important.

Conclusion: The results of this study provide a control population for assessment of the effects of HIV infection on the normal development and distribution of lymphocyte subsets in children of both sexes, all races, and all ethnic backgrounds from birth through 18 years of age in an urban population. This study's findings will also prove invaluable in interpreting the immune changes in children with many other chronic diseases, such as primary immunodeficiency, malignancy, rheumatoid arthritis, and asthma.
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http://dx.doi.org/10.1016/j.jaci.2003.07.003DOI Listing
November 2003

Long-term assessment of T-cell populations in DiGeorge syndrome.

J Allergy Clin Immunol 2003 Mar;111(3):573-9

Allergy and Immunology Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

Background: Patients with DiGeorge syndrome present with a broad range of T-cell deficiency. Partial DiGeorge syndrome (pDGS) is a preferred designation for patients with detectable T-cell function. Among immunology experts, there is no uniform opinion on the necessity of T-cell precautions for pDGS patients. Few studies have addressed the natural course of their immune function over time.

Objective: The objective of this study was to describe the natural history of immune parameters in pDGS.

Methods: We reviewed the medical records of 45 pDGS patients. Peripheral blood T-cell subsets counts and percentages were recorded at 1, 6, 12, 18, 24, 30, 48, 60, 72, 96, and 120 months of age, and the rates of change of T-cell measurements over the follow-up period (slopes) were calculated for each individual. Humoral immunity was evaluated by quantification of immunoglobulins and by testing antibody titers to recall antigens.

Results: T-cell subsets counts from pDGS patients were generally lower than those of age-matched normal populations but were not severely depressed (ie, CD4+ T-cell percentage less than 15%). The median of the slopes for CD3+, CD4+, and CD8+ T-cell percentages were -0.7%, -0.8%, and -0.1%/month, respectively, in the first year of age and 0.1%/month for each subpopulation from 12 to 120 months of age. Lymphoproliferative responses to phytohemagglutinin were adequate at all ages. Immunoglobulin deficiencies or inadequate production of specific antibodies were not detected.

Conclusions: In our pDGS patient cohort, a significant deterioration of T-cell number or function did not occur over time. Clinical implications of this finding include the possibility of discontinuing T-cell deficiency precautions and frequency of reevaluations of pDGS patients with stable and adequate immune function.
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http://dx.doi.org/10.1067/mai.2003.165DOI Listing
March 2003

Suppression of human anti-inflammatory plasma cytokines IL-10 and IL-1RA with elevation of proinflammatory cytokine IFN-gamma during the isolation of the Antarctic winter.

J Allergy Clin Immunol 2002 May;109(5):854-7

Baylor College of Medicine, Houston, USA.

Cellular immune function has been shown to be decreased and latent virus shedding to be increased in human beings isolated during the Antarctic winter, a model used for assessing some effects of space flight. However, the balance of proinflammatory (IFN-gamma) and anti-inflammatory (IL-10 and IL-1RA) cytokines has not previously been evaluated. We therefore sought to determine whether isolation during the Antarctic winter would alter the proinflammatory and anti-inflammatory cytokine balance. Cytokine levels were measured with ELISA in monthly plasma samples from January through September 1999 in 21 study subjects in the Antarctic and 7 control subjects on Macquarie Island. There was a significant time-dependent increase in plasma IFN-gamma (P =.039) as well as decreases in IL-10 (P =.042) and IL-1RA (P =.053) in the study subjects compared with the control subjects. The study subjects also had significantly increased plasma IFN-gamma levels (P < or =.045) but decreased IL-10 and IL-1RA levels (P < or =.036) at individual time points of isolation. Isolation of human beings in the Antarctic appears to shift the plasma cytokine balance toward a proinflammatory profile. These observations are consistent with T-cell activation that might be due to activation of latent viruses, and they could hold importance for determining the risks of space flight.
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http://dx.doi.org/10.1067/mai.2002.123873DOI Listing
May 2002