HIV-1 seroreversion in HIV-1-infected children: do genetic determinants play a role?

Background: HIV-1 seroreversion in infants with vertically transmitted HIV-1 infection who started ART in the first months of life has been reported in only a subset of patients. However, the reason why most infants remain seropositive despite similar treatment response is not understood. Here, we assessed whether HIV-1 seroreversion in maternally infected infants is associated with genetic determinants. Methods: HIV-1-infected infants with a history of documented HIV-1 seroreversion were identified throughout Germany using a standardized questionnaire. At study entry immune reconstitution and anti-HIV-1 antibody expression were monitored as clinical parameters. To search for genetic determinants high-resolution HLA genotyping was performed. In addition, the coding sequence of the chemokine receptor CCR5 was analyzed by Sanger sequencing regarding potential mutations. Results: Patients showed normal numbers and frequencies of lymphocyte subpopulations. Five out of eight patients still had seronegative HIV-1 antibody status at study entry. HLA genotyping revealed the enrichment of HLA-DQB1*03 and DQB1*06 alleles within the patient cohort. Only one patient was found to carry a 32 bp-deletion within the CCR5 gene. Conclusion: Our results indicate that the phenotype of HIV-1 seroreversion in infants might correlate with the presence of HLA class II alleles DQB1*03 and DQB1*06. This finding supports the idea of genetic predisposition determining HIV-1 seroreversion in vertically infected infants effectively treated with AR

Long-term posaconazole treatment and follow-up of rhino-orbital-cerebral mucormycosis in a diabetic girl

Tarani L, Costantino F, Notheis G, Wintergerst U, Venditti M, Di Biasi C, Friederici D, Pasquino AM. Long-term posaconazole treatment and follow-up of rhino-orbital-cerebral mucormycosis in a diabetic girl.Pediatric Diabetes 2009: 10: 289-293. To demonstrate that the 2-yr clinical follow-up of our patient strongly suggests that long-term therapy with posaconazole (POS) is safe and beneficial in treatment and prevention of relapses of, otherwise fatal, central nervous system mucormycosis. Mucormycosis is a very rare opportunistic mycotic infection of diabetic children. We present the 30-month follow-up of a 12-yr-old girl affected by diabetic ketoacidotic coma, complicated by rhinocerebral mucormycosis and successfully treated with POS at the initial daily dose of 5 mg/kg t.i.d. with fatty food for 3 wk, followed by a daily dose of 10 mg/kg in four doses for 2 months and then 20 mg/kg/d in four doses for 16 months and in two doses for further 5 months. The previous amphotericin B, granulocyte colony-stimulating factor, hyperbaric oxygen and nasal and left maxillary sinus surgical debridement therapy was ineffective in stopping the progression of the infection to the brain. The patient improved within 10 d with reduced ocular swelling and pain, and 6 months after therapy stop, she is in good health and cultures are sterile. This article demonstrates that POS may be a useful drug in mucormycosis in children. We also strongly draw the attention to the main preventive procedure against invasive fungal infection that is the correct management of antidiabetic therapy that prevents the predisposing temporary neutrophils activity deficit, contributing to a better survival rate of diabetic children

A structured patient empowerment programme for primary immunodeficiency significantly improves general and health-related quality of life.

Introduction Primary immunodeficiencies (PIDs) are a heterogeneous group of rare diseases characterized by increased susceptibility to infections and a reduced quality of life (QoL). The influence of a patient empowerment programme for PID (PID-PEP) on general and health-related QoL was assessed in the present study. Material and methods PID-PEP is provided by a multidisciplinary team for patients with PID and immunoglobulin G (IgG) replacement therapy during a weekend course to improve patient self-management regarding chronic disease and long-term therapy. Twenty-six adult patients with PID undergoing PID-PEP were recruited. Short Form-36 (SF-36) and the Life Quality Index (LQI) were assessed as generic and disease-specific QoL instruments before as well as 6 months after the programme. Results Median visual analogue scale (VAS) values of present health status significantly increased from 68 at baseline to 76 after PID-PEP (p = 0.002). Furthermore, the SF-36 mental component summary (MCS) significantly improved from 36 to 43 following the programme (p = 0.042). Of the eight SF-36 dimensions, vitality (VT) significantly improved (p = 0.025). Median LQI index significantly increased from 77 at baseline to 86 after PID-PEP (p = 0.008). Furthermore, the LQI domains treatment interference (I) and therapy-related problems (II) significantly improved. Conclusions Our PID-PEP significantly improved general and health-related QoL. It needs to be evaluated in future studies whether the beneficial effects of PID-PEP are sustained over longer periods of time and whether repeated PID-PEP sessions further improve QoL outcome

Dysregulation of innate immune receptors on neutrophils in chronic granulomatous disease

BACKGROUND: Chronic granulomatous disease (CGD) is the most common inherited disorder of neutrophil function, is caused by mutations in the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and results in recurrent bacterial infections. OBJECTIVE: We sought to investigate the expression and function of innate immune receptors on neutrophils in patients with CGD. METHODS: We quantified mRNA and protein expression of Toll-like receptors (TLRs), complement receptors, and chemokine receptors on neutrophils from 15 patients with CGD compared with that seen in healthy control subjects (n = 15) and control patients with bacterial pneumonia (n = 15). Phagocytosis, chemotaxis, and TLR function of isolated neutrophils were analyzed. The effect of NADPH oxidase inhibition on receptor expression and function was analyzed in control neutrophils. RESULTS: Neutrophils from patients with CGD had lower expression levels of TLR5, TLR9, CD11b, CD18, CD35, and CXCR1 compared with those from healthy control subjects, whereas similar or increased receptor expressions were found in patients without CGD but with bacterial pneumonia. Reduced TLR5 expression resulted in impaired neutrophil activation by bacterial flagella, reduced CD11b/CD18 expression was associated with impaired phagocytosis of Staphylococcus aureus, and reduced CXCR1 expression was associated with decreased chemotaxis. TLR5 and CD18 expression levels correlated with disease severity in patients with CGD. TLR5 and TLR9 expression were greater in patients with residual NADPH oxidase activity. Inhibition of the NADPH oxidase in control neutrophils in vitro decreased TLR5 and TLR9 expression and impaired TLR5 function. CONCLUSION: These results provide the first evidence that innate immune receptors are dysregulated in patients with CG

Class switch recombination defects: impact on B cell maturation and antibody responses

To assess how B cell phenotype analysis correlates with antigen responses in patients with class switch recombination defects (CSRD) we quantified memory B cells by flow-cytometry and immunized CSRD patients with the neoantigen bacteriophage phiX174 (phage). CSRD patients showed uniformly absent or markedly reduced switched memory B cells (IgM−IgD−CD27+). CD40L patients had reduced CD27+ memory B cells (both non-switched and switched). In NEMO patients, results varied depending on the IKKγ gene variant. Three of four AID patients had normal percentages of CD27+ memory B cells while CD27+IgM−IgD− switched memory B cells were markedly reduced in all AID patients. Antibody response to phage was remarkably decreased with lack of memory amplification and class-switching in immunized CD40L, UNG deficient, and NEMO patients. Distinct B-cell phenotype pattern correlated with abnormal antibody responses to a T-cell dependent neoantigen, representing a powerful tool to identify CSRD patients

Outcome and management of pregnancies in severe chronic neutropenia patients by the European branch of the severe chronic neutropenia international registry

Long-term granulocyte-colony stimulating factor treatment has been shown to be safe and effective in severe chronic neutropenia patients. However, data on its use during pregnancy are limited. To address this issue, we analyzed all pregnancies reported to the European branch of the Severe Chronic Neutropenia International Registry since 1994. A total of 38 pregnancies in 21 women with chronic neutropenia (16 pregnancies in 10 women with congenital, 10 in 6 women with cyclic, 12 in 5 women with idiopathic neutropenia) were reported. Granulocyte-colony stimulating factor was administered throughout pregnancy in 16 women and for at least one trimester in a further 5 women. No major differences were seen between treated and untreated women with respect to pregnancy outcome, newborn complications and infections. In addition, we evaluated the genetic transmission of known or suspected genetic defects in 16 mothers having 22 newborns as well as in 8 men fathering 15 children. As a proof of inheritance, neutropenia was passed on to the newborn in 58% from female and in 62% from male patients with ELANE mutations, but also to some newborns from parents with unknown gene mutation. Based on our results, granulocyte-colony stimulating factor therapy has been shown to be safe for mothers throughout pregnancies and for newborns without any signs of teratogenicity. With an increasing number of adult patients, genetic counseling prior to conception and supportive care of mothers during pregnancy are crucial. The acceptance of having affected children may reflect the high quality of life obtained due to this treatment. © 2014 Ferrata Storti Foundation

Successful combination of sequential gene therapy and rescue Allo-HSCT in two children with X-CGD - importance of timing

We report on a series of sequential events leading to long-term survival and cure of pediatric X-linked chronic granulomatous disease (X-CGD) patients after gamma-retroviral gene therapy (GT) and rescue HSCT. Due to therapyrefractory life-threatening infections requiring hematopoietic stem cell transplantation (HSCT) but absence of HLAidentical donors, we treated 2 boys with X-CGD by GT. Following GT both children completely resolved invasive Aspergillus nidulans infections. However, one child developed dual insertional activation of ecotropic viral integration site 1 (EVI1) and signal transducer and activator of transcription 3 (STAT3) genes, leading to myelodysplastic syndrome (MDS) with monosomy 7. Despite resistance to mismatched allo-HSCT with standard myeloablative conditioning, secondary intensified rescue allo-HSCT resulted in 100 % donor chimerism and disappearance of MDS. The other child did not develop MDS despite expansion of a clone with a single insertion in the myelodysplasia syndrome 1 (MDS1) gene and was cured by early standard allo-HSCT. The slowly developing dominance of clones harboring integrations in MDS1-EVI1 may guide clinical intervention strategies, i.e. early rescue allo-HSCT, prior to malignant transformation. GT was essential for both children to survive and to clear therapy-refractory infections, and future GT with safer lentiviral self-inactivated (SIN) vectors may offer a therapeutic alternative for X-CGD patients suffering from life-threatening infections and lacking HLA-identical HSC donors

X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: A multicenter study on the manifestations, management and outcome of the disease

X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression. © 2011 by The American Society of Hematology