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BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

SP7/Osterix is a transcription factor critical for osteoblast maturation and bone formation. Homozygous loss-of-function mutations in SP7 cause osteogenesis imperfecta type XII, but neomorphic (gain-of-new-function) mutations of SP7 have not been reported in humans. Here we describe a de novo dominant neomorphic missense variant (c.926 C > G:p.S309W) in SP7 in a patient with craniosynostosis, cranial hyperostosis, and long bone fragility. Histomorphometry shows increased osteoblasts but decreased bone mineralization. Mice with the corresponding variant also show a complex skeletal phenotype distinct from that of Sp7-null mice. The mutation alters the binding specificity of SP7 from AT-rich motifs to a GC-consensus sequence (typical of other SP family members) and produces an aberrant gene expression profile, including increased expression of Col1a1 and endogenous Sp7, but decreased expression of genes involved in matrix mineralization. Our study identifies a pathogenic mechanism in which a mutation in a transcription factor shifts DNA binding specificity and provides important in vivo evidence that the affinity of SP7 for AT-rich motifs, unique among SP proteins, is critical for normal osteoblast differentiation.

We report on four female adolescents, who presented with inflammatory symptoms. Extensive diagnostic workup revealed tumors on different locations. After surgical removal, clinical and laboratory signs of inflammation disappeared rapidly. On histology, the tumors showed a mixture of inflammatory cells characteristic of inflammatory pseudotumors in three of the patients.In patients with unclear inflammatory symptoms, inflammatory pseudotumor should be added to the differential diagnosis.• The inflammatory pseudotumor (IPT) is a mostly benign myofibroblastic tumor of the soft tissue and causes inflammatory symptoms. What is new: • IPTs have may wider than hitherto defined histologic features. Removal of IPT is curative.

Background Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; pInterpretation Mortality in children admitted to hospital for sepsis or severe focal infections is low in Europe. The disease burden is mainly in children younger than 5 years and is largely due to vaccine-preventable meningococcal and pneumococcal infections. Despite the availability and application of clinical procedures for microbiological diagnosis, the causative organism remained unidentified in approximately 50% of patients.

The immunodeficiency disorder Wiskott-Aldrich syndrome and its milder form X-linked thrombo-cytopenia are caused by mutations in the WASp gene. Wiskott-Aldrich syndrome is characterized by a plethora of clinical symptoms which are due to functional defects of haematopoietic cells, including the inability of macrophages to form actin-rich adhesion structures called podosomes. In contrast, X-linked thrombocytopenia patients show reduced platelet size and counts but no cytoskeletal white blood cell defects have been detected so far. Here we use immunofluorescence technique to evaluate podosome formation in macrophages from X-linked thrombocyto-penia and Wiskott-Aldrich syndrome patients and from healthy donors. We find that X-linked thrombocytopenia macrophages, cells previously thought to be unaffected in this disorder, are compromised in the formation of podosomes. Western blot analysis shows that this phenotype is not due to lower levels of WASp expression. Interestingly, the bacterial chemoattractant formyl-methionyl-leucyl-phenylalanine can rescue podosome formation in X-linked thrombocytopenia cells. Our findings indicate that: 1. The spectrum of WASp-dependent disorders contains defects more subtle than originally recognized and 2. in X-linked thrombocytopenia, some of these defects may not be evident under conditions of bacterial stimulation. Further evaluation of this and other, as yet unrecognized, cellular defects may provide a more complete picture of the continuum of Wiskott-Aldrich syndrome and X-linked thrombocytopenia defects.

We studied the expression of the CD95 receptor (APO-1/Fas) on peripheral blood T cell subpopulations in 37 HIV-1-infected children and adolescents stratified according to disease stage or antiretroviral treatment regimen and compared the results to values obtained in 12 healthy age-matched control subjects. CD95 expression on CD45RA(+) CD45RO(-)/CD62L(+) (resting/naive) and CD45RO(+) CD45RA(-) (primed/memory) CD4(+) and CD8(+) T cells was assessed quantitatively by four-color and three-color flow cytometry. CD4(+) T cells contained a population of predominantly CD95(-) resting/naive cells and a population of CD95(high) primed/memory cells, whereas CD8(+) T cells had a more uniform pattern of CD95 expression. The percentage of CD95(+) CD4(+) T cells increased with disease progression because of both an augmented median fluorescence intensity on resting/naïve cells and an increased percentage of CD95(high) cells. Patients with highly active antiretroviral combination therapy who maintained stable CD4 counts in the presence of elevated plasma viral load had nearly normal numbers of CD95(-) resting/naive CD4(+) T cells, whereas CD95 expression in the CD8(+) T cell subset was still elevated compared with control subjects. Low CD95 expression on resting/naive CD4(+) T cells may therefore indicate a low risk for disease progression in antiretrovirally treated and untreated patients.

Objective: In an intent-to-treat study increase in CD4 cell count, reduction of viral load, clinical benefit and adverse reactions were examined in HlV-infected previously treatment-naive children taking triple therapy. Methods: sixteen HlV-infected children in category A or B on antiretroviral triple therapy were followed-up for a period of 12 months. In group I eight patients received zidovudine, lamivudine and nelfinavir; in group II eight patients received stavudine, didanosine and nelfinavir. Viral load and CD4 cell count were measured every 4-8 weeks. Plasma nelfinavir levels were assessed once in all patients at baseline and monitored in patients with increasing viral load. Results: No significant differences were observed between treatment groups in terms of CD4 cell counts and viral load. A median viral load reduction of 2.8 log 10 (range, 1.4-4.2 log 10 ) was achieved over a period of 12 months in both groups. Viral load < 500 copies/m was found in 69% of patients and viral load < 50 copies/ml in 44% of patients after 12 months. Median CD4 cell count increased from 656 × 10 6 to 850 × 10 6 cells/l after 3 months and was maintained at 813 × 10 6 cells/l after 12 months of treatment. Main side-effects were diarrhoea, rash and hyperlipidaemia. Except for application problems, both regimens were well tolerated. Appropriate formula and individual counselling must be performed during the first weeks of treatment in order to achieve good compliance in paediatric patients. Conclusion: Triple antiretroviral therapy shows a stronger and more sustained reduction of viral load in HlV-infected children compared with studies combining two nucleoside analogues.

Objective. The effects of two antiretroviral triple combinations including the protease inhibitor indinavir on the surrogate markers, viral load and CD4 cells were evaluated. Methods. Fifteen patients with high viral load or disease progression under their prior antiretroviral therapy were switched to zidovudine/ lamivudine/indinavir (Group A, n = 10) or stavudine/lamivudine/indinavir (Group B, n = 5). Serial determinations of viral load and CD4 cells were performed. Results. The median reduction of the viral load was 0.6 log after 3 months and 0.8 log after 6 months in Group A and 2.5 and 2.4 log after 3 and 6 months in Group B, respectively. After 3 and 6 months 3 of 10 patients in Group A and 3 of 5 patients in Group B had viral load reductions below the detection limit of the assay. Patients with an additional switch of nucleoside analogues at start of indinavir therapy (regardless of the specific reverse transcriptase inhibitor used) had significantly better reductions of the viral load than patients without such a switch (median 2.3 log vs. 0.2 log after 6 months, P < 0.05). In Group A the median of the relative increase of CD4 cells was 37% after 3 months and 57% after 6 months (P = 0.002); in Group B the medians of the relative increase of CD4 cells were 145 and 163% (not significant), respectively. Two patients from Group A and 1 from Group B developed renal calculi, which resolved after adequate hydration. One patient was withdrawn because of intractable vomiting attributed to indinavir. Conclusion. In a small cohort of HIV-infected pediatric patients with extensive prior antiretroviral treatment, triple therapy including indinavir had a sustained effect on the decrease of the viral load and the increase of CD4 cells similar to results obtained in antiretrovirally experienced adults. This effect was significantly better in patients with an additional switch of a nucleoside analogue at start of triple therapy with indinavir than in patients without such a change.

Objective: To assess human immunodeficiency virus (HIV) ribonucleic acid load in children and adolescents with HIV infection who are being treated with antiretroviral combination therapy. Study design: Five patients whose disease progressed with their prior antiretroviral therapy had treatment regimens changed to zidovudine (ZDV)/didanosine (DDI) (group A), and the regimens of six patients were changed to ZDV/lamivudine (3TC) (group B). Patients were followed every 4 to 8 weeks for an average period of 8.6 months. Serial determinations of viral copy numbers and CD4 cells were performed. Results: In group A patients' mean relative changes in CD4 cells showed a 20% increase after 4 months (difference not significant [NS]) and a return to baseline after 8 months; in group B patients' mean relative increases of CD4 cells were 72% ( p = 0.046) and 50% (NS), respectively. In group A mean relative viral load increased 21% (0.08 log 10 , NS) and 71% (0.23 10 log, NS), whereas in group B viral load decreased 22% (0.1 log 10 , NS) and 74% (0.58 log 10 , p = 0.03) after 4 and 8 months, respectively. After starting antiretroviral combination therapy in group A, there was a slight trend of a decreasing ratio of viral load per number of CD4 cells, whereas in group B this ratio significantly decreased, indicating a marked suppression of viral turnover with ZDV/3TC treatment. Conclusion: In a small cohort of pediatric patients, combination therapy with ZDV/3TC was well tolerated and had a strong and sustained effect on the decrease of viral load similar to results obtained in adults. In patients with ZDV/DDI therapy the reduction of viral load was less pronounced, but treatment groups A and B were not comparable for statistic evaluation. (J Pediatr 1997;130:293-9)

Mucormycosis is associated with high morbidity and mortality and is perceived as an emerging fungal infection. However, contemporary paediatric data are limited. We present a series of paediatric cases of mucormycosis reported from Germany and Austria collected within a voluntary epidemiological survey through standardised, anonymized case report forms. Twelve cases were reported between January 2004 and December 2008 (six men; mean age: 12.6 years, range: 0.1-17 years). Mucormycosis was proven in nine, and probable in three cases. Isolates included Lichtheimia (syn. Absidia pro parte, Mycocladus) (five), Rhizopus (three) and Mucor (one) species. Infection was limited to soft tissue in three cases, the lung in two cases, and an infected thrombus in one case; rhinocerebral disease was found in three cases, and pulmonary-mediastinal, pulmonary-cerebral and soft tissue-cerebral involvement in one case each. All three patients with isolated soft tissue infection were cured, whereas seven of the remaining patients died (one patient without follow-up). The overall mortality rate was 67%. While these data cannot provide conclusive data on incidence and disease burden of mucormycosis in paediatric patients, they reflect the continuing threat of these infections to immunocompromised patients and the need for improved diagnosis and management.

Teresa Español, [et al.], A large proportion of patients with mutations in the Wiskott-Aldrich syndrome (WAS) protein gene exhibit the milder phenotype termed X-linked thrombocytopenia (XLT). Whereas stem cell transplantation at an early age is the treatment of choice for patients with WAS, therapeutic options for patients with XLT are controversial. In a retrospective multicenter study we defined the clinical phenotype of XLT and determined the probability of severe disease-related complications in patients older than 2 years with documented WAS gene mutations and mild-to-moderate eczema or mild, infrequent infections. Enrolled were 173 patients (median age, 11.5 years) from 12 countries spanning 2830 patient-years. Serious bleeding episodes occurred in 13.9%, life-threatening infections in 6.9%, autoimmunity in 12.1%, and malignancy in 5.2% of patients. Overall and event-free survival probabilities were not significantly influenced by the type of mutation or intravenous immunoglobulin or antibiotic prophylaxis. Splenectomy resulted in increased risk of severe infections. This analysis of the clinical outcome and molecular basis of patients with XLT shows excellent long-term survival but also a high probability of severe disease-related complications. These observations will allow better decision making when considering treatment options for individual patients with XLT. © 2010 by The American Society of Hematology., We also thank the staff of the European Society for Immunodeficiencies registry for their support. This work was supported in part by a grant from Biotest AG, Dreieich, Germany (M. H. A.).

Background: We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. Methods: We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. Results: All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07 x 10(sup 9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one). Conclusions: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.) N Engl J Med 2009;360:447-58. RI rossi, paolo/D-6504-2012; galimberti, stefania/H-2594-2012 BACKGROUND:We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency.METHODS:We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells.RESULTS:All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07x10(9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one).CONCLUSIONS:Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.) BackgroundWe investigated the long-term outcome of gene therapy for severe combined immunodeficiency(SCID) due to the lack of adenosine deaminase (ADA), a fatal disorderof purine metabolism and immunodeficiency.MethodsWe infused autologous CD34+ bone marrow cells transduced with a retroviral vectorcontaining the ADA gene into 10 children with SCID due to ADA deficiency wholacked an HLA-identical sibling donor, after nonmyeloablative conditioning withbusulfan. Enzyme-replacement therapy was not given after infusion of the cells.ResultsAll patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transducedhematopoietic stem cells have stably engrafted and differentiated into myeloidcells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%)and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patientsdo not require enzyme-replacement therapy, their blood cells continue to expressADA, and they have no signs of defective detoxification of purine metabolites. Ninepatients had immune reconstitution with increases in T-cell counts (median countat 3 years, 1.07×109 per liter) and normalization of T-cell function. In the five patientsin whom intravenous immune globulin replacement was discontinued, antigenspecificantibody responses were elicited after exposure to vaccines or viral antigens.Effective protection against infections and improvement in physical development madea normal lifestyle possible. Serious adverse events included prolonged neutropenia(in two patients), hypertension (in one), central-venous-catheter–related infections (intwo), Epstein–Barr virus reactivation (in one), and autoimmune hepatitis (in one).ConclusionsGene therapy, combined with reduced-intensity conditioning, is a safe and effectivetreatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers,NCT00598481 and NCT00599781.)

The feasibility of rectal administration of didanosine (DDI) was studied in six human immunodeficiency virus-infected patients. After oral intake of a DDI solution (100 mg/m 2 of body surface area) combined with an antacid (Maalox), pharmacokinetic parametric values were in accordance with previously published data; the mean ± standard deviation for terminal half-life was 59.5 ± 15.0 min, that for peak concentration was 5.2 ± 3.9 μmol/liter, and that for the area under the time-concentration curve (AUC) was 494 ± 412 min · μmol/liter. After rectal administration of a similarly prepared DDI solution (100 mg/m 2 of body surface area), plasma DDI levels were below the detection limit (0.1 μmol/liter) at all time points in five of the six patients, and in the remaining patient the AUC after rectal application was only 5% of that after oral administration. We conclude that oral administration of DDI cannot be easily replaced by rectal application.

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.

Objective To characterize common variable immunodeficiency disorder (CVID) in childhood. Study design We retrospectively investigated clinical findings in 32 children with primary CVID by questionnaire and file review. Results Clinical presentation included recurrent or chronic respiratory tract infections (88%), sinusitis (78%), otitis media (78%), and intestinal tract infections (34%), mainly with encapsulated bacteria. Meningitis was found in 25%, sepsis in 16%, and pyelonephritis in 16% of patients. Poliomyelitis after vaccination occurred in 2 patients and opportunistic infections occasionally. Allergic disorders were present in 38%, and autoimmune disease in 31% of patients. Eighty percent of the patients underwent surgical procedures because of recurrent infections. Growth retardation was seen in 28% of patients, and 16% showed retarded mental development. Bronchiectasis developed in 34%, and lymphoid proliferative disease in 13%. Incidence of allergic and autoimmune diseases was increased in first-degree relatives with normal immunologic findings. Mean time between symptoms and induction of immunoglobulin substitution therapy was 5.8 years (0.2-14.3). Conclusions CVID in children presents with comparable symptoms and disorders as in adults. We found a significant influence on growth and development. The marked delay of diagnosis may be due to overlap with common pediatric disorders, while also reflecting insufficient awareness of these disorders.

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 CGD.

Item does not contain fulltext OBJECTIVES: To obtain data on the pharmacokinetics of efavirenz in children in clinical practice. METHODS: HIV-1-infected children received efavirenz capsules or tablets in accordance with manufacturer's dosing recommendations. Plasma was collected at regular visits and analysed by HPLC. The therapeutic range of efavirenz was defined as 1.0-4.0 mg/L. RESULTS: Thirty-three children were included. Median (range) age, body weight, dose and dose/kg were 8.2 (2.1-16.7) years, 24 (12-62) kg, 300 (200-800) mg and 13.3 (9.7-22.5) mg/kg, respectively. Median (range) efavirenz plasma concentration at first sampling was 2.8 (0.13-11.6) mg/L. Plasma concentrations were not dependent on age (P = 0.97) or dose/kg (P = 0.87). A total of 307 efavirenz plasma concentrations were determined. Forty-five samples (14.7%) contained >4.0 mg/L, and 27 samples (8.8%) contained 4.0 mg/L) in subjects who reported efavirenz adverse events: 25.9% versus 12.8% (P = 0.23; t-test). Viral load was

"Hair-on-end" skull changes are typically seen in individuals suffering from thalassaemia. They are induced by widening of the diploic space due to marrow expansion that is a consequence of ineffective and excessive erythropoiesis. We present a child with severe congenital neutropenia who exhibited the typical hair-on-end sign on plain skull radiographs and MRI. In this patient the skull changes were very likely induced by the expansion of white blood cell precursors induced by long-term daily injections of recombinant human granulocyte colony stimulating factor (G-CSF) to treat his confounding disease. This case report is the first description of hair-on-end changes associated with the use of G-CSF.

Objective: In HIV-infected adults Pneumocystis jirovecii pneumonia (PCP) prophylaxis can be safely withdrawn after immune reconstitution due to the introduction of highly active antiretroviral therapy (HAART). With regard to children only a small amount of data has been published. The present study investigated whether the withdrawal of PCP prophylaxis after immune reconstitution is safe in HIV-infected children. Methods: A retrospective analysis at 10 European centers belonging to the Pediatric European Network on the treatment of AIDS (PENTA) using a standardized questionnaire. Results: A total of 113 questionnaires were received. In 82 children the indication for PCP prophylaxis was provided following Centers for Disease Control (CDC) guidelines (72 primary and 10 secondary). Prophylaxis was withdrawn after the CD4 cell count increased above the age-related CDC thresholds. The observation period off prophylaxis was 335 years (300 years for primary and 35 years for secondary prophylaxis) and the median time per patient off prophylaxis was 4.1 years (range, 0.3-7.7 years). No episode of PCP occurred during the study period. In comparison with the incidence rate from historical data before the introduction of PCP prophylaxis and HAART, this was a significant reduction (P < 0.05). Conclusions: The increase in CD4 cell count provides functional reconstitution of the immune system in children. Our data suggests that the risk of developing a PCP after immune reconstitution is sufficiently low to withdraw PCP prophylaxis.

Management of immunodeficient patients includes monitoring of growth, diet, personal hygiene and life habits, including environmental factors. Major therapeutic stays are prevention, early detection and the decisive treatment of infections. Attenuated live vaccines, non-irradiated blood products and blood containing CMV antibodies should not be applied. In the case of antibody defects immunoglobulin substitution is a specific form of treatment. Enzyme replacement is a causal approach to an adenosine deaminase defect. For numerous primary immune defects, bone marrow transplantation represents the best causal therapeutic measure. In the absence of a bone marrow donor, alternative gene therapy is available for the management of severe combined immunodeficiency on the X-chromosome (X-SCID), and adenosine deaminase deficiency (ADA deficiency).

Chronic granulomatous disease (CGD) is a rare congenital disorder in which the patients' phagocytes fail to kill ingested microbes due to an inability to generate superoxide and other microbicidal oxygen derivatives. This inability is Caused by mutations in one of the four components of the phagocyte-specific NADPH oxidase. A small Subgroup of CGD patients has mutations in the CYBA gene that encodes the p22-phox subunit of the NADPH oxidase. This subunit forms, together with gp91-phox, a flavocytochrome 1)558 heterodimer in the phagocyte plasma membrane. Expression of both subunits is required for normal expression of this heterodimer. Here, we report an autosomal recessive CGD patient with neutrophils that did not express flavocytochrome b(558), and did not generate superoxide upon activation. Analysis of genomic DNA revealed a 4-bp deletion at the exon-1/intron-1 boundary in CYBA (IVS1 + 4_7delAGTG). In the patient's cDNA, we found a low expression of an abnormal product, containing exon I extended by 79 nucleotides from intron 1, joined to exon 2. This extension is apparently caused by the activation of a cryptic donor splice site with a GT sequence at position 84-85 in intron 1. Both parents of the patient had the same Mutation in their genomic DNA, in heterozyous form, but their cDNA contained exclusively the wild-type p22-phox cDNA Sequence, indicating that the Mutant mRNA was labile. This is, as far as we know, the first description of the molecular and clinical consequences of a donor splice site mutation in intron I of any gene reported so far. (c) 2005 Elsevier Inc. All rights reserved

Five heavily pretreated HIV-infected children were put on amprenavir and delavirdine plus two nucleoside inhibitors to reverse transcriptase to boost amprenavir levels and to use the antiretroviral activity of a non-nucleoside reverse transcriptase inhibitor. No data are available about this combination in children. It w;as well tolerated, and the median reduction in viral load was 1.5 log after 18 months. Delavirdine boosted amprenavir trough levels more than 10-fold, and delavirdine trough levels remained i several fold above susceptible HIV strains.

In this retrospective study the effect of antiretroviral combination regimens including the non nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) on viral load (VL) and CD4-cell count in heavily pretreated HIV-infected children was investigated.The data of 15 children (16 years) were evaluated during a treatment period of at least 52 weeks. Patients received a median of 4 prior antiretroviral regimens and were changed to combinations with EFV because of renewed increasing VL.Viral load (Amplicor, detection limit 50 copies/ml) and CD4-cells were measured every 4-8 weeks.The median reduction of the viral load for the total study population was 1.9 log10 (0.8 - 4.7), 2.3 log(10) (0.5 - 4.7) and 2.6 log(10) (0-4.7) after 12, 24 and 52 weeks, respectively. After 24 weeks 7/15 children and after 52 weeks 9/15 patients had reductions of the VL below the detection limit. The median increase of CD4-cells in the study population during the treatment period were 104 cells/microl (189-969), 220 cells/microl (170-831) and 321 cells/ml (162-574) after 12, 24 and 52 weeks, respectively.In children with intensive prior antiretroviral therapy and multiple therapeutic failures with PI-containing regimens, combination therapy including EFV resulted in an excellent antiretroviral efficacy. After 52 weeks 9/15 patients had persistent reductions of the VL below 50 copies/ml, although none of these children reached this level of viral suppression during their multiple prior protease inhibitor-containing regimens.

Background. In this retrospective study we compared the antiretroviral effect of regimens consisting of simultaneous administration of two protease inhibitors (PI) with at least one nucleoside reverse transcriptase inhibitor on plasma viral load (VL) and CD4 cell count in HIV-infected children intensively pretreated with nucleoside reverse transcriptase inhibitors and PIs. Methods. Eleven HIV-infected children were changed to antiretroviral combination regimens including two PIs and followed for a median time of 24 weeks. Group A comprised six patients who were given ritonavir + saquinavir (SQV) and Group B consists of five patients who were changed to nelfinavir + SQV. Patients were treated with these combinations with 2 PIs because of treatment failure (increasing viral load) of prior PI therapy or clinical signs of disease progression. Outcome measures. Serial determinations of plasma viral load (Amplicor, Roche) and CD4 cells were performed every 4 to 8 weeks. The detection limit of the Amplicor-reverse transcriptase-PCR assay was 50 copies/ml (1.7 log 10 ). Results. In Group A the median VL reduction was 1.1 log 10 after 3 months and 1.4 log 10 after 6 months. In Group B median VL decreased 0.1 and 0.2 log 10 after 3 and 6 months. In both groups during the study period none of the patients reached undetectable VL. The relative changes of CD4 cells above baseline in Group A showed a median increase of 7% after 3 months and 23% after 6 months. In Group B after 3 months CD4 cells did not increase, and after 6 months the median relative increase was only 7%. Both combination therapies were well tolerated, not necessitating any drug interruption during study period. Conclusions. In children with intensive prior antiretroviral treatment, a salvage therapy including two PIs demonstrated antiretroviral efficacy in some patients. In this study the reduction of the VL as well as the increase of CD4 cells was more pronounced with ritonavir + SQV than with nelfinavir + SQV. With both combinations complete suppression of HIV replication was not achieved. Therefore the long term effect of these combinations may be limited by the emergence of resistant HIV strains.

The data of 29 patients with X-linked agammaglobulinemia, who received immunoglobulin replacement therapy between 1965 and 1990, were analyzed for dose-dependent long-term results concerning infectious complications. Patients who received high-dose intravenous immunoglobulin replacement (greater than 400 mg/kg every 3 weeks) showed a significant increase in trough serum IgG levels and a significant decrease in the incidence of pneumonias and the number of days spent in the hospital compared with patients receiving intravenous immunoglobulin low-dose (less than 200 mg/kg every 3 weeks) or intramuscular immunoglobulin (less than 100 mg/kg every 3 weeks) treatment. Improvements in therapeutic outcome were particularly evident when high-dose intravenous immunoglobulin replacement therapy was started before the age of 5 years. Bacterial meningitis, chronic pulmonary disease, and bronchiectasis occurred in the intramuscular immunoglobulin group but did not occur in either of the intravenous immunoglobulin groups. High-dose intravenous immunoglobulin therapy may have a positive impact on the clinical course and may prevent severe complications in patients with X-linked agammaglobulinemia.

Focal viral encephalitis in childhood is a rare but life-threatening disease. Animal experiments and case reports suggest a positive effect of an additional therapy with interferon-beta on the course of the disease. Therefore, we initiated a prospective, double-blind placebo-controlled study to investigate the benefit of a combination therapy of Aciclovir (ACV) and recombinant interferon-beta (rIFN-beta) in juvenile focal viral encephalitis. - Initial inclusion criterium was suspicion of focal viral encephalitis. Diagnosis was proven by demonstration of characteristic focal lesions in cerebral imaging or virological evidence of HSV in cerebrospinal fluid. Patients were treated with ACV plus rIFN-beta or ACV plus placebo. Neurological outcome was determined 21 days and 3 months after onset of the disease. - Initially 59 patients were enrolled in the study. Encephalitis was proven in 14 patients (7 ACV + rIFN-beta, 7 ACV + placebo). The study groups were balanced in terms of important prognostic criteria. 10 patients (5 ACV + rIFN-beta, 5 ACV + placebo) were cured or had slight defects, 4 patients (2 ACV + rIFN-beta, 2 ACV + placebo) showed moderate to severe defects. There was no significant difference in favour of the additive therapy with rIFN-beta.