Inflammatory pseudotumor (IPT)-surgical cure of an inflammatory syndrome.

UNLABELLED: 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. CONCLUSION: In patients with unclear inflammatory symptoms, inflammatory pseudotumor should be added to the differential diagnosis. WHAT IS KNOWN: • 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.

[Guideline for antiretroviral therapy of HIV-infected children and adolescents]. / Leitlinie der Pädiatrische Arbeitsgemeinschaft AIDS (PAAD) e.V. zur antiretroviralen Therapie bei HIV-infizierten Kindern und Jugendlichen (2011).

The HIV-infection in adults or children and adolescent differs substantially. Differences include the mode of infection, viral dynamics facing a developing immune system and the clinical course of the infection. In addition to the virological, immunological and epidemiological aspects the psychosocial situation is also very different. The above aspects and the decreased number of antiretroviral substances underline the need for specific guidelines for HIV-therapy in children and adolescents. The German Pediatric Working group AIDS (PAAD) has formulated this guideline in 2011 based on new study results, changes in international recommendations and newly available drugs.

Terminally differentiated CD8 cells in HIV-infected children: HIV-GAG/POL specificity and IFN-γ production.

BACKGROUND: CD8 cells are key to antiviral immunity and can be divided by phenotype into early (CD28+ CD27+), intermediate (CD28-CD27+) and terminally differentiated subsets (CD28- CD27-). Despite effective HAART there is an unexplained expansion of CD8+CD28-CD27-T cells in HIV-infected children. The cytokine production and specificity of this terminally differentiated CD8 T cell subset in chronic virus infection is unclear. PATIENTS, METHODS & RESULTS: In a cohort of 26 HIV-infected children the cytokine production of terminally differentiated CD8 cells was analyzed by intracellular staining and FACS analysis and was compared to children with chronic hepatitis B infection and to healthy children. The specificity of CD8 subsets was analyzed by staining with Gag/Pol tetramers in a cohort of 13 patients. We show that an increased production of interferon-γ in terminally and early/intermediate differentiated CD8 cell subsets after stimulation is specific for HIV-infection. The expanded population of terminally differentiated CD8+CD28-CD27- T cells does include HIV Gag/Pol specific T cells in adults but not in children. CONCLUSION: The expansion of terminally differentiated CD8 cells might be important for immunomodulation but in children it does not appear to play a role in HIV Gag and Pol specific immunity.

Successful long-term correction of autosomal recessive hyper-IgE syndrome due to DOCK8 deficiency by hematopoietic stem cell transplantation.

Autosomal dominant hyper-IgE syndrome (AD-HIES), characterised by eczema, increased susceptibility to skin and lung infections, elevated IgE and skeletal abnormalities is associated with heterozygous STAT3 mutations. The autosomal recessive variant (AR-HIES) has similar immunological findings but mainly lacks extraimmune manifestations. Several AR-HIES patients have recently been shown to harbour mutations in the gene for dedicator of cytokinesis 8 (DOCK8). Here, we present the long-term outcome of a girl having received a hematopoietic stem cell graft for an at that time genetically undefined combined immunodeficiency associated with severe eczema, multiple food allergies, excessively elevated serum IgE levels and eosinophilia. She was recently found to carry a homozygous nonsense mutation in the DOCK8 gene. HSCT resulted in complete immunological correction, even though mixed donor chimerism occurred. Clinically, the outcome was characterised by disappearance of skin manifestations and severe infections, improvement of pulmonary function and constant decline of IgE levels. Outcome in untransplanted DOCK8 deficient patients is poor because of frequent life-threatening infections, CNS bleeding and infarction, and increased susceptibility to malignancy. This argues for early curative therapeutic approaches, supported by this report of successful long-term outcome after HSCT.

Clinical score for nonbacterial osteitis in children and adults.

OBJECTIVE: To accurately differentiate nonbacterial osteitis (NBO) from other bone lesions by applying a clinical score through the use of validated diagnostic criteria. METHODS: A retrospective study was conducted to assess data on patients from a pediatric clinic and an orthopedic tertiary care clinic, using administrative International Classification of Diseases codes as well as laboratory and department records from 1996 to 2006. Two hundred twenty-four patients older than age 3 years who had either NBO (n = 102), proven bacterial osteomyelitis (n = 22), malignant bone tumors (n = 48), or benign bone tumors (n = 52) were identified by chart review. Univariate logistic regression was used to determine associations of single risk factors with a diagnosis of NBO, and multivariable logistic regression was used to assess simultaneous risk factor associations with NBO. RESULTS: NBO was best predicted by a normal blood cell count (odds ratio [OR] 81.5), symmetric bone lesions (OR 30.0), lesions with marginal sclerosis (OR 26.8), normal body temperature (OR 20.3) a vertebral, clavicular, or sternal location of lesions (OR 13.9), presence of >1 radiologically proven lesion (OR 10.9), and C-reactive protein level > or =1 mg/dl (OR 6.9). The clinical score for a diagnosis of NBO based on these predictors ranged from 0 to 63. A score for NBO of > or =39 had a positive predictive value of 97% and a sensitivity of 68%. CONCLUSION: The proposed scoring system helps to facilitate the diagnostic process in patients with suspected NBO. Use of this system might spare unnecessary invasive diagnostic and therapeutic procedures.

Disease progression in HIV-1 infected children and adolescents--results of a German-Austrian cohort study.

OBJECTIVE: The Paediatric Working Group AIDS (PAAD) initiated a prospective cohort study in order to investigate disease progression in HIV- infected children and adolescents and the effect of antiretroviral treatment regimes. PATIENTS AND METHODS: Between 1998 and 2003, paediatric centres documented HIV-infected patients under clinical care using a questionnaire for basic data and annual follow up. Main outcome measures were: use of antiretroviral therapy, adverse events, disease progression and change of therapeutic regimes. RESULTS: 174 HIV- infected paediatric patients were followed up in 12 centres in Germany and Austria between 1998 and 2003. Initially 54 (31%) patients had no antiretroviral therapy, 35 (20%) received a two-drug regimen (ART) and 85 patients (49%) a highly active antiretroviral therapy (HAART>or=3 drugs). After an observation period of 5 years, 8 patients (4%) had no therapy, 17 (10%) were on ART and 134 patients on HAART (77%). The number of patients with salvage therapy (>or=4 drugs) increased from 5 (3%) to 15 patients (9%). 72 of 166 treated patients (43%) had no change of their drug regimes, 68 patients (41%) had one change and 26 patients (16%)>or=2 changes. Main reasons for changes were increased viral load (49%), immunologic deterioration (21%) and adverse events (14%). During the follow up period no patient died. According to the CDC classification, disease progression was seen in 48 of 174 patients (28%), of whom 20 had deteriorations of clinical categories (A, B, C) and 28 of immunologic categories. Using Kaplan-Meier curves, the mean time from study onset until change of clinical categories was 61 months for patients on HAART, 26 months for patients on ART and 14 months for patients without ART. CONCLUSION: In paediatric patients with HIV infection, disease progression has declined substantially by introduction of HAART. Superiority of HAART compared with ART was demonstrated. Non-adherence as well as other reasons for treatment failure have to be studied more carefully.

Antiviral efficacy, tolerability and pharmacokinetics of efavirenz in an unselected cohort of HIV-infected children.

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 <1.0 mg/L. Eight children (24%) reported persistent adverse events probably caused by efavirenz [concentration problems (5), sleep disorder (1), psychotic reaction (1) and seizure (1)]; six discontinued efavirenz for this reason. A non-significant trend existed towards a higher proportion of toxic efavirenz plasma concentrations (>4.0 mg/L) in subjects who reported efavirenz adverse events: 25.9% versus 12.8% (P = 0.23; t-test). Viral load was <50 copies/mL in all 27 subjects who continued efavirenz, despite occasional subtherapeutic efavirenz plasma concentrations in 12 children. The occasional subtherapeutic levels suggest that temporal non-adherence was present. CONCLUSIONS: Efavirenz as part of highly active antiretroviral therapy was highly effective in children able to tolerate the drug. Therapeutic drug monitoring (TDM) as part of toxicity management may prevent discontinuation in a subset of patients. Temporal non-adherence occurs frequently. TDM may allow initiation of adherence interventions before viral load becomes detectable.

Lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children.

OBJECTIVE: To describe the long-term efficacy over 5 years of regimens including combinations of abacavir, lamivudine and/or zidovudine in previously untreated children in the PENTA 5 trial. DESIGN: PENTA 5 was a 48-week randomised controlled trial comparing three dual nucleoside reverse transcriptase inhibitor (NRTI) combinations as part of first triple antiretroviral therapy (ART). METHODS: 128 ART-naïve children were randomised to zidovudine\lamivudine (n = 36), zidovudine\abacavir (45) or lamivudine\abacavir (47). Asymptomatic children (n = 55) were also randomised to nelfinavir or placebo; all other children received open-label nelfinavir. Analyses are intent-to-treat and adjusted for minor baseline imbalances and receipt of nelfinavir/placebo. RESULTS: Median follow-up was 5.8 years. By 5 years, 17 (47%), 28 (64%) and 18 (39%) children had changed their randomised NRTIs in the zidovudine\lamivudine, zidovudine\abacavir and lamivudine\abacavir groups respectively, but 18%, 50% and 50% of these changes were either early single drug substitutions for toxicity or switches with viral suppression (HIV-1 RNA < 400 copies/ml; e.g. to simplify regimen delivery). At 5 years, 55%/32% zidovudine\lamivudine, 50%/25% zidovudine\abacavir and 79%/63% lamivudine\abacavir had HIV-1 RNA < 400/< 50 copies/ml respectively (p = 0.03/p = 0.003). Mean increase in height-for-age 0.42, 0.68, 1.05 (p = 0.02); weight-for-age 0.03, 0.13, 0.75 (p = 0.02). Reverse transcriptase resistance mutations emerging on therapy differed between the groups: zidovudine\lamivudine (M41L, D67N, K70R, M184V, L210W, T215Y); zidovudine\abacavir (M41L, D67N, K70R, L210W, T215F/Y, K219Q); lamivudine\abacavir (K65R, L74V, Y115F, M184V). CONCLUSIONS: Five year data demonstrate that lamivudine\abacavir is more effective in terms of HIV-1 RNA suppression and growth changes, with lower rates of switching with detectable HIV-1 RNA than zidovudine\lamivudine or zidovudine\abacavir, and should be preferred as first-line NRTI backbone.

Effect of first line therapy including efavirenz and two nucleoside reverse transcriptase inhibitors in HIV-infected children.

OBJECTIVE: In an intent-to-treat study, reduction of viral load, increase in CD4 cell count, clinical benefit and adverse reactions were examined in HIV-infected children receiving first line therapy including efavirenz. METHODS: The data of 10 perinatally infected children (median age: 5.8 years) were evaluated during a treatment period of 24 months. Viral load and CD4 cell count were measured every 4 - 8 weeks. Pharmacokinetic evaluations of efavirenz were performed in all patients at study onset. Adverse reactions were reported after obtaining interval history and examination. RESULTS: At base line, median CD4 cell count was 378 cells/microl (21%) and median viral load was 350,000 copies/ml (5.5 log10 copies/ml). After 24 months of treatment, the median viral load reduction was > 3.5 log10 copies/ ml and HIV-1 RNA < 50 copies/ml was found in 8/10 children (80%). Median CD4 cell count increased to 721 cells/microl (24%) after 3 months and was maintained at a level of >1000 cells/microl (> 25%) after 24 months of treatment. Regarding efavirenz levels, C min. values ranged from 845 to 3550 ng/ml (median: 1845 ng/ml) and C max. values from 2380 to 24 200 ng/ ml (median: 3670 ng/ml). The most common adverse effect was a mild skin rash (4/10 children). CNS symptoms were recorded in one patient and no hyperlipidaemia was seen. CONCLUSION: First line therapy with efavirenz and two NRTIs was well tolerated by HIV-1 infected children and the reduction of viral load seems to be similar to single protease inhibitor-containing regimens.

[Could it be an immune defect? Background and diagnosis]. / Gezielte Frühdiagnostik zur Abklärung von Immundefekten. Wenige Untersuchungen--aber die richtigen!

With modern immunological and molecular biological laboratory techniques, some 100 primary immunodeficiencies can now be diagnosed and differentiated. The importance of diagnosing a primary immunodeficiency (PID) as early as possible cannot be overemphasized. In patients with PID, recurrent infections can lead to permanent damage and sometimes even to death. On the occasion of a first visit to the physician, the patient usually presents with nonspecific symptoms, in particular recurrent infections, a challenging situation in terms of making the correct diagnosis. Relevant warning signals and a possible family history should also prompt at least such simple laboratory tests as a blood differential and the quantitative determination of immunoglobulins, followed where necessary by more specific evaluations. Early treatment, for example, with immunoglobulins may enable many patients to lead a virtually normal life, and in some cases bone marrow transplantation or gene therapy may even result in a cure.

[Treatment of primary immune defects]. / Therapie primärer Immundefekte. Infektionen konsequent behandeln.

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).

LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.

We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gamma(c)) deficiency] in 9 out of 10 patients by retrovirus-mediated gamma(c) gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.

Effect of antiretroviral triple combinations including the protease inhibitor nelfinavir in heavily pretreated children with HIV-1 infection.

BACKGROUND: In this retrospective study the effect of antiretroviral triple therapy including the protease-inhibitor nelfinavir (NFV) on CD4-cells and viral load (VL) in heavily pretreated HIV-infected children was evaluated. PATIENTS AND METHODS: 20 children (<18 years) were included. Median duration of antiretroviral pretreatment was 27 months (range, 7 65), median initial VL was 4.7 log subset 10 (3.2 6.1) and median relative CD4-cells was 17.5% (3 33). Patients were put on combinations with NFV because of treatment failure (increasing VL), intolerance to prior therapy with PIs or adherence problems with prior indinavir. Viral load (RT-PCR, detection limit 50 copies/ml) and CD4-cells were measured every 4-8 weeks. RESULTS: Median viral load decreased 1.2 log(10) (-1.3 2.5), 0.9 log(10) (-0.8 - 2.5) and 0.4 log(10) (-0.5 - 3.0) after 12, 24 and 36 weeks. The VL of 2 patients was below the detection limit (50 copies/ml) after 24 weeks. The relative CD4-cell count increased from a median of 17.5% to 22%, 23% and 25% after 12, 24 and 36 weeks, respectively. Side effects of NFV were usually mild. WHO grade 1 or 2 diarrhea occurred in 70% and moderate elevations of triglycerides in 40% of the patients. At 48 weeks 18/20 patients had to be switched to other combinations due to virological failure. CONCLUSIONS: In children with intensive prior antiretroviral therapy combination therapy including NFV lead to a modest short-term reduction of the VL and increase in CD4-cells. However, the long-term antiretroviral effect was poor.

Allogeneic bone marrow transplantation for active Epstein-Barr virus-related lymphoproliferative disease and hemophagocytic lymphohistiocytosis in an infant with severe combined immunodeficiency syndrome.

A 5-month-old male presented with fever, hepatosplenomegaly, leukocytosis with atypical lymphoblasts, anemia and thrombocytopenia. Severe combined imunodeficiency syndrome (T-, B+, NK+), B lymphoproliferative disease and hemophagocytic lymphohistiocytosis triggered by Epstein-Barr virus (EBV) were diagnosed. As his clinical situation deteriorated rapidly, BMT was performed with unmanipulated marrow stem cells from his EBV-positive HLA-identical sister after conditioning with dexamethasone (1.75 mg/kg/day), cyclophosphamide (114 mg/kg) and etoposide (10 mg/kg), with no immunosuppression given post transplant. Engraftment occurred on day 6 with explosive proliferation of donor CD8(+) T cells. The patient died 3 days later from acute respiratory distress syndrome. Autopsy revealed full donor engraftment and no signs of hemophagocytic lymphohistiocytosis or B lymphoproliferative disease. Thus, transplanted T cells can expand very rapidly within days after BMT and clear EBV lymphoproliferative disease and hemophagocytic lymphohistiocytosis.

Bromelain is an accelerator of phagocytosis, respiratory burst and Killing of Candida albicans by human granulocytes and monocytes.

OBJECTIVE: The aim of this study was to examine the influence of immuno modulating agents like bromelain and trypsin (e.g. Wobenzym on granulocyte and monocyte functions in healthy volunteers and patients with disorders of the humoral immuno system X-linked agammaglobulinaemia (XLA) and common variable immuno deficiency (CVID) and to find out whether the unspecific immunity could be improved by these enzymes. METHODS: In a whole-blood assay kinetics of phagocytosis, respiratory burst and killing (PBK) were measured in blood samples incubated with and without bromelain and trypsin (B/T) using Candida albicans as target organism. The time-reaction curves were analysed determining their gradient (T1) and their onset (T2) as well as the half effect time (HET). RESULTS: Phagocytes from patients with XLA showed a significantly accelerated basal phagocytosis (reduction of HET by 24% p < 0.001) compared to healthy controls. After incubation with B/T (10 microg/ml each) speed of phagocytosis was nearly doubled (phagocyte activity p < 0.0001, Candida uptake p < 0.003), T2 of respiratory burst was reduced by 65 % (p < 0.0001) and killing was accelerated by 27% (p < 0.046). However, the maximal activities of all kinetics were not altered. Incubation of phagocytes from healthy controls with B/T accelerated phagocytosis to a level comparable to that of untreated phagocytes from patients with XLA and also accelerated reactive oxygen species (ROS) production (reduction of HET by 28%, p < 0.012). In contrast to phagocytes from patients with XLA, phagocytes of patients with CVID showed a similar stimulation by B/T like healthy controls. Further experiments with the single substances showed that bromelain was the active compound. CONCLUSION: Our data suggest, that bromelain possesses immuno stimulatory properties. Phagocytes of XLA patients appear to be particularly susceptible to this stimulation.

CD95 (APO-1/Fas) expression on naive CD4(+) T cells increases with disease progression in HIV-infected children and adolescents: effect of highly active antiretroviral therapy (HAART).

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.