ABSTRACT
Human T-cell function is dependent on T-cell antigen receptor (TCR) and co-signalling as evidenced by immunodeficiencies affecting TCR-dependent signalling pathways. Here, we show four human patients with EBV+ disseminated smooth muscle tumours that carry two homozygous loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and myosin 1 linker 2. These patients lack regulatory T cells without evidence of organ-specific autoimmunity, and have defective CD28 co-signalling associated with impaired T-cell activation, differentiation and function, as well as perturbed cytoskeletal organization associated with T-cell polarity and migration disorders. Human CARMIL2-deficiency is therefore an autosomal recessive primary immunodeficiency disorder associated with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics.
Subject(s)
Immunologic Deficiency Syndromes/genetics , Microfilament Proteins/metabolism , CD28 Antigens/genetics , CD28 Antigens/metabolism , Child , Child, Preschool , Genotype , Homozygote , Humans , Microfilament Proteins/genetics , Mutation , Signal TransductionABSTRACT
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.
Subject(s)
Granuloma, Plasma Cell , Adolescent , Anti-Bacterial Agents/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Child , Diagnosis, Differential , Female , Granuloma, Plasma Cell/diagnosis , Granuloma, Plasma Cell/pathology , Granuloma, Plasma Cell/therapy , Humans , Positron-Emission TomographyABSTRACT
BACKGROUND: Increased serum IgE levels are characteristic but not specific for allergic diseases. Particularly, severe atopic dermatitis (AD) overlaps with hyper-IgE syndromes (HIES) regarding eczema, eosinophilia, and increased serum IgE levels. HIES are primary immunodeficiencies due to monogenetic defects such as in the genes DOCK8 and STAT3. As it is not known to date why allergic manifestations are not present in all HIES entities, we assessed the specificity of serum IgE of AD and HIES patients in the context of clinical and immunological findings. METHODS: Clinical data, skin prick tests, specific IgE to aero- and food allergens, and T helper (Th) subpopulations were compared in AD and molecularly defined HIES patients. RESULTS: Total serum IgE levels were similarly increased in STAT3-HIES, DOCK8-HIES, and AD patients. The ratio of aeroallergen-specific IgE to total IgE was highest in AD, whereas DOCK8-HIES patients showed the highest specific serum IgE against food allergens. Overall, clinical allergy and skin prick test results complied with the specific IgE results. Th2-cell numbers were significantly increased in DOCK8-HIES and AD patients compared to STAT3-HIES patients and controls. AD patients showed significantly higher nTreg-cell counts compared to STAT3-HIES and control individuals. High Th17-cell counts were associated with asthma. Specific IgE values, skin prick test, and T-cell subsets of STAT3-HIES patients were comparable with those of healthy individuals except decreased Th17-cell counts. CONCLUSION: Hyper-IgE syndromes and atopic dermatitis patients showed different sensitization pattern of serum IgE corresponding to the allergic disease manifestations and Th-cell subset data, suggesting a key role of DOCK8 in the development of food allergy.
Subject(s)
Dermatitis, Atopic/immunology , Guanine Nucleotide Exchange Factors/immunology , Immunoglobulin E/immunology , Job Syndrome/immunology , STAT3 Transcription Factor/immunology , Adult , DNA Mutational Analysis , Dermatitis, Atopic/blood , Female , Flow Cytometry , Guanine Nucleotide Exchange Factors/genetics , Humans , Immunoglobulin E/blood , Job Syndrome/blood , Job Syndrome/genetics , Male , Middle Aged , STAT3 Transcription Factor/genetics , Skin Tests , T-Lymphocytes, Helper-Inducer/immunology , Young AdultABSTRACT
X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.
Subject(s)
Immunologic Deficiency Syndromes/genetics , Lymphohistiocytosis, Hemophagocytic/genetics , X-Linked Inhibitor of Apoptosis Protein/deficiency , Adolescent , Adult , Child , Child, Preschool , Genotype , Humans , Immunologic Deficiency Syndromes/immunology , Lymphohistiocytosis, Hemophagocytic/immunology , Male , Mutation , Natural Killer T-Cells/immunology , Phenotype , X-Linked Inhibitor of Apoptosis Protein/genetics , X-Linked Inhibitor of Apoptosis Protein/immunology , Young AdultABSTRACT
In 2009, a federally funded clinical and research consortium (PID-NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies (PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency (CVID), the most prevalent PID.
Subject(s)
Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/epidemiology , Registries , Adolescent , Adult , Age Factors , Aged , Child , Child, Preschool , Databases, Factual , Female , Germany , Humans , Immunologic Deficiency Syndromes/genetics , Infant , Infant, Newborn , Male , Middle Aged , Prevalence , Young AdultABSTRACT
The importance of serum immunoglobulin (Ig)G concentration in IgG replacement therapy for primary immunodeficiency diseases is established in certain settings. Generally, IgG is infused via the intravenous (IVIG) or subcutaneous (SCIG) route. For IVIG infusion, published data demonstrate that higher IgG doses and trough levels provide patients with improved protection from infection. The same conclusions are not yet accepted for SCIG; data from two recent Phase III studies and a recent post-hoc analysis, however, suggest the same correlation between higher SCIG dose and serum IgG concentration and decreased incidence of infection seen with IVIG. Other measures of clinical efficacy have not been considered similarly. Thus, combined analyses of these and other published SCIG studies were performed; a full comparison of the 13 studies was, however, limited by non-standardized definitions and reporting. Despite these limitations, our analyses indicate that certain clinical outcomes improve at higher SCIG doses and associated higher serum IgG concentrations, and suggest that there might be opportunity to improve patient outcomes via SCIG dose adjustment.
Subject(s)
Immunization, Passive , Immunoglobulin G/administration & dosage , Immunologic Deficiency Syndromes/therapy , Bacterial Infections/etiology , Humans , Immunization, Passive/adverse effects , Immunoglobulin G/blood , Immunologic Deficiency Syndromes/complications , Infusions, Subcutaneous , Treatment OutcomeABSTRACT
A prospective, open-label, multicenter, single-arm, Phase III study evaluated the efficacy and safety of Hizentra(®), a 20% human IgG for subcutaneous administration, in 51 primary immunodeficiency patients over 40 weeks. Patients previously on intravenous or subcutaneous IgG were switched to weekly subcutaneous infusions of Hizentra(®) at doses equivalent to their previous treatment. IgG levels achieved with Hizentra(®) were similar to pre-study levels with subcutaneous, and higher by 17.7% than pre-study levels with intravenous IgG. No serious bacterial infections were reported in the efficacy period. The rate of all infections was 5.18/year/patient, the rates of days missed from work/school, and days spent in hospital were 8.00/year/patient and 3.48/year/patient, respectively. Local reactions (rate 0.060/infusion) were mostly mild (87.3%). No serious, Hizentra(®)-related adverse events were reported. Individual median infusion durations ranged between 1.14 and 1.27 h. Hizentra(®) maintained or improved serum IgG levels without dose increases and effectively protected patients against infections.
Subject(s)
Immunoglobulin G/administration & dosage , Immunologic Deficiency Syndromes/therapy , Adolescent , Adult , Agammaglobulinemia/blood , Agammaglobulinemia/immunology , Agammaglobulinemia/therapy , Child , Child, Preschool , Common Variable Immunodeficiency/blood , Common Variable Immunodeficiency/immunology , Common Variable Immunodeficiency/therapy , Female , Genetic Diseases, X-Linked/blood , Genetic Diseases, X-Linked/immunology , Genetic Diseases, X-Linked/therapy , Humans , Immunoglobulin G/adverse effects , Immunoglobulin G/blood , Immunoglobulins, Intravenous/administration & dosage , Immunoglobulins, Intravenous/adverse effects , Immunoglobulins, Intravenous/blood , Immunologic Deficiency Syndromes/blood , Immunologic Deficiency Syndromes/immunology , Infusions, Intravenous , Infusions, Subcutaneous , Male , Middle Aged , Prospective Studies , Treatment Outcome , Young AdultABSTRACT
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.
Subject(s)
Guanine Nucleotide Exchange Factors/deficiency , Guanine Nucleotide Exchange Factors/genetics , Hematopoietic Stem Cell Transplantation , Job Syndrome/genetics , Job Syndrome/therapy , STAT3 Transcription Factor/genetics , Child , Child, Preschool , Consanguinity , DNA Mutational Analysis , Female , Follow-Up Studies , HumansABSTRACT
BACKGROUND: Subcutaneous immunoglobulin (SCIG) therapy is an alternative to intravenous immunoglobulin (IVIG) therapy. METHODS: We evaluated the efficacy and safety of the SCIG Vivaglobin(formerly known as Beriglobin SC) under real-life conditions in a post-marketing observational study in 82 patients with primary or secondary antibody deficiencies. Health-related quality of life (HRQoL) was evaluated in a subset of 30 patients previously treated with IVIG (including 11 children <14 years) using the Short Form 36 (SF-36) for patients > or = 14 years of age (adults) and the Child Health Questionnaire - Parental Form 50 (CHQ-PF50) for children <14 years of age. Treatment preferences were assessed in adults. RESULTS: The mean serum immunoglobulin G (IgG) trough level during SCIG treatment (7.5 g/L) was higher than during previous IVIG treatment (6.6 g/L; p<0.01). The investigators assessed the efficacy of SCIG therapy as "excellent" in 89% of patients. No systemic adverse drug reactions were observed. Improvements by > or = 5 points were observed in 5 of 8 SF-36 subscales and in 6 of 12 CHQ-PF50 subscales. Statistically significant improvements (p< or =0.05) were observed for the SF-36 subscales of bodily pain, general health perceptions, and vitality (adults), and for the CHQ-PF50 subscales of general health perceptions, parental impact - time, parental impact - emotional, and family activities (children). Patients preferred SCIG over IVIG therapy (92%) and home therapy over therapy at the clinic/physician (83%). CONCLUSION: This study confirms that therapy with Vivaglobin at home is effective, safe, well tolerated, and improves quality of life in patients with antibody deficiency.
Subject(s)
Immunoglobulins/administration & dosage , Immunologic Deficiency Syndromes/therapy , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Health Status , Humans , Immunoglobulins/blood , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/physiopathology , Immunotherapy/methods , Infant , Injections, Subcutaneous , Male , Middle Aged , Product Surveillance, Postmarketing , Prospective Studies , Quality of Life , Severity of Illness Index , Young AdultABSTRACT
Nijmegen breakage syndrome (NBS) is characterized by chromosomal instability, radiation hypersensitivity, characteristic facial appearance, immunodeficiency and strong predisposition to lymphoid malignancy. Traditionally, NBS patients have not undergone hematopoietic SCT (HSCT) owing to concerns about increased toxicity. We therefore report on the HSCT experience in NBS patients in Europe. Six patients were transplanted either for resistant or secondary malignancy (four patients) or severe immunodeficiency (two patients). Five patients received reduced-intensity conditioning regimens. After a median follow-up of 2.2 years, five patients are alive and well. One patient who received myeloablative conditioning died from sepsis before engraftment. Acute GVHD grades I-II occurred in three of five patients, mild chronic GVHD in one. All five surviving patients exhibit restored T-cell immunity. The experience in these six patients suggests that HSCT in NBS is feasible, can correct the immunodeficiency and effectively treat malignancy. Acute toxicity seems to be reasonable with reduced-intensity conditioning regimens.
Subject(s)
Hematopoietic Stem Cell Transplantation , Nijmegen Breakage Syndrome/therapy , Transplantation Conditioning/methods , Adolescent , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , Male , Retrospective Studies , Transplantation ChimeraABSTRACT
A patient with idiopathic CD4 T-lymphopenia was diagnosed with a recurrent disseminated Mycobacterium avium infection. Because of progressive disease, treatment with interferon-gamma (IFN-γ) and interleukin-2 (IL-2) was started. The patient was successfully treated with IFN-γ-1b and IL-2 in addition to anti-mycobacterial combination therapy. To our knowledge, this is the first report of successful combination therapy with IFN-γ-1b and IL-2 in a patient with idiopathic CD4 T-lymphopenia. Short-term IFN-γ-1b and IL-2 might be considered as therapeutic options in refractory mycobacterial infections in patients with idiopathic CD4 lymphopenia.
Subject(s)
Interferon-gamma/therapeutic use , Interleukin-2/therapeutic use , Lymphopenia/complications , Mycobacterium avium-intracellulare Infection/drug therapy , Adjuvants, Immunologic/therapeutic use , CD4 Lymphocyte Count , HIV Seronegativity , Humans , Lymphopenia/immunology , Male , Middle Aged , Mycobacterium avium-intracellulare Infection/etiology , Recombinant Proteins , Recurrence , SyndromeABSTRACT
AIM OF THE STUDY: To evaluate the immunogenicity, safety and reactogenicity of a seven-valent pneumococcal conjugate vaccine (PCV7) when given concomitantly with a fully liquid DTaP-IPV-HBV-Hib combination vaccine. METHODS: Two hundred and sixty-six healthy infants in France (n=136) and Germany (n=130) were randomized to receive DTaP-IPV-HBV-Hib and PCV7 (test group) at the age of 2, 3 and 4 months (primary series) and 12-15 months (booster dose), or to receive DTaP-IPV-HBV-Hib at the same time points but PCV7 at the ages of 5, 6, 7 and 13-16 months (control group). Antibody levels to all vaccine antigens were measured before dose 1, 1 month after dose 3, at the time of booster, and 1 month later. Safety data were collected after each vaccine dose. RESULTS: Two hundred and fifty-seven infants (test group, 131; control group, 126) completed the primary immunization series and two hundred and forty-five received the booster dose (test group, 125; control group, 120). Depending on the serotype, 92.8-100% of subjects in the test group achieved antibody levels >or=0.15 microg/mL for PCV7 antigens at 5 months of age, and 89.7-99.1% of them antibody levels >or=0.50 microg/mL 1 month after booster. For DTaP-IPV-HBV-Hib, there was no statistically significant difference between the two groups in the proportion of infants that achieved pre-defined seroprotective levels for each antigen at 5 months and 1 month after booster. Frequency of local and systemic reactions was similar in both groups except for fever above 38.0 degrees C, which was more frequent in the test group after dose 1, 2 or 4. Fever >39.0 degrees C was only reported from three children in each group. CONCLUSION: The PCV7 vaccine was highly immunogenic, well tolerated, and safe when coadministered with the DTPa-IPV-HBV-Hib vaccine at 2, 3, and 4 months of age and a booster dose at 12-15 months. In this study, PCV7 did not show any relevant influence on the immunogenicity and safety of the concurrently administered DTPa-IPV-HBV-Hib vaccine.
Subject(s)
Diphtheria-Tetanus-Pertussis Vaccine/administration & dosage , Diphtheria-Tetanus-Pertussis Vaccine/immunology , Haemophilus Vaccines/administration & dosage , Haemophilus Vaccines/immunology , Hepatitis B Vaccines/administration & dosage , Hepatitis B Vaccines/immunology , Immunization, Secondary , Vaccines, Conjugate/administration & dosage , Vaccines/immunology , Child, Preschool , Diphtheria-Tetanus-Pertussis Vaccine/adverse effects , Female , France , Haemophilus Vaccines/adverse effects , Hepatitis B Vaccines/adverse effects , Humans , Immunization Schedule , Infant , Male , Safety , Vaccines/administration & dosage , Vaccines/adverse effects , Vaccines, Combined/adverse effects , Vaccines, Combined/immunology , Vaccines, Conjugate/adverse effectsABSTRACT
OBJECTIVES: To study the clinical outcome, treatment response, T-cell subsets and functional consequences of a novel tumour necrosis factor (TNF) receptor type 1 (TNFRSF1A) mutation affecting the receptor cleavage site. METHODS: Patients with symptoms suggestive of tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and 22 healthy controls (HC) were screened for mutations in the TNFRSF1A gene. Soluble TNFRSF1A and inflammatory cytokines were measured by ELISAs. TNFRSF1A shedding was examined by stimulation of peripheral blood mononuclear cells (PBMCs) with phorbol 12-myristate 13-acetate followed by flow cytometric analysis (FACS). Apoptosis of PBMCs was studied by stimulation with TNFalpha in the presence of cycloheximide and annexin V staining. T cell phenotypes were monitored by FACS. RESULTS: TNFRSF1A sequencing disclosed a novel V173D/p.Val202Asp substitution encoded by exon 6 in one family, the c.194-14G>A splice variant in another and the R92Q/p.Arg121Gln substitution in two families. Cardiovascular complications (lethal heart attack and peripheral arterial thrombosis) developed in two V173D patients. Subsequent etanercept treatment of the V173D carriers was highly effective over an 18-month follow-up period. Serum TNFRSF1A levels did not differ between TRAPS patients and HC, while TNFRSF1A cleavage from monocytes was significantly reduced in V173D and R92Q patients. TNFalpha-induced apoptosis of PBMCs and T-cell senescence were comparable between V173D patients and HC. CONCLUSIONS: The TNFRSF1A V173D cleavage site mutation may be associated with an increased risk for cardiovascular complications and shows a strong response to etanercept. T-cell senescence does not seem to have a pathogenetic role in affected patients.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Familial Mediterranean Fever/genetics , Immunoglobulin G/therapeutic use , Mutation , Receptors, Tumor Necrosis Factor, Type I/genetics , Receptors, Tumor Necrosis Factor/therapeutic use , Adolescent , Adult , Amino Acid Sequence , Apoptosis/immunology , Base Sequence , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cardiovascular Diseases/genetics , Cardiovascular Diseases/immunology , Cells, Cultured , Cellular Senescence/immunology , DNA Mutational Analysis/methods , Etanercept , Familial Mediterranean Fever/complications , Familial Mediterranean Fever/drug therapy , Familial Mediterranean Fever/immunology , Female , Humans , Male , Middle Aged , Molecular Sequence Data , Monocytes/immunology , Pedigree , Receptors, Tumor Necrosis Factor, Type I/blood , Receptors, Tumor Necrosis Factor, Type II/blood , T-Lymphocyte Subsets/immunology , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/immunologyABSTRACT
BACKGROUND: Immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome) is a rare autosomal recessive disease characterised by facial dysmorphism, immunoglobulin deficiency and branching of chromosomes 1, 9 and 16 after PHA stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients which is explained by mutations in the DNA methyltransferase gene DNMT3B in some, but not all, ICF patients. OBJECTIVE: To obtain a comprehensive description of the clinical features of this syndrome as well as genotype-phenotype correlations in ICF patients. METHODS: Data on ICF patients were obtained by literature search and additional information by means of questionnaires to corresponding authors. RESULTS AND CONCLUSIONS: 45 patients all with proven centromeric instability were included in this study. Facial dysmorphism was found to be a common characteristic (n = 41/42), especially epicanthic folds, hypertelorism, flat nasal bridge and low set ears. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (n = 39/44). Opportunistic infections were seen in several patients, pointing to a T cell dysfunction. Haematological malignancy was documented in two patients. Life expectancy of ICF patients is poor, especially those with severe infections in infancy or chronic gastrointestinal problems and failure to thrive. Early diagnosis of ICF is important since early introduction of immunoglobulin supplementation can improve the course of the disease. Allogeneic stem cell transplantation should be considered as a therapeutic option in patients with severe infections or failure to thrive. Only 19 of 34 patients showed mutations in DNMT3B, suggesting genetic heterogeneity. No genotype-phenotype correlation was found between patients with and without DNMT3B mutations.
Subject(s)
Chromosomal Instability , Craniofacial Abnormalities/genetics , Immunologic Deficiency Syndromes/genetics , Adolescent , Adult , Centromere/genetics , Child , Child, Preschool , Craniofacial Abnormalities/pathology , DNA (Cytosine-5-)-Methyltransferases/genetics , Female , Genotype , Humans , Infant , Male , Mutation , Phenotype , Syndrome , DNA Methyltransferase 3BABSTRACT
BACKGROUND: Administration of two doses of hepatitis A (HA) vaccine to children > or = 2 years of age has been shown to be protective. The present study assessed whether HA vaccine can be administered as early as 6 months of age and whether it can be administered concomitantly with a hexavalent (HV) vaccine at this age. METHODS: In an open label, randomized, parallel group study, the liquid HV vaccine (HEXAVAC) (diphtheria, tetanus, 2-component acellular pertussis, inactivated poliomyelitis vaccine, Haemophilus influenzae type b conjugated to tetanus protein and hepatitis B) was administered at 2, 4, 6, and 12 months of age to all children. HA vaccine (VAQTA) was given at 7 and 13 months in the separate administration group (Group 1) and at 6 and 12 months in the concomitant administration group (Group 2). Serum samples were obtained at 2, 7, 12, and 14 months in Group 1 and at 2, 7, 12, and 13 months in Group 2. The primary immunogenicity outcomes were the seroconversion rates for HA 1 month after the second dose of HA vaccine in initially seronegative subjects, and the seroconversion rates for each HV antigen 1 month after the third dose of the HV vaccine (both at 7 months of age). RESULTS: HA seropositivity rates 1 month after the second dose were 100% in both groups, regardless of initial serostatus. The responses to each HV antigen 1 month after the third dose were similar in both groups. The vaccines were generally well tolerated in both groups regardless of vaccine(s) administered. CONCLUSIONS: A schedule of two doses of HA vaccine, 6 months apart beginning at 6 months of age is highly immunogenic and well tolerated when administered alone or concomitantly with HV vaccine at 6 and 12 months of age.
Subject(s)
Hepatitis A Vaccines/immunology , Vaccines, Combined/immunology , Age Factors , Child, Preschool , Female , Hepatitis A Antibodies/blood , Hepatitis A Vaccines/administration & dosage , Hepatitis A Vaccines/adverse effects , Humans , Immunization Schedule , Infant , Infant, Newborn , Male , Vaccines, Combined/administration & dosage , Vaccines, Combined/adverse effectsABSTRACT
OBJECTIVE: To define non-bacterial osteitis (NBO) as a clinical entity possibly associated with autoimmune manifestations. Patients with sterile osteitis were analysed to develop diagnostic criteria. METHODS: A total of 89 patients with non-bacterial inflammatory bone lesions were observed for a median of 49 months. History, diagnostic imaging, laboratory and histological data were obtained. Mutation analysis in the genes PSTPIP1 and PSTPIP2 was performed. RESULTS: Patients had an onset of disease at a median age of 10 yrs [interquartile range (IQR) 7.5-12] and suffered a median period of 21 (IQR 9-52) months with a median of three foci per patient. Twenty percent of all the patients demonstrated associated autoimmune disorders, particularly of the skin and bowel. The majority of bone lesions were located in the vertebrae and metaphyses. Slight-to-moderate elevation of inflammation values were found in all the patients and antinuclear antibodies were elevated in 30%. Non-steroidal anti-inflammatory drugs (NSAIDs) were effective in 85% of the patients. HLA-B27 and Human Leukocyte Antigen-DR (HLA-DR)-classification did not differ from the general population. Autoimmune diseases in 40% of all the families, multiply affected family members, linkage to 18q21 and mouse models strongly indicate a genetic basis for NBO. We observed three different courses of disease regarding the duration of complaints, rate of complications and associated autoimmune manifestations leading to a new classification of NBO. CONCLUSIONS: Clinical analysis of our cohort leads us to define NBO as a distinct disease entity with three clinical presentations: acute NBO, chronic recurrent multifocal osteomyelitis or persistent chronic NBO. Diagnostic criteria were proposed to differentiate NBO from diseases with similar clinical presentation.
Subject(s)
Autoimmune Diseases/diagnosis , Osteitis/diagnosis , Adaptor Proteins, Signal Transducing/genetics , Adolescent , Adult , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Child , Child, Preschool , Chronic Disease , Cytoskeletal Proteins/genetics , Diagnosis, Differential , Female , Fractures, Spontaneous/etiology , Humans , Inflammation Mediators/blood , Male , Middle Aged , Mutation , Osteitis/complications , Osteitis/genetics , Osteitis/immunology , Prognosis , Recurrence , Retrospective Studies , Spinal Fractures/etiologyABSTRACT
Invasive fungal infections are usually associated with immunocompromised states About 40-60% of these patients are refractory to standard antifungal therapy We describe the effect of posaconazole in the treatment of a 12 years-old girl with uncontrolled diabetes mellitus with life-threatening cerebral mucor mycosis and a 4 year old girl boy with chronic granulomatous disease presenting with invasive Aspergillus nidulans infection.
Subject(s)
Antifungal Agents/therapeutic use , Aspergillosis/drug therapy , Central Nervous System Fungal Infections/drug therapy , Lung Diseases, Fungal/drug therapy , Mucormycosis/drug therapy , Sinusitis/drug therapy , Triazoles/therapeutic use , Antifungal Agents/administration & dosage , Aspergillosis/microbiology , Aspergillus nidulans/drug effects , Aspergillus nidulans/isolation & purification , Central Nervous System Fungal Infections/microbiology , Child , Child, Preschool , Diabetes Mellitus, Type 1/complications , Drug Resistance, Fungal , Female , Granulomatous Disease, Chronic/complications , Humans , Immunocompromised Host , Lung Diseases, Fungal/microbiology , Male , Mucormycosis/microbiology , Rhizopus/drug effects , Rhizopus/isolation & purification , Sinusitis/microbiology , Treatment Outcome , Triazoles/administration & dosageABSTRACT
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.
Subject(s)
Acyclovir/therapeutic use , Antiviral Agents/therapeutic use , Encephalitis, Viral/drug therapy , Focal Infection/drug therapy , Herpes Simplex/drug therapy , Interferon-beta/therapeutic use , Adolescent , Child , Child, Preschool , Double-Blind Method , Drug Therapy, Combination , Encephalitis, Viral/pathology , Encephalitis, Viral/physiopathology , Female , Focal Infection/pathology , Herpes Simplex/pathology , Humans , Infant , Male , Nervous System/pathology , Nervous System/physiopathology , Recombinant Proteins/therapeutic use , Recovery of Function/drug effects , Treatment OutcomeABSTRACT
Hyper-IgE syndrome is a rare primary immunodeficiency of unknown etiology characterized by recurrent infections of the skin and respiratory system, chronic eczema, elevated total serum IgE, and a variety of associated skeletal symptoms. Recent reports about susceptibility to pyogenic bacterial infections and high IgE levels in patients and animals with defects in toll-like receptor (TLR) signaling pathways prompted us to search for TLR signaling defects as an underlying cause of hyper-IgE syndrome. Blood samples from six patients with hyper-IgE syndrome were analyzed for serum cytokine levels, intracellular cytokine production in T cells after stimulation with PMA/ionomycin, and cytokine production from peripheral blood mononuclear cells stimulated by TLR ligands and bacterial products including LPS (TLR4), peptidoglycan (TLR2), PolyIC (TLR3), R848 (TLR7/8), CpG-A, and CpG-B (TLR9), zymosan and heat killed Listeria monocytogenes. All results were compared to data from healthy controls. A reduction in IFN-gamma, IL-2, and TNF-alpha producing T cells after PMA stimulation suggested a reduced inflammatory T cell response in patients with hyper-IgE syndrome. Increased serum levels of IL-5 indicated a concomitant Th2 shift. However, normal production of cytokines (TNF-alpha, IL-6, IL-10, IFN-alpha, IP-10) and upregulation of CD86 on B cells and monocytes after TLR stimulation made a defect in TLR signaling pathways highly unlikely. In summary, our data confirmed an imbalance in T cell responses of patients with hyper-IgE syndrome as previously described but showed no indication for an underlying defect in toll-like receptor signaling.
Subject(s)
Job Syndrome/immunology , Signal Transduction/immunology , Toll-Like Receptors/physiology , Adolescent , Adult , Candidiasis/immunology , Child , Child, Preschool , Cytokines/biosynthesis , Cytokines/blood , Female , Genetic Predisposition to Disease , Humans , Immunoglobulin E/biosynthesis , Immunoglobulin E/blood , Infant , Job Syndrome/blood , Job Syndrome/microbiology , Ligands , Male , Staphylococcal Infections/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Toll-Like Receptors/metabolismABSTRACT
HISTORY AND ADMISSION FINDINGS: A 64 year old man complained about progressive pain in his right upper leg and pelvis since 4 weeks without any history of trauma. He noticed a reduced general health status for several months with weight loss and subfebrile temperatures. The patient's medical history revealed several malignant tumours and recurrent infections with atypical mycobacteria and herpes viruses. INVESTIGATIONS: Laboratory findings showed signs of chronic inflammation. Multiple disseminated osteolytic bone lesions, hepatosplenomegaly, lymphadenopathy and multiple splenic lesions were detected by CT scan. Mycobacterium avium was isolated from an osteolytic lesion of the pelvic bone. Malignant disease and acquired immunodeficiency syndrome were excluded. Lymphocyte counts showed lymphocytopenia with reduced T cells, B cells and a reduced CD4-/CD8-ratio. Interferon-gamma-pathway defects as described in patients with susceptibility to atypical mycobacteria could not be identified. TREATMENT AND COURSE: Clinical and immunologic findings indicated a link between recurrent Mycobacterium avium infections and an idiopathic CD-4 T-cell lymphopenia (low CD4 syndrome). Antimycobacterial treatment at standard doses was started according to the resistance test obtained from microbiological culture. Medical and radiological checkup after 3 months of therapy showed signs of progressive disease. CONCLUSIONS: Osteolytic lesions can be caused by mycobacterium avium infection. Disseminated atypical mycobacteriosis is an opportunistic disease in patients with congenital or acquired immunodeficiency syndrome.