Hereditary angioedema (HAE) in children and adolescents--a consensus on therapeutic strategies.

Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short-term and long-term prophylaxis.

[Interdisciplinary AWMF guideline for the treatment of primary antibody deficiencies]. / Interdisziplinäre AWMF-Leitlinie zur Therapie primärer Antikörpermangelerkrankungen.

BACKGROUND: Currently, management of antibody deficient patients differs significantly among caregivers. Evidence and consensus based (S3) guidelines for the treatment of primary antibody deficiencies were developed to improve the management of these patients. METHODS: Based on a thorough analysis of current evidence (systematic literature search in PubMed; deadline November 2011) 14 recommendations were finalized during a consensus meeting in Frankfurt in November 2011 using structured consensus methods (nominal group technique). Experts were nominated by their scientific societies/patient initiatives (Tab. 1). RESULTS: The guidelines focus on indication, practical issues and monitoring of immunoglobulin replacement therapy as well as on different routes of administration. Furthermore recommendations regarding supportive measures such as antiinfective therapy, vaccinations and physiotherapy are given. Combining literature evidence and experience of caregivers within this evidence and consensus based guidelines offers the chance to improve the quality of care for anti-body deficient patients.

[Diagnostics and exclusion of hereditary angioedema : a standarized approach for the practice]. / Diagnostik und Ausschluss des hereditären Angioödems : Ein standardisierter Ansatz für die Praxis.

The differentiation between mast cell mediator-mediated and bradykinin-mediated forms of angioedema can be difficult. Bradykinin-mediated hereditary angioedema is a rare autosomal dominant hereditary disease which is characterized by recurrent edema attacks of varying magnitude. The edema occurs in the skin and mucous membranes and can be temporarily disfiguring, very painful and life-threatening by attacks in the laryngeal region. Because of the multitude of differential diagnoses, a final diagnosis is only achieved after an average duration of more than 10 years. The anamnestic and laboratory diagnostic algorithm presented here is designed to assist a simpler differentiation of the various forms of angioedema and to reach the correct diagnosis more quickly.

Efficacy and safety of Hizentra(®) in patients with primary immunodeficiency after a dose-equivalent switch from intravenous or subcutaneous replacement therapy.

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.

Hyperbilirubinemia and rapid fatal hepatic failure in severe combined immunodeficiency caused by adenosine deaminase deficiency (ADA-SCID).

Adenosin deaminase (ADA) deficiency is the cause for Severe Combined Immunodeficiency (SCID) in about 15% of patients with SCID, often presenting as T (-)B (-)NK (-)SCID. Treatment options for ADA-SCID are enzyme replacement, bone marrow transplantation or gene therapy. We here describe the first patient with ADA-SCID and fatal hepatic failure despite bone marrow transplantation from a 10/10 HLA identical related donor. As patients with ADA-SCID may be at yet underestimated increased risk for rapid hepatic failure we speculate whether hepatitis in ADA-SCID should lead to the immediate treatment with enzyme replacement by pegylated ADA.

A 12-year-old boy with multidrug-resistant human immunodeficiency virus type 1 successfully treated with HAART including ritonavir-boosted tipranavir oral solution and enfuvirtide.

For intensively pretreated pediatric patients with human immunodeficiency virus type 1 (HIV-1) infection, the treatment options available are limited. We report the case of a highly treatment-experienced 12-year-old boy with multidrug-resistant HIV-1, who was successfully treated with highly active antiretroviral therapy (HAART) including ritonavir-boosted tipranavir oral solution, a novel non-peptic protease inhibitor, and enfuvirtide.

Delayed onset of (severe) combined immunodeficiency (S)CID (T-B+NK+): complete IL-7 receptor deficiency in a 22 months old girl.

BACKGROUND: Usually IL-7 receptor deficiency presents as (T-B+NK+) (Severe) Combined Immunodeficiency (SCID) within the first six months of life. All published IL-7R-deficient patients so far have been diagnosed and received stem cell transplantation within the first year of life. PATIENT AND METHODS: We present a female patient born to non-consanguineous German parents with delayed manifestation. She presented with superinfected dermatitis at 6 months of life and developed a first pneumonia at age 9 months. On admission to our department at 22 months the patient presented with severe T cell lymphopenia. PNEUMOCYSTIS JIROVECI pneumonia was diagnosed from broncho-alveolar lavage fluid. RESULTS: Sequencing of IL7RA in the patient revealed compound heterozygous mutations. FACS analysis showed no expression of IL-7 receptor alpha-chain on the patient's lympho- and monocytes. The patient successfully received haematopoietic stem cell transplantation from a 9/10 matched unrelated donor at age 24 months. CONCLUSION: [corrected] Despite almost absent T cell functions clinical symptoms occurred late compared to previously published patients. Thus even in patients with moderate clinical symptoms and delayed onset a (T-B+NK+) (Severe) Combined Immunodeficiency ((S)CID)) due to missing IL-7 receptor signalling must be considered.

Expression of mRNA for the proto-oncogene c-fos in rat basophilic leukaemia cells.

Recently, the expression of the mRNA for the proto-oncogene c-fos following activation of the high-affinity receptor for immunoglobulin E in rodent mast cells has been reported. In the present study we investigated different biochemical events that may play a role in signal transduction pathways culminating in the expression of c-fos mRNA in rat basophilic leukaemia cells. Similar to IgE-mediated cell degranulation we demonstrated inhibition of the c-fos signal in the absence of calcium and after preincubation of cells with the protein tyrosine kinase inhibitor genistein. Activation of RBL-2H3 cells by short term PMA treatment failed to induce cell degranulation or expression of mRNA for c-fos. Depletion of protein kinase C by PMA pre-treatment resulted in substantial inhibition of the c-fos signal. In contrast to IgE-mediated cell degranulation, expression of mRNA for c-fos was not dependent on continued receptor aggregation. In addition, we demonstrate that c-fos mRNA expression is not restricted to Fc epsilon RI activation but can be induced by a variety of IgE independent mechanisms including calcium influx by ionophore A 23187 and stimulation of G proteins.

Anti-ganglioside monoclonal antibody AA4 selectively inhibits IgE-induced signal transduction pathways in rat basophilic leukemia cells.

In rat basophilic leukemia 2H3 (RBL-2H3) cells, mAb AA4 binds to two derivatives of ganglioside GD1b that associate with the Src family kinase p53/56lyn and a serine kinase. Pre-incubation of cells with mAb AA4 blocks immunoglobulin E (IgE) mediated histamine release. In the present study we investigated the effect of incubation with mAb AA4 on signal transduction events. In addition to stimulation of the high affinity IgE receptor (Fc epsilonRI), cells were also activated by the calcium ionophore A23187 and the acetylcholine agonist carbachol in RBL-2H3 cells transfected with the G protein-coupled m3 muscarinic receptor. Incubation of cells with mAb AA4 in a dose-dependent manner inhibited the following Fc epsilonRI-induced signal transduction events: the increase of intracellular free calcium, phosphoinositol breakdown, tyrosine phosphorylation of proteins including the beta- of Fc epsilonRI and secretion. However, there was no inhibition of degranulation or of these biochemical events when cells were stimulated with calcium ionophore or activated via a G protein-coupled pathway. Our results demonstrate that mAb AA4 selectively blocks Fc epsilonRI-induced cell activation at a very early step upstream of receptor tyrosine phosphorylation. As mAb AA4 has previously been found to bind to gangliosides associated with Fc epsilonRI, inhibition of very early biochemical events may be due to interaction of mAb AA4 with the Fc epsilonRI induced signal transduction cascade at the receptor level.

Pilot study of zidovudine-lamivudine combination therapy in vertically HIV-infected antiretroviral-naive children.

OBJECTIVE: To examine tolerance and efficacy of a zidovudine plus lamivudine combination in HIV-infected children without previous exposure to antiretroviral drugs. METHODS: Thirteen vertically infected children (aged 4 months to 10 years) were treated with zidovudine (approximately 100 mg/m2 three times daily) and lamivudine (4 mg/kg twice daily). CD4 T-cell count, plasma HIV RNA concentration, complete blood count and blood chemistry profile were monitored before treatment and at months 1, 3 and 6. RESULTS: In general, treatment was well tolerated. One child developed slight neutropenia in the presence of antineutrophil antibodies. CD4 cell count increased from 851+/-621 x 10(6)/l at baseline to 1073+/-945 x 10(6)/l at month 3 (P < 0.05) and to 1133+/-728 x 10(6)/l at month 6 (P = 0.01). CD4+ cell count increased in 10 patients after 3 months and in 11 patients treated for 6 months. One child showed a continuous decrease of CD4 cells despite treatment. Before treatment the plasma HIV RNA concentration was elevated in nine children (> 4.0 log10 copies/ml) and decreased in all of them: by month 1, the mean reduction was -1.16 log10 copies/ml; by month 3, -1.38 log10 copies/ml; and by month 6, -1.53 log10 copies/ml compared with baseline. However, one child showed steadily increasing viral load from 2.7 log10 copies/ml to a maximum of 4.52 log10 copies/ml, surprisingly in association with increasing numbers of CD4 cells. This child was switched to a new combination regimen after 6 months of treatment. Plasma HIV RNA levels below limit of detection were reached in six patients: after 1 month of treatment in one patient, after 3 months in five patients, and after 6 months in six patients. There was a mean reduction of viral load from 4.56 log10+/-4.63 log10 copies/ml (n = 13) to 3.8 log10+/-3.9 log10 copies/ml (P < 0.05; n = 9) after 1 month, to 3.67 log10+/-3.88 log10 copies/ml (P < 0.01; n = 13) after 3 months, and to 3.64 log10+/-3.95 log10 copies/ml after 6 months of treatment (P < 0.001; n = 13). CONCLUSIONS: This pilot study demonstrates the feasibility of zidovudine-lamivudine combination in children not previously exposed to antiretroviral drugs. This promising combination should therefore be evaluated in larger trials.

Association and linkage of atopic dermatitis with chromosome 13q12-14 and 5q31-33 markers.

Atopic dermatitis is a chronic inflammatory skin disease that affects 10-20% of the population. Linkage of atopy, asthma, allergic rhinitis, and total serum IgE levels to several different chromosomal regions have been described extensively, but little is known about the genetic control of atopic dermatitis. We tested for the association and linkage between atopic dermatitis and five chromosomal regions: 5q31-33, 6p21.3, 12q15-24.1, 13q12-31, and 14q11.2/14q32.1-32.3. Marker analysis was performed in two Caucasian populations: (i) 192 unrelated German children with atopic dermatitis and 59 non-atopic children from a German birth cohort study (MAS'90), parental DNA was tested in 77 of 192 children with atopic dermatitis; (ii) 40 Swedish families with at least one family member with atopic dermatitis selected from the International Study of Asthma and Allergy in Children. Evidence for linkage and allelic association for atopic dermatitis was observed for markers on chromosome 13q12-14 and 5q31-33.

Nitric oxide mediates intracytoplasmic and intranuclear zinc release.

We previously described that NO. leads to destruction of ZnS clusters and release of Zn2+ from various proteins including zinc finger transcription factors. To assess the relevance in living cells, we investigated, whether exogenous NO. leads to an increase of cytoplasmic and nuclear free Zn2+. L929 cells, mouse splenocytes, or rat aorta endothelial cells were labeled with Zinquin-E, a Zn2+-specific fluorophore, and were treated with two different spontaneous NO donors, S-nitrosocysteine or DETA/NO. Both NO donors strongly increased the Zn2+-dependent fluorescence in the cellular cytosol and also in nuclei as compared to controls. NO-dependent Zn2+ release in splenocytes was quantitated by flow cytometry. These results show for the first time, that nitrosative stress mediates intracellular and intranuclear Zn2+ release which may be relevant in altering gene expression patterns.

Immunoblot analysis of the eighth component of human complement. Demonstration of subunits and detection of C8 alpha-gamma double and triple bands.

Using SDS-PAGE/immunoblot analysis of the eighth component of human complement, C8, we have been able to demonstrate an 85 kDa C8 alpha-gamma and a 62 kDa C8 beta subunit in normal human serum. Serum from an undiagnosed patient who presented undetectable hemolytic C8 activity possessed only the 85 kDa subunit, suggesting a defect in the C8 beta subunit. Serum of a patient with known C8 alpha-gamma deficiency possessed only the complementary 62 kDa subunit. Both sera used together were able to lyse antibody-sensitized sheep erythrocytes, whereas individual sera could not. Optimum conditions for C8 immunoblotting were determined using small amounts of serum or plasma, during low voltage electrophoresis and a sensitive staining technique (nitrobluetetrazolium/bromochloroindoxylphosphate). Using these conditions, the C8 alpha-gamma subunit was found to be composed of up to three bands, termed C8 alpha-gamma 1, -2 and -3. All three bands were found in pooled normal sera. Individual sera had at least the C8 alpha-gamma 2 and C8 alpha-gamma 3 bands. Two C8 beta-deficient sera from two unrelated patients exhibited only the C8 alpha-gamma 2 and C8 alpha-gamma 3 bands. We conclude that immunoblotting of C8 permits a detailed analysis of the molecular composition of this component and helps to establish a precise diagnosis in inherited C8 deficiencies.

Adverse reactions in selected patients following intravenous infusions of gamma globulin.

Fifteen patients with hypogammaglobulinemia or agammaglobulinemia were treated with intravenous gamma globulin preparation over a 17-month period. The patients were selected for treatment if they had chronic antibody deficiency syndromes associated with increased susceptibility to infections. Levels of circulating immune complexes, C1q, C3, and C3d were determined in serum samples obtained before treatment and immediately following treatment with the gamma globulin. In every patient studied, circulating immune complexes were detectable in the postinfusion samples. Two patients had adverse reactions to the intravenous gamma globulin therapy. Analysis of the serum samples of both of these patients showed that one patient had an autoantibody to IgA and the other had an autoantibody to beta-lipoprotein. Both IgA and beta-lipoprotein were present in the intravenous gamma globulin preparations. Therefore, reaction with each of the autoantibodies by the antigens activated the complement system in vivo with production of split products of C3.

The fat emulsion agglutination test: a reliable and cost effective alternative to the latex agglutination test for rapid bedside CRP measurement.

We compared two tests for bedside C reactive protein (CRP) measurement: the latex agglutination test (LAT) and the fat agglutination test (FAT). FAT is based on the property of CRP to agglutinate fat emulsions in the presence of CaCl2. The sensitivity, specificity and accuracy of FAT and LAT to detect a CRP > 10 mg/l, determined with radial immunodiffusion (n = 500 pediatric patients, CRP range 0- > 80 mg/l), were 91%, 82% and 90% respectively for FAT and 82%, 95% and 85% for LAT. FAT reagent could be stabilized with NaN3 (0.02%) for at least one year, when stored at 4 degrees C (n = 49). NaN3 (0.02%) had no effect on agglutination of FAT (n = 40). In conclusion, in pediatric patients, FAT is a reliable and cost effective alternative to LAT, if serum samples are used.

Acute lethal necrotising pancreatitis in childhood systemic lupus erythematosus--possible toxicity of immunosuppressive therapy.

We report on a 16 year old girl with a three-year history of systemic lupus erythematosus who developed a case of acute lethal haemorrhagic pancreatitis. She presented with high grade fever, skin rash, malaise, and arthralgias. Laboratory lupus activity parameters were markedly elevated. In the absence of renal, pulmonary, cardiac or cerebral involvement, our patient developed pancreatitis leading to pancreatogenic shock. Until 14 days before the onset of pancreatitis, the patient's medications included prednisolone, azathioprine and methotrexate. At autopsy, no autoimmune vasculitis was found in the affected pancreatic tissue. Therefore, an etiologic role of combination therapy had to be considered. Whereas methotrexate has never been reported to be linked to pancreatitis, a few publications describing prednisolone and azathioprine in connection with pancreatitis do exist. Thus, if pancreatitis is not just termed idiopathic, it must be attributed to a combination regimen of drugs including methotrexate. A review of the literature shows that pancreatitis in SLE is rare and has never been associated with methotrexate therapy before.

Glycyl-glutamine improves in vitro lymphocyte proliferation in AIDS patients.

BACKGROUND: Glutamine (Gln) is a major nutrient for rapidly proliferating cells. Unlike glutamine itself, the dipeptide glycyl-glutamine as a source for Gln is stable in aqueous solutions ex vivo. In order to evaluate the possible therapeutic role of glycyl-glutamine on lymphocyte proliferation we investigated its influence on lymphocytes of AIDS patients and healthy controls under stimulation with different mitogens. MATERIAL AND METHODS: Lymphocytes were collected from 11 adult patients suffering from AIDS according to the CDC definition and from 7 adult healthy donors. Glutamine (Gln) and glycyl-glutamine (GlyGln), respectively, were added to cell cultures at concentrations between 0 and 1.0 mmol/l. ConA or SAC served as T or B cell mitogens, respectively. Plasma amino acid levels were determined. RESULTS: Proliferation upon ConA-stimulation with GlyGln-supplementation was similar to Gln-supplementation and peaked dose dependently at 1.0 mmol/l. When SAC was used Gln seemed slightly superior to GlyGln with a peak at 0. 4 mmol/l but the results did not reach the level of statistical significance. An identical response pattern was demonstrated in HIV-patients, however at lower absolute proliferation rates. Normal values could not be restored. Overall, the use of either source of glutamine in equimolar concentrations did not result in major differences of proliferation. Glutamine and glycin plasma levels did not differ between HIV patients and controls. CONCLUSION: GlyGln can be used as a substitute for Gln with regard to lymphocyte proliferation. Lymphocytes from AIDS patients show, as controls do, an enhanced proliferation under supplementation either glutamine source. Supplementation of GlyGln might enhance lymphocyte proliferation and thus improve immunity.

Papillon-Lefèvre syndrome--successful treatment with a combination of retinoid and concurrent systematic periodontal therapy: case reports.

Papillon-Lefevre syndrome is a rare autosomal-recessive congenital differentiation disorder; the external signs are hyperkeratosis of the palms and soles. Intraorally, the most salient manifestations are dystrophic periodontal problems that affect both the primary and permanent dentitions and frequently lead to premature tooth loss. Two children were treated with acitretin 0.5 mg/kg of body weight per day from November 1992 to November 1993, and another child since October 1993. Concurrently, the children received professional oral hygiene care (scaling, root planing, and curettage). The combination of retinoid therapy and periodontal treatment improved the dermatologic and periodontal conditions.