Incidence of and mortality from epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) in France during 2003-16: a four-source capture-recapture estimate.

BACKGROUND: Because of its rarity, the exact incidence of and mortality from epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) is difficult to establish and closely depends on the size and type of the data source. OBJECTIVES: To estimate the incidence of and mortality due to epidermal necrolysis in France over a 14-year period. METHODS: Data from four national databases were analysed. A capture-recapture analysis was performed. RESULTS: A total of 2635 incident cases of epidermal necrolysis were recorded in at least one of the four databases during the study period [males: 47·9%; median age: 52 (interquartile range 25-72) years]. On capture-recapture analysis, the estimated total number of cases was 5686, for an overall estimated annual incidence of 6·5 (95% confidence interval 4·1-8·9) cases per million inhabitants. The estimated annual incidence rates were 4·1 (0·3-7·9) cases per million inhabitants < 20 years of age, 3·9 (1·5-6·3) cases per million inhabitants aged 20-64 years and 13·7 (5·4-22·0) cases per million inhabitants ≥ 65 years of age. The estimated overall annual mortality rate from epidermal necrolysis was 0·9 (0·1-1·8) case per million inhabitants. It was 0·6 (0·1-1·5) case per million inhabitants aged 20-64 years and 2·8 (0·9-6·6) cases per million inhabitants ≥ 65 years of age (deaths in people < 20 years old were too rare to provide an accurate estimate). CONCLUSIONS: The annual incidence of epidermal necrolysis is higher than the one to five cases per million inhabitants usually reported. Such estimations could be helpful in establishing appropriate healthcare plans for people with epidermal necrolysis, in particular the need for specialized care units. What's already known about this topic? Few data are available regarding incidence of and mortality from epidermal necrolysis in the general population. Experts in epidermal necrolysis have recently proposed an annual incidence of one to five cases per million individuals. The overall mortality rate is usually reported to be between 10% and 20%. What does this study add? Using a four-source capture-recapture method and data from a 14-year period (2003-16), the annual incidence of and mortality from epidermal necrolysis were estimated to be 6·5 (95% confidence interval 4·1-8·9) and 0·9 (0·1-1·8) cases per million French inhabitants, respectively. Such estimations could be helpful in establishing appropriate healthcare plans, in particular the need for specialized care units.

[Epidemiology of Behçet's disease]. / Épidémiologie de la maladie de Behçet.

With more than 30 published prevalence estimates for Behçet's disease (BD), covering many different regions worldwide, the prevalence of BD is quite well described. Even though the interpretation of these data is complicated by between-study differences in methodology, which may substantially influence the results, these data suggest large geographic variations in frequency of BD, with prevalence rates of 20-420/100,000 inhabitants for Turkey, 2.1-19.5 for other Asian countries, 1.5-15.9 for southern Europe and 0.3-4.9 for northern Europe. Additional epidemiological studies or case series from North and South America, the Caribbean Islands, and individuals of sub-Saharan ancestry further suggest that the geographic distribution of BD is much wider than the boundaries of the ancient Silk Road. The few available incidence rates prevent from making strong inferences as to whether the frequency of BD has changed over time. Recent population-based studies of immigrants or migrant populations consistently indicate that migrants from areas of high BD prevalence remain at high risk for BD, which may even be close to the prevalence observed in their countries of origin. Genetic factors, which are not detailed in this review, seem to play a preponderant role in BD development, although they cannot explain the wide between-country disparities in BD prevalence. However, environmental risk factors, including infectious and non-infectious causes, remain poorly investigated and have not yet produced solid hints.

[Clinical aspects and treatment of recurrent aphthous ulcers]. / Klinik und Therapie chronisch rezidivierender Aphthen.

Recurrent aphthous ulcers are the most common inflammatory lesions of the oral mucosa, occurring in up to 10% of the population and even more common in children. The history, morphological characteristics, predilection sides and typical stages of aphthae help to distinguish them from other diseases that may exhibit aphthous-like lesions. Underlying diseases should be excluded. The main goals of therapy are to minimize pain and functional disabilities as well as decrease frequency and severity of recurrences. Topical symptomatic relief is the standard of care for simple cases of recurrent aphthosis. In cases of major aphthosis or systemic involvement, topical therapies are still useful but should be combined with systemic therapy, such as colchicine, pentoxifylline or prednisolone. In case of Adamantiades-Behçet disease, systemic immunomodulatory drugs can inhibit the development of new lesions. This overview summarizes morphological and presentation forms of aphthae, differential diagnoses and evidence-based therapeutic possibilities.

[Epidemiology and clinical aspects of Adamantiades-Behçet disease in Gemany. Current data]. / Epidemiologie und Klinik des Morbus Adamantiades-Behçet in Deutschland. Aktuelle Daten.

Of the 721 documented patients in the German Registry for Adamantiades-Behçet disease (registered charity), 258 were of German and 308 of Turkish descent, along with 30 other countries of origin. The prevalence in Germany is 0.9:100,000. Manifestation of the disease was predominantly in the third decade of life (median age: 26.5 years) and in 10.7% the disease onset was under 16 years of age. The full clinical picture developed on average in 2.9 years (median 3 months). Patients of Turkish descent showed androtopism in contrast to those of German descent (female:male 1.9:1), which was also detected in the whole collective in a ratio of 1.4:1. In 12.4% there was a family history with differences between German and Turkish patients (3.8% versus 14.6%) as well as in patients with disease onset in young and adult age (25.0% versus 7.3%). Most frequent features included oral aphthae (98.5%), cutaneous lesions (81%), genital ulcers (64.7%), ocular manifestations (51.6%), arthritis (52.4%) and positive pathergy test (30.8%). Turkish patients suffered significantly more often from eye manifestations compared with Germans, while in German patients prostatitis/epididymitis and gastrointestinal involvement were more frequently documented. As serious complications arose blindness 6.8%, meningoencephalitis 4.0%, severe arthritis 2.6%, fatal outcome 1.2%, hemoptysis 1.1% and gastrointestinal perforation 0.5%. The HLA-B5 antigen was positive in 58.1% and showed an association with eye manifestations. The relative risk of HLA-B5 positive individuals is high in both Germans (6.57) and Turks (5.81).

[Pathogenic role of antimyeloperoxidase antibodies]. / Rôle pathogène des anticorps antimyéloperoxydase.

Antimyeloperoxidase antibodies are a variety of antineutrophil cytoplasm antibodies (Anca), which can be detected in systemic small-sized vessel vasculitides such as microscopic polyangiitis, Wegener's granulomatosis and Churg-Strauss syndrome. Antimyeloperoxidase antibodies have been also associated with the development of lung fibrosis. Their pathogenic role has been well established, both in vitro and in vivo. These autoantibodies can activate neutrophils and trigger their oxidative burst leading to the release of free oxygen species and cytotoxic proteins. The oxidative burst is deleterious for the endothelium. Another mechanism by which antimyeloperoxidase may act is the activation of myeloperoxydase leading to an increased production of hypochlorous acid, which is highly toxic for the endothelial cells. These mechanisms contribute to the development of vasculitis.

Immunomagnetic isolation of CD4+CD25+FoxP3+ natural T regulatory lymphocytes for clinical applications.

Although CD4(+)/CD25(+) T regulatory cells (T(regs)) are a potentially powerful tool in bone marrow transplantation, a prerequisite for clinical use is a cell-separation strategy complying with good manufacturing practice guidelines. We isolated T(regs) from standard leukapheresis products using double-negative selection (anti-CD8 and anti-CD19 monoclonal antibodies) followed by positive selection (anti-CD25 monoclonal antibody). The final cell fraction (CD4(+)/CD25(+)) showed a mean purity of 93.6% +/- 1.1. Recovery efficiency was 81.52% +/- 7.4. The CD4(+)/CD25(+bright) cells were 28.4% +/- 6.8. The CD4(+)/CD25(+) fraction contained a mean of 51.9% +/- 15.1 FoxP3 cells and a mean of 18.9% +/- 11.5 CD127 cells. Increased FoxP3 and depleted CD127 mRNAs in CD4(+)CD25(+)FoxP3(+) cells were in line with flow cytometric results. In Vbeta spectratyping the complexity scores of CD4(+)/CD25(+) cells and CD4(+)/CD25(-) cells were not significantly different, indicating that T(regs) had a broad T cell receptor repertoire. The inhibition assay showed that CD4(+)/CD25(+) cells inhibited CD4(+)/CD25(-) cells in a dose-dependent manner (mean inhibition percentages: 72.4 +/- 8.9 [ratio of T responder (T(resp)) to T(regs), 1:2]; 60.8% +/- 20.5 (ratio of T(resp) to T(regs), 1:1); 25.6 +/- 19.6 (ratio of T(resp) to T(regs), 1:0.1)). Our study shows that negative/positive T(reg) selection, performed using the CliniMACS device and reagents, enriches significantly CD4(+)CD25(+)FoxP3(+) cells endowed with immunosuppressive capacities. The CD4(+)CD25(+)FoxP3(+) population is a source of natural T(reg) cells that are depleted of CD8(+) and CD4(+)/CD25(-) reacting clones which are potentially responsible for triggering graft-versus-host disease (GvHD). Cells isolated by means of this approach might be used in allogeneic haematopoietic cell transplantation to facilitate engraftment and reduce the incidence and severity of GvHD without abrogating the potential graft-versus-tumour effect.

Selective up-regulation of functional CXCR4 expression in erythroid cells by HIV-1 Tat protein.

CXCR4 is the high affinity receptor for the SDF-1 alpha chemokine and represents the main coreceptor for HIV-1 T-tropic strains. The surface expression of CXCR4 was analysed in CD34+ haematopoietic progenitors, induced to differentiate along the erythroid or granulocytic lineages, in liquid cultures supplemented or not with HIV-1 Tat protein. At concentrations as low as 1-10 ng/ml, synthetic Tat protein significantly increased the surface expression of CXCR4 in erythroid but not in granulocytic cells. The Tat-mediated up-regulation of surface CXCR4 was accompanied by a concomitant increase of CXCR4 mRNA and total CXCR4 protein content in cells developing along the erythroid lineage after 6-10 days of culture. Moreover, addition of SDF-1 alpha (200 ng/ml) induced a significant higher rate of apoptosis in Tat-treated erythroid cells in comparison with control cells. These results demonstrated for the first time a direct positive role in haematopoietic gene regulation of Tat protein, and suggest the possible involvement of Tat in HIV-1-induced anaemia.

HIV-1 Tat protects CD4+ Jurkat T lymphoblastoid cells from apoptosis mediated by TNF-related apoptosis-inducing ligand.

We have here investigated the effect of TNF-related apoptosis-inducing ligand (TRAIL), a new member of the TNF cytokine superfamily, on the survival of Jurkat lymphoblastoid cell lines stably transfected with plasmids expressing the wild-type or mutated (Cys22) human immunodeficiency virus type 1 (HIV-1) tat gene. Jurkat cells transfected with wild-type tat were resistant to TRAIL-mediated apoptosis, while Jurkat cells mock-transfected with the control plasmid or with a mutated nonfunctional tat cDNA were highly susceptible to TRAIL-mediated apoptosis. Also, pretreatment with low concentrations (10-100 ng/ml) of extracellular synthetic Tat protein partially protected Jurkat cells from TRAIL-mediated apoptosis. Taken together, these results demonstrated that endogenously expressed tat and, to a lesser extent, extracellular Tat block TRAIL-mediated apoptosis. Since it has been shown that primary lymphoid T cells purified from HIV-1-infected individuals are more susceptible than those purified from normal individuals to TRAIL-mediated apoptosis, our findings underscore a potentially important role of Tat in protecting HIV-1-infected cells from TRAIL-mediated apoptosis.

Viral load trend in HIV-1 seropositive patients with different CD4 cell counts before starting HAART.

BACKGROUND: The efficacy of highly active antiretroviral therapy (HAART) was prospectively monitored in HIV-1 seropositive patients by analyzing HIV-1 RNA viral load. OBJECTIVES: The aim of the study was to evaluate the viral load course in two different groups of patients (group 1: CD4>400/mm(3), group 2: CD4<200/mm(3)) during a period ranging from 9 to 25 months. STUDY DESIGN: HIV-1 viral load, at the start and during HAART, was analyzed in 117 patients who had previously been treated only with two anti-transcriptase drugs but were naive for protease inhibitors. RESULTS: The results showed that, after the beginning of therapy, high plasma HIV-1 RNA levels dropped to undetectable values (<50 copies HIV-RNA/ml) in one third of patients over a mean period of about 9 months irrespective of the initial CD4 cell count, even though a viral reduction of at least 2log(s) in a significantly shorter period of time (P<0.001) was observed only among patients who began retroviral therapy with a higher CD4 cell count. CONCLUSION: The response to HAART was not dramatically affected by the initial CD4 count. Though restricted to a small number of subjects, the data support the idea that therapeutic intervention can be effective even in an advanced stage of HIV-1 infection, when patients show a decreased number of CD4 T-lymphocytes.

In a human lymphomyeloid progenitor cell line (KG-1) HIV-1 gp120 binds to chemokine-receptors CXC-R4 and CCR5, only in the presence of CD4.

A CD34+ human hematopoietic progenitor cell lines, KG-1, became susceptible to HIV-1 infection in the presence of a concurrent infection by human herpesvirus-6 (HHV-6). We have now analyzed the possible mechanism(s) underlying this phenomenon, in the light of the recent demonstration that at least two members of the chemokine receptor family, CXCR4 (LESTR/fusin) and CCR5 molecules, are the HIV-1-specific co-receptors, necessary, together with the high affinity receptor CD4, for the entry into target cells of HIV-1. Cytofluorimetric analysis demonstrated that in KG-1 cells, after HHV-6 infection, more than 40% of cell population became CD4 positive and only in KG-1 cells expressing the CD4+ phenotype, the exposure to r-gp120 masks a significant amount, not only of CD4, but also of both CXCR4 and CCR5 chemokine receptors. In fact, only when pre-infected by HHV-6, KG-1 cells, after exposure to r-gp120, exhibit a significant reduction in the percentage of CXCR4 or CCR5-positive cells.

A comparison of immunocomplex-dissociated serum HIV-1 p24 antigenemia and plasma HIV-1 viral load: assessment of 3,129 paired assays.

In order to compare HIV-1 p24 antigenemia and plasma HIV-1 RNA levels as markers of viral replication, 3,129 paired determinations of alkaline immunocomplex-dissociated serum HIV-1 p24 antigenemia (performed with an immunoenzymatic assay), and plasma HIV-1 RNA levels (carried out with a branched DNA method, a reverse transcriptase-coupled polymerase chain reaction, and a nucleic acid sequence-based assay) were assessed over a two-year-period. When excluding samples with undetectable plasma HIV-1 RNA levels (which tested negative or borderline positive at serum p24 antigen assay in 97.9% of cases), immunocomplex-dissociated p24 antigenemia proved significantly less sensitive than viral load at all considered HIV-1 RNA reference levels, although the profile of positive serum p24 antigen assays (values above 10 pg/ml) paralleled the trend of plasma HIV-1 viral load, especially at higher levels. However, serum HIV-1 p24 antigenemia (even after immunocomplex dissociation) can be longer suggested as a the sole virological tool in the laboratory management of HIV-1 infection, due to its significantly lower sensitivity levels compared with viral load assessment.