SANI definition of Clinical Remission in Severe Asthma: a Delphi consensus

: Severe Asthma affects about 10% of the asthmatic population, and it is characterized by a low lung function and a higher count of blood leucocytes, mainly eosinophils. To date, various definitions are used in clinical practice and in the literature to identify asthma remission: clinical remission, inflammatory remission, and complete remission. The aim of this work is to highlight a consensus for asthma remission using a Delphi method. In the context of SANI (Severe Asthma Network Italy), accounting for 57 Severe Asthma Centers and more then 2200 patients, a Board of six expert drafted a list of candidate statements in a questionnaire, which has been revised to minimize redundancies and ensure clear and consistent wording for the first round (R1) of the analysis. 32 statements have been included in the R1 questionnaire, and then submitted to a panel of 80 experts, which used a 5-points Likert scale to measure their agreement to each statement. Then, an Interim Analysis of R1 data have been performed, items were discussed and considered to produce a consistent questionnaire for the round 2 (R2) of the analysis. After this, the Board set the R2 questionnaire, which included only the important key topics. Panelists have been asked to vote the statements in the R2 questionnaire afterwards. During R2, the criteria of complete clinical remission (the absence of need for OCS, symptoms, exacerbations/attacks, and a pulmonary function stability) and those of partial clinical remission (the absence of need for OCS, and 2 out of 3 criteria: the absence of symptoms, exacerbations/attacks, and a pulmonary stability) were confirmed. This SANI Delphi Analysis defined a valuable, independent and easy to use tool to test the efficacy of different treatments in patients with severe asthma enrolled into the SANI registry

A Cd3(+)cd8(+) T-cell Population Lacking Cd5 Antigen Expression Is Expanded In Peripheral-blood of Human Immunodeficiency Virus-infected Patients

In this study we analyzed the behavior of a CD3(+) T cell subpopulation lacking CD5 antigen expression in PBMC from HIV-1-infected patients. CD3(+)CD5(-) lymphocytes were greatly increased in peripheral blood of HIV-1(+) patients, accounting for 20.6 +/- 9.9% of the total CD3(+) cells, compared to seronegative individuals (5.5 +/- 3.2%). In both seropositive patients and controls, CD3(+)CD5(-) cells belonged to the CD8(+) compartment; they were nonactivated, TCR alpha/beta(+), naive lymphocytes, and in seronegative individuals preferentially expressed NK cell-associated markers, such as CD11b, CD16, CD56, and CD57. The phenotypic profile of this subset was slightly different in seropositive patients; while TCR expression and CD45RA/RO profile were comparable, CD11b and CD16 expression was lower compared to control figures, while CD56 expression was not changed, and CD57 expression was enhanced. Functional analysis of enriched CD3(+)CD8(+)CD5(-) cells showed an impaired ability to proliferate in response to mitogenic and antigenic stimuli; despite their NK-like phenotype, CD3(+)CD8(+)CD5(-) cells did not exert any NK cytotoxic activity, and only a lectin-dependent cytotoxic potential could be evidenced in this population. These results describe a novel alteration in the lymphocyte phenotypic profile during HIV-1 infection, involving a ''transitional'' population, which shares some properties of the T and of the NK cell lineage. (C) 1995 Academic Press, Inc

Tumor outgrowth in peripheral blood mononuclear cell-injected SCID mice is not associated with early Epstein-Barr virus reactivation

Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disease develops in severe combined immunodeficient (SCID) mice inoculated with peripheral blood mononuclear cells (PBMC) from EBV(+) individuals (SCID/hu mice). In this study, we investigated the contribution of EBV reactivation and de novo infection of B lymphocytes to tumor outgrowth in SCID/hu mice. Evaluation of BZLF-1, an early EBV activation transcript, in cells recovered from the mouse peritoneal cavity within 16 days following PBMC transfer did not reveal EBV reactivation, while BZLF-1 expression was only detected in tumor masses or in vitro established lymphoblastoid cell lines. To confirm these data by a different strategy, we coinjected PBMC from seropositive donors with purified B cells from seronegative donors of different sex. Fluorescence in situ hydridization analysis of the resulting tumor masses disclosed that the overwhelming majority of lymphoma cells originated from the seropositive donor, implying that no substantial in vivo production and transmission of virus had occurred. Further, treatment of SCID/hu mice with ganciclovir did not prevent lymphoma development. Our results suggest that in the SCID/hu mouse, early EBV replication and secondary infection of bystander B cells does not occur, and that the direct outgrowth of the transformed B lymphocytes present within the PBMC inoculum is the predominant mechanism, which leads to lymphoma generation in this experimental model

Antigen-detection, Virus Culture, Polymerase Chain-reaction, and Invitro Antibody-production In the Diagnosis of Vertically Transmitted Hiv-1 Infection

Polymerase chain reaction (PCR), virus culture (V), antigen detection (Ag), and in vitro antibody production (IVAP) assays may be useful for the early detection of vertically transmitted HIV-1 infection in infants under 18 months of age, when a diagnosis cannot be based on seropositivity because of maternal antibody persistence. To assess the reliability of these procedures and to correlate diagnostic results with infection status, 101 children born to HIV-1-seropositive mothers were evaluated by all these techniques within the first 6 months of life. The children were then followed up to the age of at least 18 months, when diagnosis was made on the basis of AIDS or AIDS-related complex (ARC) onset or persistence of HIV-1 seropositivity. Out of 27 children classified as infected according to the above criteria, 25 (92.5%) were repeatedly positive in IVAP test, 22 (81.5%) in the first PCR analysis, and only 19 (70.3%) in the initial V assay. On further testing, a total of 24 children (88.9%) were found positive in PCR assay, and 23 (85.2%) in V test. All these assays were found to be more sensitive than antigen detection for HIV-1 infection diagnosis, but the antigenaemia was shown to be a useful prognostic marker of disease onset. We also found that both Ag and IVAP assays could give false-positive results in the first 2 months of life, which severely limits their diagnostic value during this period of time. False-positive results in PCR assay could occur at any time of the tested period and were unrelated to the child's age. Interestingly, positive results in both PCR and V assays were obtained in three out of 74 asymptomatic children who lost HIV-1 antibodies

In-vitro Spontaneous Production of Anti-siv Antibodies Is A Reliable Tool In the Follow-up of Protection of Siv-vaccinated Monkeys

To assess the reliability of the spontaneous in vitro synthesis of simian immunodeficiency virus (SIV)-specific antibodies as a marker in the monitoring of protection in SIV-vaccinated animals, Macaca fascicularis monkeys were immunized with formalin-inactivated SIV(mac)251 or SIV(mac)251/32H, and challenged with human-derived (SIV(mac)251/32H) or monkey-derived live SIV. As judged by virus isolation and polymerase chain reaction (PCR) techniques, immunized animals were protected against human-derived SIV challenge, and no spontaneous in vitro synthesis of anti-SIV antibody was observed in nonstimulated peripheral blood mononuclear cell cultures over a 4-month follow-up. On the contrary, human cell-grown SIV(mac)251 immunization did not afford protection against monkey-derived SIV, and all the animals became infected and showed spontaneous in vitro synthesis of anti-SIV antibodies. These data demonstrate that lack of protection in SIV-vaccinated monkeys is strictly associated with PBMC ability of spontaneously produce anti-SIV antibodies in vitro following challenge, and suggest that this parameter might also constitute a reliable marker for monitoring protection in large-scale HIV vaccination and immunotherapy programs

Weight, height and human immunodeficiency virus infection in young children of infected mothers. The European Collaborative Study

In a longitudinal study of weight and height over the first 4 years of life, 123 human immunodeficiency virus (HIV)-infected and 654 uninfected children of similar social background were compared. By 3 months of age there was a 400-g (8.0%) difference in weight and an 0.8-cm (1.3%) difference in height between infected and uninfected children. After age 1 year the differences stabilized and infected children were, on average, approximately 6% less heavy and 2% shorter than uninfected children. Most of the weight difference was explained by differences in height, particularly after age 1 year. Although statistically significant the difference between infected and uninfected children was small. Weight and height measurements were not useful indicators of infection. Before 6 months of age differences in weight velocity could not be explained by HIV-related morbidity and might have been related to a primary HIV infection. At older ages growth failure associated with HIV infection could be attributed to secondary HIV-related morbidit

B-cell Activation During Hiv-1 Infection .2. Cell-to-cell Interactions and Cytokine Requirement

This study examined the mechanisms underlying the intense activation of HIV-1-specific B cells observed in peripheral blood of HIV-1-infected subjects. Spontaneous in vitro synthesis of anti-HIV-1 antibodies, as well as total Ig production, were dramatically reduced by accessory cell, but not T cell removal. This fall was counteracted by addition of rIL-6, but not other cytokines, to monocyte-depleted cultures; moreover, antisera against IL-6 suppressed spontaneous anti-HIV-1 antibody synthesis in a dose-dependent manner. Although IL-6 apparently sustained HIV-1-specific B cell activation, no increase in serum IL-6 levels was observed; PBMC from seropositive subjects did not produce increased amounts of IL-6 in vitro, compared to seronegative controls, both spontaneously and in the presence of LPS stimulation; finally, no constitutive expression of IL-6 gene could be documented in freshly isolated PBMC. These findings indicate that IL-6 may play a central role in HIV-1-specific B cell activation in seropositive patients, and further stress the importance of this cytokine during HIV-1 infection

Vaccination of Pregnant Cynomolgus Monkeys With Whole Formalin-inactivated Siv(mac251)

Five pregnant (two to three and one-half months) Macaca fascicularis seroconverted following immunization with sucrose-gradient purified and formalin-inactivated whole simian immunodeficiency virus (SIV(mac251)). No untoward effects on fetal maturation were observed during the immunization of the mothers. Antibodies to SIV(mac251) (also those with in vitro neutralizing activity) were passively transferred to the offspring but disappeared within two to six months after birth. Antibodies to env glycoprotein (gp130) lasted longer than those against viral gag proteins (p26,p60)

Immunization of Macaca-fascicularis With Inactivated Siv Preparations - Challenge With Human-derived Or Monkey-derived Siv and the Effects of A Longer Immunization Schedule

In cynomolgus monkeys, we compared two human-derived SIV(mac)251 whole virus vaccines, a long vs short immunization schedule, and two different challenge viruses. Both vaccines induced protection after challenge with human-derived SIV(mac)251/32H. There was no difference between the two schedules of immunization. Seven monkeys, five of which were protected following the first challenge, were reboosted and rechallenged with monkey-derived SIV(mac)251, but no protection was observed. The titers of anti-human cell or -SIV neutralizing antibodies were not related to protection