Rapid Push vs Pump-Infused Subcutaneous Immunoglobulin Treatment: a Randomized Crossover Study of Quality of Life in Primary Immunodeficiency Patients.

PURPOSE: Subcutaneous immunoglobulin replacement therapy (IgRT) may be administered once a week with a pump or every other day with a syringe (rapid push). The objective of the study was to compare the impact of pump and rapid push infusions on patient's life quality index (LQI). METHODS: This study was a randomized, crossover, multicenter, non-inferiority trial conducted in adults with primary immunodeficiency (PID) accustomed to weekly infusions at home by pump. Patients used pump or rapid push for 3 months each according to the randomized sequence. Main criterion was PID-LQI factor I (treatment interference). Non-inferiority ratio was set at 90%. RESULTS: Thirty patients entered the study; 28 completed the two periods. IgRT exposure was similar during each period. At the end of each period, mean LQI factor 1 was 87.0 (IC95% [80.3; 94.3]) and 77.80 (IC95% [71.5; 84.7]) for pump and rapid push, respectively. There was a slightly larger effect of rapid push on treatment interference than with pump so that the primary endpoint could not be met. No difference was found on other LQI components, satisfaction (TSQM), or quality of life (SF36v2). Eight patients declared to prefer rapid push while 19 others preferred pump. Of rapid push infusions, 67.2% led to local reactions vs 71.8% of pump infusions (p = 0.11) illustrating its good tolerance. Rapid push and pump infusions achieved similar trough IgG levels with similar incidence of infections. Rapid push saved 70% of administration cost when compared to pump. CONCLUSIONS: Since IgRT is a lifelong treatment in PID patients, individualization of treatment is of paramount importance. Rapid push is a new administration method in the physician's armamentarium which is preferred by some patients and is cost-effective. CLINICALTRIALS. GOV IDENTIFIER: NCT02180763 CLINICAL IMPLICATIONS: Self-administration of small volumes of immunoglobulins at home, every other day, using a syringe (rapid push) is a cost-effective alternative to administration of larger volumes by pump once a week. This study compared subcutaneous infusions of immunoglobulins either weekly via a pump or every other day via a syringe (rapid push). Rapid push is preferred by some patients and is cost-effective, therefore completing a physician's armamentarium.

In-depth interviews of patients with primary immunodeficiency who have experienced pump and rapid push subcutaneous infusions of immunoglobulins reveal new insights on their preference and expectations.

PURPOSE: Patients with primary immunodeficiency (PID) often receive immunoglobulin replacement therapy (IgRT). Physicians and patients have the choice between various methods of administration. For subcutaneous immunoglobulin infusions, patients may use an automated pump (P) or push the plunger of a syringe (rapid push [RP]). P infusions are performed once a week and last around 1 hour. RP decreases the duration of administration, but requires more frequent infusions. PATIENTS AND METHODS: Eight out of 30 patients (coming from a single center) who had participated in the cross-over, randomized, open-label trial comparing P and RP participated in a focus group or underwent in-depth interviews. Patients had a long history of home-based subcutaneous immunoglobulin using P. The trial suggested that RP had slightly greater interference on daily life than P, but similar efficacy and better cost-effectiveness. When asked about the delivery method they had preferred, around one-third of patients pointed out RP rather than P. In-depth interviews may reveal unforeseen reasons for patients' preferences. RESULTS: Interviews underlined the complexity of the relationship that the patients maintain with their disease and IgRT. Even if they recognized the genetic nature of the disease and claimed PID was a part of them, patients tried not to be overwhelmed by the disease. IgRT by P was well integrated in patients' routine. By contrast, RP too frequently reminded the patients of their disease. In addition, some patients pointed out the difficulty of pushing the plunger due to the viscosity of the product. Coming back too frequently, RP was not perceived as time saving over a week. Long-lasting use of P could partly explain patients' reasonable reluctance to change to RP. CONCLUSION: In-depth interviews of PID patients highlighted unforeseen reasons for patients' preference that the physician needs to explore during the shared medical decision-making process.

A cohort of French pediatric patients with primary immunodeficiencies: are patient preferences regarding replacement immunotherapy fulfilled in real-life conditions?

OBJECTIVE: To assess quality of life and satisfaction regarding immunoglobulin-replacement therapy (IgRT) treatment according to the route (intravenous Ig [IVIg] or subcutaneous Ig [SCIg]) and place of administration (home-based IgRT or hospital-based IgRT). SUBJECTS AND METHODS: Children 5-15 years old treated for primary immunodeficiency disease (PIDD) with IgRT for ≥3 months were included in a prospective, noninterventional cohort study and followed over 12 months. Quality of life was assessed with the Child Health Questionnaire - parent form (CHQ-PF)-50 questionnaire. Satisfaction with IgRT was measured with a three-dimensional scale (Life Quality Index [LQI] with three components: factor I [FI], treatment interference; FII, therapy-related problems; FIII, therapy settings). RESULTS: A total of 44 children (9.7±3.2 years old) receiving IgRT for a mean of 5.6±4.5 years (median 4.1 years) entered the study: 18 (40.9%) were receiving hospital-based IVIg, two (4.6%) were receiving home-based IVIg, and 24 (54.6%) were treated by home-based SCIg. LQI FIII was higher for home-based SCIg than for hospital-based IVIg (P=0.0003), but there was no difference for LQI FI or LQI FII. LQI FIII significantly improved in five patients who switched from IVIg to SCIg during the follow-up when compared to patients who pursued the same regimen (either IVIg or SCIg). No difference was found on CHQ-PF50 subscales, LQI FI, or LQI FII. CONCLUSION: Home-based SCIg gave higher satisfaction regarding therapy settings than hospital-based IVIg. No difference was found on other subscales of the LQI or CHQ-PF50 between hospital-based IVIG and home-based SCIG.

Negativity of the basophil activation test in quinolone hypersensitivity: a breakthrough for provocation test decision-making.

BACKGROUND: Quinolone hypersensitivity reactions are being more frequently reported. Skin tests in investigations of patients are known to not be fully reliable. The provocation test thus remains the gold standard in the definitive diagnosis of allergy, despite the risks involved. The aim of this study was to evaluate basophil activation tests (BATs) in the diagnosis of immediate-type reactions to quinolones. METHODS: Thirty-four patients who presented an immediate-type hypersensivity reaction less than an hour after quinolone administration were studied. The allergologic workup of these patients consisted of a careful clinical history, a skin test and a BAT with the culprit quinolone. If not contraindicated, and in the case of high probability of a nonallergic reaction, provocation tests were performed to assess the nonimmunologic nature of the hypersensitivity. RESULTS: Among the 34 patients studied, 17 (50%) presented a negative BAT to the suspected quinolone, while the other 17 (50%) patients presented a positive BAT for quinolone at the time of their reaction. Among the 17 patients with negative BATs, 15 (2 of whom had had positive skin tests) had quinolone successfully reintroduced. CONCLUSIONS: Our report suggests that the BAT, if negative for the culprit quinolone, is a valuable tool in the decision whether or not to perform provocation tests in patients with a history of immediate-type reaction to quinolones, in order to exclude an allergic reaction.

Abnormal cellular reactivity to microbial antigens in patients with uveitis.

PURPOSE: The purpose of the present study was to evaluate the cellular response to microbial antigens in patients with idiopathic uveitis. METHODS: Blood lymphocytes from 31 patients with uveitis and 24 healthy controls were cultivated with microbial antigens and analyzed by flow cytometry after staining with monoclonal antibodies against CD3, CD4, and activation markers CD69 and CD25. RESULTS: Although no difference was noted in circulating lymphocytes, the activation of T cells, detected with CD69, was higher in 24-hour blood culture from uveitis patients with Candida albicans antigen (Ca-Ag) than from controls, especially in posterior uveitis and panuveitis. Moreover, late response, detected with CD25, to different microbial antigens was higher in patient with uveitis. CONCLUSIONS: Such results suggest the role of Ca-Ag and microbial antigens in the pathogenic mechanisms of idiopathic uveitis.

Recurrent idiopathic thrombotic thrombocytopenic purpura: a role for vaccination in disease relapse?

The presence of antibodies against a disintegrin-like metalloproteinase with thrombospondin type 1 motif, isoform 13 (ADAMTS 13 protease) is the main cause (70% to 80%) of idiopathic and recurrent thrombotic thrombocytopenic purpura (TTP). However, etiologic factors that trigger the onset and potential relapses of TTP remain unclear. Immunologic deregulation and infectious agents are suspected. We report the case of a 51-year-old white man presenting with idiopathic TTP caused by autoantibodies against ADAMTS 13 protease. The first acute TTP episode needed long-term plasma exchanges because of early relapses. Consequently, vincristine therapy and splenectomy were performed. Those treatments induced TTP remission for 18 months. Relapses occurred twice between 1 and 3 months after vaccination. However, those relapses were not as severe as the first acute episode and responded to short-course plasma exchanges. ADAMTS 13 antibodies and decreased ADAMTS 13 protease activity were searched for and detected first during the second relapse. This case challenges the role of vaccination as an etiologic factor in the recurrence of idiopathic TTP.

Staphylococcal enterotoxin-like toxins U2 and V, two new staphylococcal superantigens arising from recombination within the enterotoxin gene cluster.

To test the hypothesis that the Staphylococcus aureus enterotoxin gene cluster (egc) can generate new enterotoxin genes by recombination, we analyzed the egc locus in a broad panel of 666 clinical isolates of S. aureus. egc was present in 63% of isolates, confirming its high prevalence. The archetypal organization of the egc locus, consisting of five enterotoxin genes plus two pseudogenes, was found in 409 of 421 egc-positive strains. The egc locus was incomplete in a few strains and occasionally harbored an insertion sequence and transposase genes. These strains may represent evolutionary intermediates of the egc locus. One strain with an atypical egc locus produced two new enterotoxins, designated SElV and SElU2, generated by (i) recombination between selm and sei, producing selv, and (ii) a limited deletion in the varphient1-varphient2 pseudogenes, producing selu2. Recombinant SElV and SElU2 had superantigen activity, as they specifically activated the T-cell families Vbeta 6, Vbeta 18, and Vbeta 21 (SElV) and Vbeta 13.2 and Vbeta 14 (SElU2). Immunoscope analysis showed a Gaussian CDR3 size distribution of T-cell receptor Vbeta chain junctional transcripts of expanded Vbeta subsets in toxin-stimulated cultures, reflecting a high level of polyclonality. These data show that egc is indeed capable of generating new superantigen genes through recombination.

Systemic T cell response to Toxoplasma gondii antigen in patients with ocular toxoplasmosis.

PURPOSE: Analysis of systemic cellular response to Toxoplasma antigen in patients with ocular toxoplasmosis. METHODS: Activated (CD25(+)) T cells were detected by flow cytometry after a 7-day culture of whole blood from patients with ocular (n = 16) or asymptomatic (n = 14) toxoplasmosis, and controls (n = 10), in the presence of soluble Toxoplasma antigen (ST-Ag). Interferon (IFN)-gamma, interleukin (IL) 4, and IL-10 were measured in culture supernatants by enzyme-linked immunosorbent assay. RESULTS: Higher percentages of CD25(+) T cells were detected in ST-Ag-activated cultures from Toxoplasma-infected patients, with or without ocular lesions (37.0 +/- 19.1% or 41.1 +/- 19.3%, respectively) than from controls (3.2 +/- 1.2%) (P < 0.0001). Differences were not statistically significant between asymptomatic and ocular toxoplasmosis (P > 0.4) or among congenital, acquired, and undetermined ocular toxoplasmosis (P > 0.2). Higher levels of IFN-gamma were detected in ST-Ag-stimulated blood cultures from infected patients than in those from controls (P < 0.0001), with no difference between patients with asymptomatic or ocular toxoplasmosis (P > 0.05). IL-10 was detected only in activated culture supernatants from three patients with ocular toxoplasmosis and two patients with asymptomatic toxoplasmosis. IL-4 was never produced in ST-Ag-activated cultures. CONCLUSIONS: Systemic cellular response to ST-Ag does not differ between the patients with ocular and asymptomatic toxoplasmosis with regard to activation markers and type 1 cytokine production.

Neutralization of Staphylococcus aureus Panton Valentine leukocidin by intravenous immunoglobulin in vitro.

Panton Valentine leukocidin (PVL) may be responsible for pulmonary necrosis in necrotizing Staphylococcus aureus pneumonia, a highly lethal infection. Commercial intravenous immunoglobulin (IVIg) preparations containing antibodies against PVL might have therapeutic value in this setting, as an adjunct to antimicrobial chemotherapy. To test this possibility, we determined anti-PVL antibody titers in commercial IVIg and the capacity of IVIg to prevent the cytopathic effects of PVL in vitro. Specific enzyme-linked immunosorbent assays based on purified recombinant PVL (rPVL) showed that IVIg contained specific anti-PVL antibodies. The cytotoxicity of rPVL and of crude culture supernatants of PVL-producing S. aureus strains were investigated by measuring ethidium-bromide incorporation by polymorphonuclear neutrophils (PMNs) in flow cytometric assays, as well as PMN ultrastructural changes by transmission electron microscopy. IVIg was found to neutralize pore formation and the cytopathic effect of both rPVL and S. aureus culture supernatants.

Progesterone fails to modulate Toxoplasma gondii replication in the RAW 264.7 murine macrophage cell line.

Cell mediated immunity is very important for host defence against intracellular pathogens and many studies have shown the role of the production of nitric oxide (NO) by interferon (IFN)-gamma/lipopolysaccharide (LPS)-activated macrophages. As the progesterone level increases during pregnancy in mammals, and as previous studies have shown that progesterone inhibits inducible nitric oxide synthase (iNOS) expression and NO production, we aimed to investigate whether progesterone might modulate intracellular replication of Toxoplasma gondii in macrophages. Our results showed that progesterone does not influence T. gondii replication in non-activated RAW 264.7 cells, and although progesterone inhibits NO production induced by IFN-gamma/LPS, we observed that it fails to restore the growth of T. gondii blocked by IFN-gamma/LPS. After discussing the reasons for this apparent discrepancy, we concluded that progesterone has no direct effect on the macrophage response. The real effect of the sex steroids in T. gondii infection and their implication in clinical toxoplasmosis therefore need to be investigated further to involve wider mechanisms of the immune system.

Principios y práctica de nuevos métodos diagnósticos en toxoplasmosis / Principles and practice of new diagnostic methods

Describe varios métodos de diagnóstico en toxoplasmosis como: 1) ELISA. 2) Detección de la inmunidad celular. 3) El Dye test o prueba del colorante. 4) Técnica de citometría en flujo. 5) Inmunidad anti-toxoplasmica.