Prolonged Impairment of Immunological Memory After Anti-CD20 Treatment in Pediatric Idiopathic Nephrotic Syndrome.

Anti-CD20 therapy is effective in idiopathic nephrotic syndrome (INS). However, transient or sustained hypogammaglobulinemia predisposing to an increased risk of infectious diseases can follow treatment in some patients. We analyzed the long-term effects of anti-CD20 therapy on immunological memory in 27 frequently-relapsing/steroid-dependent INS pediatric patients after more than 4 years from the first and at least 2 years from the last anti-CD20 infusion. Twenty-one INS children, never treated with anti-CD20 and under an intense oral immunosuppression with prednisone, mycophenolate mofetil, and calcineurin inhibitors were also included as control group. Levels of circulating B-cell subpopulations, total serum immunoglobulins and IgG and memory B cells directed against hepatitis B virus (HBV) and tetanus were determined and correlated with clinical characteristics. Nine patients never relapsed after more than 2 years from the last anti-CD20 administration (5 after the first, 3 after the second, and 1 after the fifth infusion). At last follow-up, most patients showed a complete recovery and normalization of total (27/27), transitional (27/27), and mature-naïve B cells (25/27). However, a sustained and significant reduction of total memory (20/27) and switched memory (21/27) B cells was found in most patients. 11/27 patients showed hypogammaglobulinemia at last follow-up and, among these, four presented with a severe hypogammaglobulinemia (IgG < 160 mg/dl). In contrast, no patient in the control group developed a severe hypogammaglobulinemia. Age at the time of first anti-CD20 administration was positively associated with IgG levels at last follow-up (p = 0.008); accordingly, younger patients had an increased risk of hypogammaglobulinemia (p = 0.006). Furthermore, severe hypogammaglobulinemia and delayed switched memory B-cell reconstitution were more frequent in non-relapsing patients. Reduced IgG levels against HBV and tetanus were observed at baseline and further declined at last follow-up. Antigen-specific memory B-cells were induced by re-immunization, but specific IgG titers remained low. In conclusion, anti-CD20 therapy can be disease-modifying in some INS patients. However, a prolonged impairment of immunological memory occurs frequently, independently from the number of anti-CD20 infusions, particularly in younger patients. Re-immunization may be necessary in these patients.

[Autoimmune disorder secondary to DiGeorge syndrome: a long-term follow-up case report and literature review].

DiGeorge syndrome is the most common chromosome microdeletion disease. The classical complications include congenital heart disease, hypothyroidism, immunodeficiency, facial abnormalities, and hypocalcemia. According to whether there is an absence or hypoplasia of the thymus, DiGeorge syndrome can be divided into two types, complete DiGeorge syndrome and partial DiGeorge syndrome. The patient was a female born with congenital heart disease, facial abnormalities and cleft palate. When the patient went to school, she had learning difficulty and had problems in communication and personal social behavior. Breath-holding occurred when she was 6 years old. She got infections about 2-3 times a year, which was easy to be cured each time. Chromosome microdeletion test of peripheral blood showed the classical 22q11.2 microdeletion, and no evidence showed that she has thymus absence, thus her disease was diagnosed as partial DiGeorge syndrome. When the patient was 6 years old, the blood routine test showed slight thrombocytopenia, and reexaminations after that indicated the similar result. When 9 years old, she was found with anemia and severe thrombocytopenia. At the age of 10, the patient was admitted to our hospital, complaining of petechia in the body and mucous of mouth. According to the various examinations results, doctors eventually considered the situation as an autoimmune disorder phenomenon. After being treated by pulse-dose methylprednisolone for three days, the bleeding ceased. Then the patient orally took prednisone acetate and pulse-dose cyclophosphamide, however the thrombocyte and hemoglobin levels had not been back to a normal range. But when the dose of prednisone acetate was reduced, the blood platelet count declined again while the hemoglobin kept normal. The long-term follow-up of this case lasted for more than 20 years. Until now, the patient is taking orally prednisone acetate as a maintainance treatment, and the anemia has been improved since, but thrombocytopenia still exists. The mechanism of DiGeorge syndrome in combination with immunodeficiency is still unclear. The most likely reason is that this phenomenon has some relationship with the dysfunction of the thymus and finally had an effect on the function of T cells. The clinical manifestation is always stubborn and need treatment and follow-up visit for a long time.

Severe strongyloidiasis with negative serology after corticosteroid treatment.

BACKGROUND: Strongyloidiasis usually presents as a chronic and limited disease, but in some immunocompromised patients it may become a life-threatening disease. CASE REPORT: A 77-year-old Haitian male, with history of temporal arteritis on 40 mg of oral prednisone presented complaining of decreased oral intake, epigastric pain, and non-bloody diarrhea. He had bi-temporal wasting and a distended abdomen but without guarding or tenderness. Laboratory examination included mild leukocytosis, anemia, negative HIV antibody, negative parasite stool exam, and negative serology for Giardia and Strongyloides. CT of the abdomen showed multiple distended loops, without obstruction. During the admission he had a 4 g hemoglobin drop and a positive occult blood test, requiring blood transfusions, IV pantoprazole, and upper endoscopy. Findings included severe duodenitis, blunted villi, and intramucosal and luminal helminthic worms and eggs. Pathology showed Strongyloides stercoralis infection, confirmed by subsequent PCR. He was given 1 day of 15 mg oral ivermectin, diarrhea resolved, and was discharged with a percutaneous endoscopic gastrostomy tube because of the persistent lack of appetite. ConCLUSIONS: Given the persistent nature of strongyloidiasis and its high susceptibility to ivermectin, it potentially would be worth consider treating high-risk patients in the appropriate clinical and epidemiological setting, irrespective of screening test results, in order to avoid false-negative result consequences.

Mucormycosis and chromoblastomycosis occurring in a patient with leprosy type 2 reaction under prolonged corticosteroid and thalidomide therapy.

Mucormycosis is an uncommon fungal infection caused by Mucorales. It frequently occurs in patients with neutropenia, diabetes, malignancy and on corticoid therapy. However, it is rare in patients with AIDS. Clinical disease can be manifested in several forms. The case reported illustrates the rare occurrence of chromoblastomycosis and mucormycosis in an immunosuppressed patient with multibacillary leprosy, under prolonged corticosteroid and thalidomide therapy to control leprosy type 2 reaction. Neutrophil dysfunction, thalidomide therapy and work activities are some of the risk factors in this case. Chromoblastomycosis was treated by surgical excision and mucormycosis with amphotericin B. Although the prognosis of mucormycosis is generally poor, in the reported case the patient recovered successfully. This case should alert dermatologists to possible opportunistic infections in immunosuppressed patients.

Mucormycosis and chromoblastomycosis occurring in a patient with leprosy type 2 reaction under prolonged corticosteroid and thalidomide therapy / Mucormicose e cromoblastomicose em um paciente com reação hansênica tipo II sob terapia prolongada com corticosteróide e talidomida

Mucormycosis is an uncommon fungal infection caused by Mucorales. It frequently occurs in patients with neutropenia, diabetes, malignancy and on corticoid therapy. However, it is rare in patients with AIDS. Clinical disease can be manifested in several forms. The case reported illustrates the rare occurrence of chromoblastomycosis and mucormycosis in an immunosuppressed patient with multibacillary leprosy, under prolonged corticosteroid and thalidomide therapy to control leprosy type 2 reaction. Neutrophil dysfunction, thalidomide therapy and work activities are some of the risk factors in this case. Chromoblastomycosis was treated by surgical excision and mucormycosis with amphotericin B. Although the prognosis of mucormycosis is generally poor, in the reported case the patient recovered successfully. This case should alert dermatologists to possible opportunistic infections in immunosuppressed patients.

Mucormicose é uma infecção fúngica incomum causada por Mucorales. Ocorre frequentemente em pacientes com neutropenia, diabetes, corticoterapia e condições malignas. Porém, é rara em pacientes com AIDS. A doença pode apresentar-se em diferentes formas. Este caso ilustra a rara ocorrência de mucormicose e cromoblastomicose em um paciente com hanseníase multibacilar, que estava sendo tratado com prednisona e talidomida devido a eritema nodoso (reação hansênica tipo II). Disfunção de neutrófilos, uso de talidomida e atividades profissionais são alguns fatores de risco neste caso. A cromoblastomicose foi tratada por excisão cirúrgica e a mucormicose com anfotericina B. Embora o prognóstico da mucormicose seja ruim, neste caso o tratamento foi bem sucedido. Este caso alerta dermatologistas para a possibilidade de infecções oportunistas em pacientes imunossuprimidos.

Anti-Escherichia coli asparaginase antibody levels determine the activity of second-line treatment with pegylated E coli asparaginase: a retrospective analysis within the ALL-BFM trials.

Hypersensitivity reactions limit the use of the antileukemic enzyme asparaginase (ASE). We evaluated Ab levels against Escherichia coli ASE and ASE activity in 1221 serum samples from 329 patients with acute lymphoblastic leukemia who had received ASE treatment according to the ALL-BFM 2000 or the ALL-REZ BFM 2002 protocol for primary or relapsed disease. ASE activity during first-line treatment with native E coli ASE and second-line treatment with pegylated E coli ASE was inversely related to anti-E coli ASE Ab levels (P < .0001; Spearman rank order correlation). An effect on ASE activity during second-line treatment with pegylated E coli ASE was, however, only observed when anti-E coli ASE Ab levels were high (> 200 AU/mL). In the presence of moderate or intermediate Ab levels (6.25-200 AU/mL) the switch from native to pegylated E coli ASE resulted in a significant increase of ASE activity above the threshold of 100 U/L (P < .05). Erwinia chrysanthemi ASE activity was not correlated with anti-E coli ASE Ab levels. Erwinia ASE was found to be the best ASE alternative if Ab levels against E coli ASE exceed 200 AU/mL. This retrospective analysis is the first to describe the relationship between the level of anti-E coli ASE Abs and serum activity of pegylated E coli ASE used second-line after native E coli ASE.

After discontinuation of calcineurin inhibitors, tapering of mycophenolate mofetil further impairs donor-directed cytotoxicity.

BACKGROUND: Recently, we described a significant decrease in donor-specific cytotoxic T-lymphocyte precursor frequency (CTLpf) after discontinuation of calcineurin inhibitors (CNI), while the proliferative capacity in mixed lymphocyte culture (MLC), and the number of interferon-gamma (IFN-gamma) producing cells (pc) in Elispot remained unchanged. METHODS: We tested T-cell reactivity in CNI free patients with stable renal graft function, on mycophenolate mofetil (MMF) or azathioprine (AZA) plus prednisone, who were tapered to 50% of their MMF or AZA dose. RESULTS: Furthermore, tapering of the MMF or AZA dose resulted in a decrease of donor-reactive CTLpf in all patients with detectable CTLpf. Detectable numbers decreased from a median of 32 to 8 CTLp/10(6) peripheral blood mononuclear cell (PBMC). No effect on third-party reactive CTLpf was found, while the T-cell reactivity to donor and third-party cells as tested in MLC and in IFN-gamma Elispot was not affected either by tapering of immunosuppression. Third-party reactivity was significantly higher than donor-specific reactivity in all tests. A control group showed no changes in any of the in vitro assays. CONCLUSION: Both withdrawal of CNI and tapering of MMF or AZA dose decreases the donor-specific CTLpf. Our data suggest that reduction of immunosuppression results in a specific decrease of donor-directed cytotoxic capacity of immunocompetent cells, while their proliferation and cytokine production capacity remained unchanged. Immunosuppression hinders development of cytotoxic non-responsiveness.

The effect of glucocorticoids on canine lymphocyte marker expression and apoptosis.

BACKGROUND: Glucocorticoids are commonly administered to dogs for the treatment of inflammatory disorders, autoimmunity and cancers such as lymphoma. Despite evidence of clinical efficacy, understanding of the effects of glucocorticoids on cells of the canine immune system is limited. HYPOTHESIS: Glucocorticoids affect the expression of phenotypic markers on canine lymphocytes and induce apoptosis. ANIMALS: Fifteen healthy mixed breed dogs. METHODS: Prospective randomized study. Prednisone was administered orally for 3 days, and cells aspirated from the popliteal lymph node before prednisone administration, and on days 1, 3, 10, 17, 24, and 38, were labeled with antibodies against canine CD3, CD4, CD8alpha, CD18, CD21, CD45, CD45RA, and CD90 molecules, and analyzed by flow cytometry. Additional samples were cultured in media with prednisolone for 24 hours and analyzed by cytometry for marker expression, and by gel electrophoresis for DNA fragmentation. RESULTS: Treatment of dogs with glucocorticoids resulted in reduced (p < or = .05) proportions of CD3 (days 1, 3, 17, and 24), CD4 (days 3 and 10), CD21 (day 1, 3, and 38), CD45RA (day 17) and CD90 (days 1, 10, and 17) expressing lymphocytes, and reduced intensity of CD18 (day 17) and CD45 (day 17 and 24) molecules on nodal lymphocytes. Culture oflymphocytes with prednisolone for 24 hours caused a significant reduction in the expression of all markers (p < or = .05) and DNA fragmentation. CONCLUSIONS AND CLINICAL IMPORTANCE: Glucocorticoids significantly alter the expression of phenotypic markers on canine lymphocytes, and in vitro induce apoptosis. These findings identify potential mechanisms for clinical immunosuppression from glucocorticoid treatment.

Significant improvement in the outcome of HCV-infected transplant recipients by avoiding rapid steroid tapering and potent induction immunosuppression.

BACKGROUNDS/AIMS: Recurrent HCV-cirrhosis occurs in a substantial proportion of transplant recipients, with higher rates reported in patients who had recently received a transplant. Over-immunosuppression has been implicated in this more unfavorable outcome. To determine whether the implementation of specific measures aimed at reducing or avoiding negative predictive variables is associated with an improvement in the outcome of recurrent hepatitis C. METHODS: Comparative study between a cohort of patients who had recently received a transplant (2001-2004) and a historical group of HCV-infected patients transplanted before the implementation of two simple measures (1999-2000): (i) use of dual initial immunosuppression (steroids + cyclosporine neoral or tacrolimus); (ii) slow steroid tapering (>6 months). Yearly biopsies were performed in these recipients, and only those with at least one protocol biopsy and those with cholestatic hepatitis (regardless of follow-up) were included in the study. End-point: rate of HCV-related severe disease (defined as bridging fibrosis, cirrhosis or fibrosing cholestatic hepatitis) within the first year post-transplantation. RESULTS: Severe disease was significantly lower in this cohort compared to the historical group (26/90, 29% vs 25/52, 48%; p=0.02). While other factors remained unchanged between the two cohorts, the proportion of patients on triple-quadruple regimes and the number of boluses of methyl-prednisolone were lower and the duration of prednisone therapy longer in more patients who had recently received a transplant. CONCLUSIONS: Improving the outcome of recurrent hepatitis C may be achieved by reducing overall immunosuppression and avoiding abrupt variations in immunosuppression.

Immunosuppression without steroids in liver transplantation is safe and reduces infection and metabolic complications: results from a prospective multicenter randomized study.

BACKGROUND/AIMS: The purpose of this study was to evaluate the efficacy of a steroid-free immunosuppression protocol. METHODS: From 2001 to 2004, 198 liver-transplant patients were randomized to receive immunosuppression with Basiliximab and cyclosporine, with (St Group) or without (NoSt Group) prednisone. The primary end points were acute rejection, and patient and graft survival. The secondary end points were infection, metabolic complications, and hepatitis C-virus recurrence. RESULTS: Overall rejection rate was 15%, with no differences (St: 13% vs NoSt: 18%; P=0.33). Infection rate was similar in both groups (St: 51% vs NoSt: 47%; P=0.56), but diabetic patients in the St Group had a significantly higher rate of bacterial infections (St: 54% vs NoSt: 14%; P=0.005). The six-month protocol biopsies showed hepatitis C recurrence in 90% of patients, without differences between groups. Hypertension was more frequent in the St Group (St: 44% vs NoSt: 25%; P=0.006). De novo diabetes rate was higher in the St Group (month 1: St: 29% vs NoSt: 18%; P=0.06), with higher glycatedHb (5.1+/-1.1 vs 4.4+/-0.8; P=0.002). Six-month survival rates were similar (St: 89% vs NoSt: 94%, P=0.62). CONCLUSIONS: Immunosuppression without steroids is safe and reduces infection and metabolic complications.

Cyclosporine monitoring with 2-hour postdose levels in heart transplant recipients.

Cyclosporine therapeutic drug monitoring based on 2-hour postdose concentration (C2) compared with conventional trough concentration (C0) can improve clinical outcomes for de novo renal and liver transplant patients. However, in heart transplant patients, published studies are limited. To determine the clinical significance of C2 compared with C0 following orthotopic heart transplantation, the authors measured CsA at C0 and C2 and estimated CsA area under the curve (AUC) using Bayesian estimation and 4 sparse sample algorithms in a cross section of 31 adult patients receiving triple-drug immunosuppression with CsA, mycophenolate mofetil (MMF), and prednisone. CsA was measured using a validated HPLC method. Endomyocardial biopsies were graded based on the ISHLT system. Mean +/- SD values for CsA dose, C0, and C2 were 4.8 +/- 1.4 mg/kg/d, 240 +/- 62 microg/L, and 1319 +/- 469 microg/L, respectively. Correlation with AUC, using different estimation algorithms, was better for C2 (r(2) = 0.79-0.99) than for C0 (r(2)= 0.11-0.52). The mean +/- SD values for C0 (microg/L) and C2 (microg/L) for rejectors (n = 3) were 215 +/- 68 and 949 +/- 204 versus 242 +/- 62 and 1359 +/- 474 for the nonrejectors (P = 0.66 and 0.12, respectively). Fisher exact test P values using the median as threshold value for C0 and C2 (234 microg/L and 1251 microg/L, respectively) were 0.6 and 0.1. Analysis of the data revealed that C0 values in rejectors have wider variability than C2. There were no rejectors among the 16 patients exceeding the C2 median value; for C0, however, there was not an easily identifiable threshold value. There is a trend for a significant relationship between C2 and the incidence of rejection, but the number of rejectors was too small to reach statistical significance. A prospective concentration-control de novo study design is recommended as the most appropriate way to fully evaluate the potential utility of C2 monitoring in heart transplant patients.

Alveolar and airway sites of nitric oxide inflammation in treated asthma.

The goal of this study was to identify airway and alveolar site(s) of inflammation using exhaled nitric oxide (NO) as a marker in treated patients with asthma, including response to oral corticosteroids, and correlate these sites with expiratory airflow limitation. In 53 (24 male) patients with asthma, age 43 +/- 23 years (mean +/- SD) and all on inhaled corticosteroids, post 180 microg aerosolized albuterol, FEV(1) was 74 +/- 23% predicted and FEV(1)/FVC was 68 +/- 11%. Exhaled NO at 100 ml/second was 27 +/- 23 ppb (p < 0.001 compared with normal, 12 +/- 15 ppb). Bronchial NO maximal flux was 2.4 +/- 3.1 nl/second (p < 0.001 compared with normal, 0.85 +/- 0.55). Alveolar NO concentration was 7.0 +/- 7.4 ppb (p = 0.01 compared with the normal value, 3.2 +/- 2.0 ppb). There was no significant correlation between FEV(1) % predicted or lung elastic recoil and NO bronchial flux or alveolar concentration. However, there was a weak but significant correlation between NO bronchial flux and alveolar concentration (Spearman r = 0.50, p < 0.001). In 10 subjects with asthma on inhaled corticosteroids, 5 days of 30 mg prednisone resulted in isolated significant decreases in NO alveolar concentration, from 13 +/- 10 to 4 +/- 4 ppb (p = 0.002). Despite treatment, including inhaled corticosteroids, patients with asthma may have ongoing separate airway and alveolar sites of NO inflammation, the latter responsive to oral corticosteroids.

Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease.

Systemic inflammation is present in chronic obstructive pulmonary disease (COPD), which has been linked to cardiovascular morbidity and mortality. We determined the effects of oral and inhaled corticosteroids on serum markers of inflammation in patients with stable COPD. We recruited 41 patients with mild to moderate COPD. After 4 weeks during which inhaled corticosteroids were discontinued, patients were assigned to fluticasone (500 mcg twice a day), oral prednisone (30 mg/day), or placebo over 2 weeks, followed by 8 weeks of fluticasone at 500 mcg twice a day and another 8 weeks at 1,000 mcg twice a day. Withdrawal of inhaled corticosteroids increased baseline C-reactive protein (CRP) levels by 71% (95% confidence interval [CI], 16-152%). Two weeks with inhaled fluticasone reduced CRP levels by 50% (95% CI, 9-73%); prednisone reduced it by 63% (95% CI, 29-81%). No significant changes were observed with the placebo. An additional 8 weeks of fluticasone were associated with CRP levels that were lower than those at baseline (a 29% reduction; 95% CI, 7-46%). Inhaled and oral corticosteroids are effective in reducing serum CRP levels in patients with COPD and suggest their potential use for improving cardiovascular outcomes in COPD.

Serum levels of soluble TNFalpha receptors (sTNFR1 and sTNFR2) during corticosteroid treatment in patients with Graves' ophthalmopathy.

UNLABELLED: TNFalpha was shown to play an important role in the autoimmune inflammatory process of Graves' ophthalmopathy (GO). In our previous study we found no significant changes in serum TNFalpha levels in GO patients. The aim of the present study was to estimate an influence of corticosteroids on serum levels of TNFalpha receptors (sTNFR1 and sTNFR2) in GO patients and to assess their potential as a guideline of immunosuppressive therapy. We detected serum sTNFRI and sTNFR2 in three groups of subjects: 18 patients with clinical symptoms of ophthalmopathy [Clinical Activity Score (CAS) > or = 4, anamnesis of GO > or = 1 yr], 16 patients with Graves' disease without ophthalmopathy (Gd) and 14 healthy volunteers. Corticosteroid therapy consisted of intravenous infusions of methylprednisolone (MP) and subsequent treatment with oral prednisone (P). The serum samples were collected 24 hours before MP, 24 hours after MP, 14 days of treatment with prednisone and after the end of the corticosteroid therapy. The levels of serum sTNFR1 and sTNFR2 were determined by ELISA. Serum levels of sTNFR1 were significantly higher in GO individuals as compared to the control group (p < 0.01). We have found a significant decrease in sTNFR1 concentration in corticosteroid-respondent patients (satisfactory clinical effect, decrease of CAS > or = 1) as compared to the pretreatment values after MP treatment (p < 0.05) and after 14 days of prednisone (p < 0.01). There were significant differences in sTNFR2 level after MP treatment (p < 0.02) and after corticosteroid administration (p < 0.05) between responders and non-responders. Baseline values of sTNFRI in GO individuals were positively correlated with CAS (r = 0.6, p < 0.02). CONCLUSIONS: TNFalpha acting through its receptors plays an important role in the pathogenesis of Graves' ophthalmopathy. Moreover, the beneficial influence of corticosteroids on the course of GO may be explained, at least in part, by an inhibition of sTNFR1 and sTNFR2. Measurement of soluble TNFalpha receptors might potentially serve as an indicator in prognostic estimation of corticosteroids' efficacy.

Glucocorticoid receptor up-regulation in early rheumatoid arthritis treated with low dose prednisone or placebo.

OBJECTIVE: Low or medium dose prednisone in early rheumatoid arthritis (RA), albeit with significant variation in clinical efficacy, reduces the progression of joint damage. The glucocorticoid receptor (GR) number in peripheral mononuclear cells (PBMC) might be helpful to predict which patients will respond to low or medium dose prednisone and therefore do not or will not need higher doses. With this in mind we determined in a double blind, placebo controlled study at baseline and yearly the GR number in PBMC. METHODS: Eighty-one early RA patients (disease duration less than one year) were included. All patients fulfilled the ACR criteria and were disease modifying antirheumatic drugs (DMARD) and glucocorticoid-naive. They were randomly assigned to treatment with 10 mg prednisone daily or placebo. From all patients disease activity (CRP, number of tender and swollen joints), the radiological joint score, bone mineral density, and the GR number in PBMC were measured annually. RESULTS: In females the GR number was up-regulated over time in both the prednisone and the placebo group. The same trend was observed in males. No correlations were found between the GR number in the prednisone users at the start of their treatment and changes in radiological scores or bone density after 2 years of treatment. No correlations were found between the GR number at the start and the clinical characteristics after a follow-up of 2 years. CONCLUSION: The GR number in the PBMC of early RA patients did not predict which patients would be prednisone responders based on clinical or radiological parameters. However, the up-regulation of the GR number in PBMC in early RA patients towards the GR number of healthy subjects during the first two years of their disease course seems to reflect a recovery or compensatory mechanism as a response to an ongoing inflammatory process. This recovery may be not enough to efficiently control the inflammatory situation.

Tumour necrosis factor-alpha concentration in severely asthmatic children.

We assessed tumour necrosis factor-alpha (TNF-alpha) concentrations in 80 asthmatic children, 26 with severe asthma in early-phase reaction, 26 with severe asthma in late-phase reaction, 28 with severe asthma controlled in between attacks with oral prednisone and 20 matched control children. TNF-alpha was measured in patients' plasma and in a supernatant of lipopolysaccharide-stimulated (LPS) peripheral blood mononuclear (PBM) cells. TNF-alpha concentrations in plasma and the supernatant of LPS-stimulated cells were positively correlated and the concentration also correlated positively with the time lapse between the start of the asthma attack and the time of blood sampling. TNF-alpha concentration was significantly higher in the late-phase reaction group compared to the other groups, indicating a need to counteract its release and/or effects early in asthma patients.

Pharmacoimmunodynamic interactions of interleukin-10 and prednisone in healthy volunteers.

OBJECTIVE: The pharmacoimmunodynamic interactions of recombinant human interleukin-10 and prednisolone were examined in 12 normal male volunteers. METHODS: Single doses of interleukin-10 (8 microg/kg subcutaneous injection), interleukin-10 with prednisone (15 mg by mouth), placebo with prednisone, or placebo were administered. Drug concentrations yielded pharmacokinetic parameters. Response measurements included whole blood lipopolysaccharide-stimulated cytokine (tumor necrosis factor-alpha, interleukin-1beta) production, phytohemagglutinin-stimulated whole blood lymphocyte proliferation, and differential white blood cell counts (including monocytes, lymphocytes, and neutrophils). Extended indirect-response models were used to deal with diverse drug interactions in assessing single and joint effects of interleukin-10 and prednisolone. RESULTS: No pharmacokinetic alterations in interleukin-10 or prednisolone were found. Dosing with interleukin-10 produced strong inhibition of ex vivo cytokine production for the 24-hour postdosing period, whereas prednisolone, the active form of prednisone, was partly inhibitory for only 3 hours. Prednisolone significantly inhibited (P < .05) ex vivo lymphocyte proliferation for 6 hours, whereas interleukin-10 failed to alter this measure. Their joint effects on these responses were inhibitory consonant with the stronger agent. Marked changes in various leukocyte kinetics occurred. The steroid caused monocytopenia, lymphocytopenia, and neutrophilia, with IC50 or SC50 values of 10 to 20 ng/mL. Interleukin-10 elevated monocytes and neutrophils and lowered lymphocyte counts, with IC50 or SC50 values of 0.7 to 1.3 ng/mL. Dynamic modeling showed loss of prednisolone effects on monocytes and additive steroid/interleukin-10 effects on lymphocytes and neutrophils, with neutrophils exhibiting greater changes in net response. CONCLUSION: Interleukin-10 and prednisolone interacted favorably for the measured pharmacoimmunodynamic indices with no kinetic alterations but net responses that were similar to or greater than effects produced by the more strongly acting agent.

Standardized estimates from categorical regression models.

We consider the problem of interpreting categorical regression models, such as the polytomous logistic model, the continuation-ratio model, the stereotype model, and the cumulative-odds model. We present a method to convert categorical regression coefficients into estimates of standardized fitted probabilities, probability differences and probability ratios. We use a delta-method approach to estimate standard errors. We then present a small simulation study to compare different transforms for setting confidence limits, and provide an illustration of our approach in an observational study of drug therapy of polymyositis.

[Effect of prednisone on skin tests with allergens]. / Efecto de la prednisona en las pruebas cutáneas con alérgenos.

A double blind study was carried out in 29 patients, 14 were treated with prednisone and 15 with placebo. Prednisone caused significant inhibition of the allergen-induced wheal and flare response, but did not suppress it. The control group, showed a significant rise in the allergen-induced wheal and flare response. The significance of the observed alterations is briefly discussed as well as their probable origin. It is suggested the use of prednisone in allergic patients who need symptomatic treatment, however, we must to think about the possibility for get false-negative results.