Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients.

Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re-examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long-term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post-splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second-line management of autoimmune cytopenia in CVID.

A multi-centre study of efficacy and safety of Intratect®, a novel intravenous immunoglobulin preparation.

We studied the efficacy, safety and pharmacokinetic profiles of Intratect®, a recently developed polyvalent intravenous immunoglobulin (IVIG) preparation. Fifty-one patients (aged 6-48 years) with primary immunodeficiencies (PID) and established replacement therapy using a licensed IVIG were enrolled and treated for 12 months with Intratect®. Retrospective patient data served as prestudy controls. The primary efficacy variable was the annual rate of acute serious bacterial infection (ASBI) per patient. Secondary parameters were annual rate of acute relevant infection (ARI), days with antibiotic use, fever, absence from school/work and hospitalization. The average IVIG dose was 0·49 g/kg, with an average infusion rate of 2·4 ml/kg/h. The annual ASBI rate/patient was 0·02 and ARIs were detected 128 times during the 630 adverse events in 40 patients, specified mainly as bronchitis, sinusitis, respiratory tract infection, rhinitis and pharyngitis. The annual rate of respiratory ARIs/patient was 2·0 and the rates/patient for days with fever >38°C, school/work absence and hospitalization were 1·81, 3·99 and 0·36, respectively. A total of 630 adverse events (AEs) were observed in 50 of 51 (98·0%) of patients. In 46 of 51 patients the AEs were not related to infusion. Pharmacokinetic studies after the first infusion revealed a mean elimination half-life of 50·8 ± 30·3 days. During this study, 19 of 649 (2·9%) IgG trough levels were below 6 g/l, better than that of reference IVIGs during the 6 months before study start (10 of 201). These data suggest that Intratect® is a well tolerated, safe and effective IgG concentrate for the treatment of patients with PID.

Reduced memory B cells in patients with hyper IgE syndrome.

Dominant-negative mutations in STAT-3 have recently been found in the majority of patients with sporadic or autosomal-dominant hyper IgE syndrome (HIES). Since STAT-3 plays a role in B cell development and differentiation, we analyzed memory B cells in 20 patients with HIES, 17 of which had STAT-3 mutations. All but four patients had reduced non-switched and/or class-switched memory B cells. No reduction in these B cell populations was found in 16 atopic dermatitis patients with IgE levels above 1000 KU/L. There was no correlation between the reduction of memory B cells and the ability to produce specific antibodies. Moreover, there was no correlation between the percentage of memory B cells and the infection history. Analysis of memory B cells can be useful in distinguishing patients with suspected HIES from patients with atopic disease, but probably fails to identify patients who are at high risk of infection.

Familial CD8 deficiency due to a mutation in the CD8 alpha gene.

CD8 glycoproteins play an important role in both the maturation and function of MHC class I-restricted T lymphocytes. A 25-year-old man, from a consanguineous family, with recurrent bacterial infections and total absence of CD8(+) cells, was studied. Ab deficiencies and ZAP-70 and TAP defects were ruled out. A missense mutation (gly90-->ser) in both alleles of the immunoglobulin domain of the CD8 alpha gene was shown to correlate with the absence of CD8 expression found in the patient and two sisters. Conversely, high percentages of CD4(-)CD8(-)TCR alpha beta(+) T cells were found in the three siblings. A novel autosomal recessive immunologic defect characterized by absence of CD8(+) cells is described. These findings may help to further understanding of the role of CD8 molecules in human immune response.

Identification of WASP mutations in 14 Spanish families with Wiskott-Aldrich syndrome.

The Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency caused by mutations in the WASP gene. The disease is known to be associated with extensive clinical variability, and mutation studies indicate that genotypes are also highly variant among WAS patients. In this study, we performed mutation analysis of the WASP gene in 14 unrelated Spanish families by single strand conformation analysis (SSCA) and sequencing, resulting in the identification of a novel mutation and nine known mutations. No mutation was identified in one family. The ten different mutations include point mutations resulting in amino acid substitutions, stop codons, and small deletions and insertions causing frameshifts. Missense mutations were preferentially located in the amino-terminal part of the protein, exons 2 and 4, whereas stop and frameshift mutations were located in the carboxyl-terminal region, exons 10 and 11. However, in two families, two missense mutations in exon 11 were identified. Our study demonstrates that WASP genotypes have some concordance with the patients' phenotypes, although mutation 1019delC, identified in a family with several affected members, resulted in high intrafamilial clinical variability.

High level of interferon gamma in tuberculous pleural effusion.

It has been observed that T-lymphocytes of patients with tuberculosis produce interferon gamma (IFN gamma) in vitro. Based on this idea, we studied IFN gamma in pleural fluid and serum. We studied 80 patients with pleural effusion; 30 patients with tuberculous pleurisy had high IFN gamma concentrations in pleural fluid. Patients with malignant pleural effusions, nonspecific pleural effusion, parapneumonic effusions and pleural transudates had low levels. The IFN gamma levels were higher in those with massive tuberculous effusion and apparent pulmonary lesion on x-ray film. We found that the T4/T8 lymphocyte ratio was higher in pleural fluid than in peripheral blood. Numbers of T3 and T4 lymphocytes were higher in tuberculous pleural effusions compared with those in other patients. There is no correlation between IFN gamma levels and lymphocyte subsets in pleural effusion. Perhaps pleural T-lymphocytes produce IFN gamma after stimulation by mycobacterial antigens and this lymphokine activates macrophages, increasing their bactericidal activity against Mycobacterium tuberculosis.

Lymphocyte proliferation and gamma-interferon production after "in vitro" stimulation with PPD. Differences between tuberculous and nontuberculous pleurisy in patients with positive tuberculin skin test.

T-lymphocytes previously sensitized by an antigen undergo blastic transformation and produce IFN tau when stimulated by the same antigen. We studied the lymphoblastic response to PPD and IFN tau production in pleural fluid and peripheral blood of 41 patients (15 with tuberculous pleural effusion, 13 with nontuberculous pleurisy and positive tuberculin skin test, and 13 with tuberculin-negative nontuberculous pleurisy). In tuberculous pleuritis, pleural lymphocyte blastic response and IFN tau production were higher than those of peripheral lymphocytes, whereas in tuberculin-positive nontuberculous patients, peripheral lymphocyte response and IFN tau production were higher than those of pleural lymphocytes. Tuberculous pleural fluid lymphocytes underwent greater blastic transformation and produced more IFN tau than pleural lymphocytes of tuberculin-positive nontuberculous patients, whereas the opposite occurred in peripheral lymphocytes. In tuberculin-negative nontuberculous patients, there was no lymphoblastic response in either the pleural fluid or peripheral blood. These results concur with the concept of immunologic compartmentalization. In tuberculous pleuritis, there would be clonal expansion of PPD-responding T-lymphocytes in the pleural compartment. This expansion of PPD-specific lymphocytes would not occur in nontuberculous pleuritis, but lymphocytes sensitized to other antigens would accumulate in the pleural compartment.

Influence of the human immunodeficiency virus in the incidence of tuberculosis in a cohort of intravenous drug users: effectiveness of anti-tuberculosis chemoprophylaxis.

SETTING: A residential program in Barcelona for drug addicts (therapeutic community) admitted between November 1988 and March 1992, and followed until September 1994. OBJECTIVE: To study the incidence of tuberculosis as related to the presence of tuberculosis infection and/or human immunodeficiency virus (HIV) infection, and to evaluate the protective effect of chemoprophylaxis with isoniazid. DESIGN: Prospective cohort study. Incidence rates were compared using the Chi-square test for cohort studies. The effectiveness of chemoprophylaxis was evaluated by the Kaplan-Meier method at the univariate level, and by logistic regression models and proportional risks analysis at the multivariate level. RESULTS: During the study of 361 individuals without previous known tuberculosis or history of anti-tuberculosis chemoprophylaxis, 25 developed tuberculosis, an overall incidence rate of 1.79/100 person-years. For HIV-positive persons, the incidence rate was 3.25/100 person-years, compared with 0.30/100 in those who were HIV-negative (P < 0.05). The highest incidence rates occurred among HIV-positive persons who did not receive chemoprophylaxis and who were either anergic (HIV-positive, purified protein derivative [PPD]-negative, Multitest-negative) or who were infected with Mycobacterium tuberculosis (PPD+), 10.0/100 person-years and 4.64/100 person-years, respectively. Of the 53 persons who received chemoprophylaxis, three developed tuberculosis, an incidence rate of 1.4/100 person-years. In comparison, in the group of 51 patients who were designated to receive chemoprophylaxis but where none was actually taken, 17 developed tuberculosis, an incidence rate of 5.7/100 person-years (P = 0.03). CONCLUSION: HIV-infected intravenous drug users, particularly those who are anergic or who are PPD positive, are at increased risk of developing tuberculosis. Anti-tuberculosis chemoprophylaxis proved effective in this population.

Node-negative breast cancers with p53(-)/HER2-neu(-) status may identify women with very good prognosis.

BACKGROUND: The contribution of p53 and HER-2/neu to the management of node-negative breast cancer (NNBC) could be improved by combining their results. MATERIAL AND METHODS: We studied paraffin-embedded primary tumors for p53 (BP-53-12-1) (n=57) and HER2/neu (pAB1) (n=63) from NNBC patients. The results were grouped in a negative (p53(-)/neu(-)) versus a positive group (one or both overexpressed). The association between both groups (negative and positive) and clinicopathologic parameters, S-phase fraction and DNA ploidy, and patients' outcome, was analyzed. RESULTS: In 28% of the tumors p53 was overexpressed, and HER2/neu in 11%. Sixty-five percent (37 out of 57) were p53(-)/neu(-), and 35% overexpressed one (31.5%) or both (3.5%) oncoproteins. Significant correlations were found between p53(-)/neu(-) tumors and age greater than 50 (p=0.003), S-phase fraction lower than 7 (p=0.03), and positive estrogen receptor contents (p=0.049). Actuarial 5-year disease-free and overall survival for p53(-)/neu(-) tumors were 88% and 97%, respectively, versus 50% and 66%, for tumors overexpressing one or both oncoproteins (p=0.004).

CCR5 genotype and HIV-1 infection in perinatally-exposed infants.

The CCR5 chemokine receptor is required by non-syncytium HIV-1 strains to infect target cells. A 32 base pair deletion (delta32) in the CCR5 gene causes a structural CCR5 modification that does not permit HIV-1 entry into cells. The rate of the CCR5 delta32 was investigated in 137 children born from HIV-infected mothers. Overall, five (10.6%) of 47 HIV-infected infants showed the defect in heterozygosis vs. eight (8.9%) of 90 uninfected children. No CCR5 delta32 homozygotes were found. Interestingly, among infected children, five (21.7%) of 23 showing a slow disease progression were heterozygous for the CCR5 delta32, meanwhile none of the 24 infants with rapid disease course had the deletion (P = 0.022). In conclusion, the CCR5 delta32 defect does not protect against vertical HIV-1 transmission, but is associated with a delayed disease progression in HIV-infected children.

[Immunologic prognostic parameters in infection by the human immunodeficiency virus]. / Parámetros inmunológicos pronósticos en la infección por el virus de la inmunodeficiencia humana.

BACKGROUND: To evaluate the use of quantitative and functional immunologic parameters as prognostic markers of infection by the human immunodeficiency virus (HIV). METHODS: The number of CD4 and CD8 lymphocytes, the CD4/CD8 ratio, the percentage of interleukin 2 (IL-2) receptors, the response to phytohemaglutinin (PHA) and the production of interferon tau (IFN-tau), were analyzed in 85 patients with HIV infection: 14 with acquired immunodeficiency syndrome (AIDS) (stage IV), 16 with persistent generalized adenopathies (stage III), and 55 asymptomatic patients (stage II). Similarly, a control group of 35 blood donors with negative HIV serology was studied. RESULTS: Over a period of 30 months, 17 patients (5 of stage III and 12 of stage II) evolved to stage IV. In a multivariate analysis the decrease in the number of CD4 lymphocytes in stage II and the decrease in the production of IFN-tau in stage II and III were the parameters associated with progression to stage IV. CONCLUSIONS: The decrease in the production of interferon tau in patients with infection by the human immunodeficiency virus in stage II and III as well as the decrease in the number of CD4 lymphocytes in stage II are prognostic factors associated with the evolution to stage IV of the infection.

[Hepatocarcinoma and killer cell activity]. / Hepatocarcinoma y actividad de las células asesinas (natural killer).

BACKGROUND: Alterations in natural killer (NK) cell activity have been described in patients with different neoplasms including hepatocellular carcinoma (HCC). Nonetheless, the relationship between this activity and the clinical situation of the patients with HCC is not well established. METHODS: A group of 33 patients with hepatic cirrhosis and non treated HCC, a group of 22 patients with only hepatic cirrhosis, and a control group of 31 healthy blood donors were studied. In all the subjects the NK cell activity was determined against the K562 cell line marked with 51Cr by the short duration cytotoxicity test, and the number of NK cells/microliters in peripheral blood was determined by flow cytometry (FACScan) using the anti-CD3, CD16 and CD56 monoclonal antibodies. RESULTS: No statistically significant differences were observed in the NK cell activity or in the number of NK cells/microliters among the three groups studied. In the patients with HCC the NK cell activity was not related to the degree of hepatic function, however the patients with tumors greater than 5 cm in diameter or multinodular tumors showed a significant decrease in NK cell activity without a decrease in the number of NK cells/microliters. CONCLUSIONS: The natural killer cell activity in patients with hepatocellular cancer is not related to subjacent hepatic cirrhosis but is related to tumor size.

[Treatment with interferon of systemic Langerhans-cell histiocytosis in an adult]. / Tratamiento con interferón de la histiocitosis de células de Langerhans sistémica en un adulto.

We report an adult patient with systemic Langerhans' cell histiocytosis (LHX), who was refractory to multiple chemotherapy courses and in whom a partial clinical and biological 3-month remission was achieved with alpha-2-interferon. The patient's response was associated with an increase in the rate of natural killer cells and to a return to normal of the H/S T-lymphocyte ratio. Immunological abnormalities have been reported in this condition, and it is now accepted that the most important one is a decrease in suppressor lymphocytes. However, it is not known whether these abnormalities are endogenous or exogenous. The experience with modifiers of the biological response for the treatment of LHX is scanty, but the probable immunological pathogenesis of the condition justifies a therapeutic trial of those agents in patients not responding to conventional therapy.

[The use of immunologic parameters to assess the effectiveness of parenteral nutrition. Preliminary study]. / Utilización de parámetros inmunológicos para valorar la eficacia de la nutrición parenteral. Estudio preliminar.

Malnutrition leads to cellular and humoral immunological response disorders. A study protocol on malnourished patients has been designed in order to assess immune response mechanisms that may be altered due to malnutrition and may or may not recover once normal metabolic conditions have been restored prior to starting the patient on parenteral feeding and control. The immune response was assessed especially regarding immunoglobulin, lymphocyte subsets and mitogen response levels. It is important to know the different malnutrition-related immunologic disorders, disorders secondary to diseases that hinder correct oral feeding, and immunologic tests may be used to assess nutritional parameters. The malnourished patients included in this trial has to be free of any other immunologic or neoplastic disease, and not receive immune response suppression therapy. The trial patients showed lower total and relative CD3 and CD4 lymphocyte values at the onset of the study, although the former lymphocyte subset recuperated sooner at the expense of increasing CD8 lymphocytes, while CD4 lymphocytes still remained low after 15 days of parenteral nutrition. Immunoglobulin levels remained within normal limits. The mitogen response capacity, which was sensibly low at the beginning, recuperated in 50% of the cases treated with parenteral nutrition. This parameters may be used as an index to assess the nutritional status of these patients. The cases studies allowed us to conclude that there was a decrease in CD4 cells and mitogen response in malnourished patients. After 15 days of parenteral nutrition, the cells did not recuperate but their function measured in terms of phytohemagglutinin, was normal in 50% of the cases.

Evolution of immunological abnormalities in HIV infection by vertical transmission.

Forty-four children infected through vertical transmission, from a total of 146 born to HIV-positive mothers, were studied. Immunological data were analysed and compared with those of the noninfected children. Two transmission patterns emerge from the clinical and immunological characteristics: (i) infants infected during pregnancy with severe immunodeficiency and clinical manifestations before the age of 1 year, and (ii) children probably infected perinatally, who have better clinical outcome. Immunological data are important for prognosis and early therapeutic protocols to be established.

[Lymphoproliferative disease in pediatric liver transplantation]. / Enfermedad linfoproliferativa en el trasplante hepático pediátrico.

Post-Transplant Lymphoproliferative Disorders are due to continuous B-lymphocyte proliferation induced by Epstein-Barr Virus (EBV) infection which is recovered in 88% of transplanted patients. These disorders may present clinically as lymphadenopathic syndrome with lymphoid tissue hyperplasia, systemic as a mononucleosis-like syndrome and lymphomatous syndrome, indistinguishable from non-Hodgkin's lymphoma. We present 10 patients of PTLD classified as 7 lymphadenopathic, 1 systemic (this patient had both syndromes) and 3 lymphomatous tumours. At present, PTLD treatment consists of surgical removal of accessible masses or post-chemotherapy (ChT) tumour rests, total or partial withdrawal of immunosuppressive drugs and ChT following the Sociéte Française d'Oncologie Pédiatrique (SFOP) protocol for non-Hodgkin's lymphoma.

[Spanish Paediatric Infectious Diseases Society consensus document on the treatment of fungal infections based on the immune response]. / Documento de consenso de la Sociedad de Infectología Pediátrica sobre el tratamiento de la infección fúngica basado en la respuesta inmunológica.

Despite the emergence of new diagnostic and therapeutic methods, invasive fungal infections are still a major cause of morbidity and mortality in immunocompromised and critical patients. Therefore, adjuvant treatments to the standard antifungal therapy are being investigated, with immunity-based therapy being one of the most important. Both immunomodulatory (dendritic and T cells transfusions, colony stimulating factors, interferón-gamma, interleukin 12, fungal vaccines, transfer factors and certain drugs such as chloroquine) and immunotherapeutic modalities (granulocyte transfusions, monoclonal antibodies and intravenous immunoglobulin) have been described. This document aims to summarise currently available data on immunity-based therapy of fungal infections and to provide basic knowledge on the immune response to fungal infections. This helps to understand how, in selected cases, immunity-based therapy may improve the response to standard antifungal treatment. The potential indications of immunity-based therapy in the paediatric patient are reviewed, although there is still a lack of scientific evidence for its use in children.