Subcutaneous immunoglobulins: product characteristics and their role in primary immunodeficiency disease.

Research on the role of subcutaneous immunoglobulin in primary immunodeficiency disease (PIDD) is ongoing. We analyzed pivotal studies for four subcutaneous immunoglobulin products: IGSC 10% (Gammagard(®) Liquid), IGIV-C 10% (Gamunex(®)-C), IGSC 16% (Vivaglobin(®)) and IGSC 20% (Hizentra(®)). To identify similarities and differences between products, we examined infusion parameters, adverse event profiles and improvements in tolerability over time. Maximum volume infused was 30 mL/site for IGSC 10%, 34 mL/site for IGIV-C 10%, 15 mL/site for IGSC 16% and 25 mL/site for IGSC 20%. Maximum number of simultaneous infusion sites was 10 for IGSC 10%, 8 for IGIV-C 10%, 6 for IGSC 16% and 4 for IGSC 20%. Local adverse reaction rate per infusion was 0.02 for IGSC 10%, 0.59 for IGIV-C, 0.49 for IGSC 16% and 0.58 for IGSC 20%. IGSC products have similar efficacy profiles; however, their tolerability profiles vary. Reasons for these differences are unknown and warrant further research.

[Pediatric infectious diseases--an ongoing battle].

Eleven articles are included in this special issue of Harefuah dedicated to pediatric infectious diseases. Herein, they present the problems and dilemmas pediatricians, as well as general practitioners, face in current practice. In spite of tremendous achievements in prevention, diagnosis and treatment, infectious diseases remain a major concern in pediatrics. Additional efforts are urgently needed including judicious use of antibiotics to reduce resistance, development of modern vaccines and antibiotics and public health measures in order to overcome the battle against infections. This can be possible only with robust governmental support.

[Infectious diseases--new horizons].

During the last decade we have witnessed important developments in the field of infectious diseases. These developments have in a large part been made possible due to our entry into the genomic period. The main areas of progress include diagnosis, understanding of the pathophysiology, genetics, anti-microbial therapy and the prevention of disease by new vaccines. The diagnosis of infection using Polymerase Chain Reaction (PCR), contributes today to the early identification of a pathogen, long before the culture and serology. In the future, we will be able to utilize molecular methodologies based on the unique response of the host to a specific infection--the genetic signature. This method will enable very early identification of the pathogen, institution of optimal treatment, and will prevent the excessive use of antibiotics. Another area that has developed in recent years is the genetics of infectious diseases. Accumulated data shows that changes in the genome, polymorphism, result in different reactions by people to different infections. As a result of these changes some people are resistant to certain infections whilst others are especially sensitive to other infections. Introduction of this knowledge into clinical practice will enable more rational medical management with an emphasis on personalized medicine. After a long period without the development of new antibiotics, there are now signs of conceptual and practical breakthroughs in the development of antibiotic agents whose activity is based on new principles and directed against sites different from those of existing antibiotics. These advances are predominantly due to progress in the field of genomics. Similarly, in the development of future vaccines, more and more vaccines will be developed using genomic methods, enabling the creation of vaccines against diseases that we have not yet succeeded to eradicate. Genomic methods will enable the design of vaccines tailored to the specific genomic structure of the host--personal vaccines. All these four aspects of progress in the field of infectious diseases are not science fiction, and it can be stated with confidence that the future is already here.

Molecular assessment of thymus capabilities in the evaluation of T-cell immunodeficiency.

T-cell immunodeficiency may pose a diagnostic challenge to clinicians, especially when the basic T-cell immune workup is not sufficiently informative. An intensive assessment of thymus capabilities that involves either measuring the recent thymic emigrant cells or analyzing the T-cell receptor (TCR) repertoire is often required to estimate the severity and nature of the immune disorder. A comprehensive T-cell immune workup, including TCR excision circles (TRECs) and TCR repertoire analyses, was performed in three patients with various degrees of severity of T-cell immunodeficiency. All three patients had normal peripheral CD3+ T lymphocytes. TCR repertoire analysis revealed oligoclonal (patient 1), restricted (patient 2), and near-normal (patient 3) patterns. TREC quantification was significantly reduced in patients 1 and 2 but normal in patient 3. Based on clinical features at presentation and at follow-up, and supported by the results of immunologic studies, patients 1 and 2 were diagnosed as having significant T-cell immunodeficiency and patient 3 as having T-cell immunocompetence. Assessment of thymus capabilities by TRECs and TCR repertoire analyses is helpful in diagnosing patients with T-cell immunodeficiency and should be part of the evaluation of every patient suspected of having that condition.

Molecular assessment of thymic capacities in patients with Schimke immuno-osseous dysplasia.

Schimke immuno-osseous dysplasia (SIOD) is caused by SMARCAL1 deficiency and characterized by defective T-cell immunity. The immunodeficiency and the role of thymic function in SIOD patients are not clearly understood. We performed thymic evaluations by assessing T-cell receptor (TCR) diversity, rearrangement, and excision circles in family members with different disease severity carrying the same bi-allelic mutation and in a heterozygous carrier. The expression of SMARCAL1 mRNA in a normal thymic sample was measured using real-time quantitative polymerase chain reaction. Thymus functions were significantly reduced in SIOD patients, and these findings were highly correlated with the clinical phenotype. Quantification of SMARCAL1 mRNA transcript was 3.86-fold higher than normal values for adult kidneys. Genotype alone apparently does not define phenotype, and analysis of TCR diversity, rearrangement, and thymus output can quantify the extent of T-cell immunodeficiency. High thymic expression of SMARCAL1 mRNA raises the possibility of its importance in thymus maintenance and function.

Reduced central tolerance in Omenn syndrome leads to immature self-reactive oligoclonal T cells.

BACKGROUND: Omenn syndrome (OS) is characterized by a peculiar severe T-cell immune deficiency associated with autoimmunelike manifestations. Dysregulations of the central and peripheral immune tolerance, mediated by the protein autoimmune regulator (AIRE) and regulatory T cells, respectively, were proposed as possible mechanisms of this aberrant inflammatory process. OBJECTIVE: We studied mechanisms of central and peripheral tolerance in patients with OS and also examined the gene expression profile associated with OS features. METHODS: T-cell receptor diversity, DNA rearrangement, and the expression of AIRE and forkhead box P3 mRNA as well as the expression of regulatory T cells in cells obtained from patients with OS were studied. Characterization of gene expression in these cells was carried out by using the TaqMan Low-Density Array. RESULTS: Transcript expression of peripheral blood AIRE but not forkhead box P3 was reduced in patients with OS. The expression of natural killer T and regulatory T cells was normal, although the latter showed an abnormal CD4-negative population. Patients with OS have oligoclonal T cells with limited DNA recombination activity, including the presence of early but not late T-cell maturation events, regardless of the genetic defect underlying the syndrome. The transcriptional profile associated with OS features reveals significant changes in 25.5% of the tested genes compared with normal control. CONCLUSION: Our findings suggest that T-cell oligoclonal expansion in OS emanates from an incomplete block before the maturation stage of negative selection, which may explain escape of autoreactive T cells from the thymus. Dysregulated genes in patients with OS are closely involved with self-tolerance and autoimmunity.

The effect of active immunization on varicella-related hospitalizations in Israel.

The purpose of this study is to report on the impact of introduction of the varicella vaccine "Varilix" on hospitalizations due to varicella, following licensure in Israel in June, 2000. Data on children hospitalized throughout Israel with the diagnosis of varicella were collected from 1998 until 2003. The national rate of varicella-related hospitalizations decreased during the period 2001-2002. However in 2003 an increase in hospitalization occurred. Based on an assumption that at least 22,000 vaccinations per year were administered, we estimate that there is a greater than 60% reduction in the risk for hospitalization in the immunized population (RR = 0.32; 0.10-1.00). In summary, no national trend in reduction of hospitalization has yet been observed, but a significant reduction in hospitalization is apparent for vaccinated children.

Leptin and C-reactive protein levels correlate during minor infection in children.

BACKGROUND: Leptin, a pleiotropic hormone, has been suggested to be part of an acute-phase response during an inflammatory stimulus. Its correlation with other acute-phase reactants during minor infection in children has not been investigated. OBJECTIVES: To study the correlation between levels of serum leptin and those of C-reactive protein, a well-documented acute-phase reactant, in a series of pediatric patients with acute minor infections. METHODS: Leptin and CRP levels were measured in 62 blood samples of pediatric patients presenting with mild febrile illness who were admitted to Dana Children's Hospital in Israel. All children were finally diagnosed as having minor infection based on the negative blood/urine cultures and favorable outcome. RESULTS: Serum leptin level was positively correlated with CRP (r2 = 0.5), total white blood cells (r2 = 0.33) and absolute neutrophil count (r2 = 0.31). The regression coefficient was the highest between leptin and CRP. CONCLUSIONS: Circulating leptin concentrations are positively correlated with CRP levels during acute minor infection in children visiting the emergency room for febrile illnesses. Our observation suggests that leptin is indeed a part of acute-phase proteins. The wide scattering showed that it is not a better marker in minor infections than CRP, but it may contribute to weight loss and anorexia seen in a minority of patients during mild infections.

Post-splenectomy antibiotic prophylaxis--unfinished story: to treat or not to treat?

Overwhelming infection in asplenic patients is a well documented occurrence in the literature. The introduction of immunization with polyvalent pneumococcal, Hemophilus Influenza and meningococcal vaccines significantly cut down the incidence of post-splenectomy sepsis and mortality. However, the issue of prophylactic antibiotic therapy in these patients remains inconclusive. There are contradictory reports bouncing between life-long treatment to no treatment. There are also more flexible approaches emerging from patient difficulties complying with a prolonged therapy. This debate calls for developing a better predictive approach based on genetic profiling of patients with different susceptibility to infectious pathogens, host-pathogens interactions as well as to identify the impact of factors such as age, on immunological competence.

Induced sputum as an additional tool in the identification of metal-induced sarcoid-like reaction.

BACKGROUND: Aluminium dust exposure produces asthma, chronic bronchitis, pulmonary fibrosis and granulomatous lung diseases. There is an increased risk of mistaken diagnosis of sarcoidosis when other interstitial lung diseases of known origin are occurring. CASE REPORT: We describe a case of a welder working in a stainless steel factory who had been exposed for more than 20 years to a dusty environment containing high levels of hazardous dust. He underwent lung function studies, a beryllium-lymphocyte transformation test (BeLTT), induced sputum (IS) analysis, aluminum-induced blastic proliferation test, and mineralogical and immunologic studies. The lung function tests raised the suspicion of sarcoidosis. T cell subsets recovered from induced sputum disclosed a helper T lymphocyte alveolitis, and transbronchial biopsies showed sarcoid-like epithelioid granulomata. Peripheral blood lymphocytes exhibited blastic transformation in the presence of soluble aluminium compounds. Scanning electron microscope studies from induced sputum-retrieved material showed abundant particles of aluminum. His final diagnosis was sarcoid-like granulomatous-induced aluminium disease. CONCLUSION: We propose an alternative non-invasive approach to identify antigenic metals in occupational exposures.

Genetic predisposition to infectious pathogens: a review of less familiar variants.

The susceptibility and clinical manifestations of infectious diseases in human populations are influenced by a variety of factors, among them host genetics. Obvious examples for the effect of host genetics on predisposition to unique infections are the primary immunodeficiency diseases. Minor gene variants that influence the host immune system are much more common. The iceberg model can be used to illustrate the epidemiology of immunodeficiency states. Accordingly only a few individuals have known and severe recognized primary immunodeficiencies, whereas many more patients have mild immunodeficiencies that may remain undiagnosed and are predisposed to a unique infectious disease. We review some of the less common variants that influence the host defense and predispose to certain infectious agents or change their outcome.

Celiac disease: extraintestinal manifestations, associated diseases, and complications.

The aim of this chapter is to increase the familiarity of physicians with conditions or complications associated with CD, a disease that is more common than had been thought in the past. The differentiation between atypical manifestations, associated disease, and complications of CD is not always clear. With careful adherence to the necessary dietary restrictions, patients with CD can remain relatively free of troublesome symptoms, their long-term prognosis is excellent, and most complications can be prevented. (24) Indeed, 5-year survival rates of patients with CD did not differ from those in the general population. (6) This review emphasizes the importance of a screening policy for silent CD, justified on the basis of later developing complications such as malignancy, development of low bone mineral density, risk of neurologic abnormalities, and associated diseases, which may be preventable by GFD.