Secondary Immunodeficiency Diseases Research Articles

Pharmacological properties of endemic plants growing in the steppes of Kazakhstan

The number of people who suffer from secondary immunodeficiency diseases is increasing. Secondary immunodeficiency diseases develop due to environmental degradation, abuse of various preservatives, stabilizers in foods and long-term storage products, abuse of the use of drugs with a cytostaticeffect, the use of antibiotics in the cultivation of cattle and poultry. The compoundswere obtained fromplants of the Halostachys caspica (Pall) C.A.Mey.ex Schrenk,Suaeda microphylla Pall., Climacoptera obtusifolia (Schrenk) Botsch.Plant extracts were investigatedon myelostimulating activity. The compoundobtained from plants of the Halostachys caspica (Pall) C.A.Mey.ex Schrenk by means of water-alcoholextractionwithout heating showed high myelostimulating activity. It effectively stimulated erythro-,thrombocyto- and leukopoiesis, and in stimulating the leukocyte population, it equally effectively increased the values of granulocyte and agranulocyte leukocytes. The compounds derived from the Suaedamicrophylla Pall. and Climacoptera obtusifolia (Schrenk) Botsch.showed low myelostimulating activity.It should be noted that the water-alcohol extracts of plants without heating showed higher activity thanthe extracts that have undergone thermal heating.Key words: myelostimulating activity, endemic plants, steppes of Kazakhstan.

Primary and Secondary Immunodeficiency Diseases in Oncohaematology: Warning Signs, Diagnosis, and Management.

Background: Immunodeficiencies (ID), in particular primary immunodeficiencies (PID), are often associated with haematological manifestations, such as peripheral cytopenias or lymphoproliferative syndromes. Early diagnosis and management have significant prognostic implications. Secondary immunodeficiencies (SID) may also be induced by oncohaematological diseases and their treatments. Haematologists and oncologists must therefore be aware of the association between blood disorders and cancer and ID, and be prepared to offer their patients appropriate treatment without delay. Our aim was to define the warning signs of primary and secondary IDs in paediatric and adult patients with oncohaematological manifestations.Methods: A multidisciplinary group of six experts (2 haematologists, 2 immunologists, and 2 paediatricians specializing in ID) conducted a literature review and prepared a document based on agreements reached an in-person meeting. An external group of 44 IDs specialists from all over Spain assessed the document and were consulted regarding their level of agreement.Results: This document identifies the haematological and extra-haematological diseases that should prompt a suspicion of PIDs in adults and children, in both primary care and haematology and oncology departments. Cytopenia and certain lymphoproliferative disorders are key diagnostic pointers. The diagnosis must be based on a detailed clinical history, physical exploration, complete blood count and standard laboratory tests. The immunological and haematological tests included in the diagnostic process will depend on the care level. Patients who are candidates for immunoglobulin replacement therapy must be carefully selected, and treatment should be offered as soon as possible to avoid the development of complications. Finally, this document recommends procedures for monitoring these patients.Conclusions: This document combines scientific evidence with the opinion of a broad panel of experts, and emphasizes the importance of an early diagnosis and treatment to avoid complications. The resulting document is a useful tool for primary care physicians and specialists who see both adult and paediatric patients with oncohaematological diseases.

Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency.

Immunoglobulin replacement therapy (IRT) is often used to support patients with primary immunodeficiency disease (PID) and secondary immunodeficiency disease (SID). Home-based subcutaneous immunoglobulin (SCIg) is reported to be a cheaper and more efficient option compared to hospital-based intravenous immunoglobulin (IVIg) for PID. In contrast, there is little information on the cost-effectiveness of IRT in SID. However, patients who develop hypogammaglobulinaemia secondary to other conditions (SID) have different clinical aetiology compared to PID. This study assesses whether SCIg provides a good value-for-money treatment option in patients with secondary immunodeficiency disease (SID). A Markov cohort simulation model with six health states was used to compare cost-effectiveness of IVIg with SCIg from a healthcare system perspective. The costs of treatment, infection and quality-adjusted life years (QALYs) for IVIg and SCIg treatment options were modelled with a time horizon of 10 years and weekly cycles. Deterministic and probabilistic sensitivity analyses were performed around key parameters. The cumulative cost for IVIg was A$151 511 and for SCIg A$144 296. The QALYs with IVIg were 3·07 and with SCIg 3·51. Based on the means, SCIg is the dominant strategy with better outcomes and at lower cost. The probabilistic sensitivity analysis shows that 88·3% of the 50 000 iterations fall below the nominated willingness to pay threshold of A$50 000 per QALY. Therefore, SCIg is a cost-effective treatment option. For SID patients in Queensland (Australia), the home-based SCIg treatment option provides better health outcomes and cost savings.

VALIDATION METHODS FOR QUANTITATIVE DETERMINATION OF 4,4'-DIMETHYL-7,7'-ETHYLENDIOXY-2H-1-DIBENZOPYRAN2,2'-DIONE SUBSTANCE

Introduction. One of the most promising synthetic compounds of coumarin derivatives is immunacor-4,4'-dimethyl-7,7'-ethylenedioxy-2H-1- dibenzopyran-2,2'-dione. As a result of preclinical studies, it has been shown that it is promising in medical practice as an immunomodulator for the treatment and prevention of secondary immunodeficiency diseases. Aim. The objective of this work is to develop methods for HPLC and UV spectrophotometry to determine the quantitative determination of the immunacor substance and to study the complex of validation characteristics of the developed methods. Materials and methods. Quantitative analysis of the substance was carried out by UV-Spectrophotometry and HPLC. Validation procedures were performed on parameters: specificity, linearity, accuracy and precision in accordance with the requirements of FP XIV. Results and discussion. Validation characteristics have been determined, and their compliance with the relevant eligibility criteria has been experimentally verified. Conclusion. Methods for quantitative determination of the active component in 4,4'-dimethyl-7,7'-ethylenedioxy-2H-1-dibenzopyran-2,2'-dione (immunacor) pharmaceutical substance by HPLC and UV spectrophotometry has been developed. It is established that methods are specific, accurate, precise and linear in the analytical field. The precision HPLC method far exceeds the UV-spectrophotometry.

Clinical and laboratory features of seventy-eight UK patients with Good's syndrome (thymoma and hypogammaglobulinaemia).

SummaryGood’s syndrome (thymoma and hypogammaglobulinaemia) is a rare secondary immunodeficiency disease, previously reported in the published literature as mainly individual cases or small case series. We use the national UK‐Primary Immune Deficiency (UKPID) registry to identify a large cohort of patients in the UK with this PID to review its clinical course, natural history and prognosis. Clinical information, laboratory data, treatment and outcome were collated and analysed. Seventy‐eight patients with a median age of 64 years, 59% of whom were female, were reviewed. Median age of presentation was 54 years. Absolute B cell numbers and serum immunoglobulins were very low in all patients and all received immunoglobulin replacement therapy. All patients had undergone thymectomy and nine (12%) had thymic carcinoma (four locally invasive and five had disseminated disease) requiring adjuvant radiotherapy and/or chemotherapy. CD4 T cells were significantly lower in these patients with malignant thymoma. Seventy‐four (95%) presented with infections, 35 (45%) had bronchiectasis, seven (9%) chronic sinusitis, but only eight (10%) had serious invasive fungal or viral infections. Patients with AB‐type thymomas were more likely to have bronchiectasis. Twenty (26%) suffered from autoimmune diseases (pure red cell aplasia, hypothyroidism, arthritis, myasthenia gravis, systemic lupus erythematosus, Sjögren’s syndrome). There was no association between thymoma type and autoimmunity. Seven (9%) patients had died. Good’s syndrome is associated with significant morbidity relating to infectious and autoimmune complications. Prospective studies are required to understand why some patients with thymoma develop persistent hypogammaglobulinaemia.

Adverse Effects of Immunoglobulin Therapy.

Immunoglobulin has been widely used in a variety of diseases, including primary and secondary immunodeficiency diseases, neuromuscular diseases, and Kawasaki disease. Although a large number of clinical trials have demonstrated that immunoglobulin is effective and well tolerated, various adverse effects have been reported. The majority of these events, such as flushing, headache, malaise, fever, chills, fatigue and lethargy, are transient and mild. However, some rare side effects, including renal impairment, thrombosis, arrhythmia, aseptic meningitis, hemolytic anemia, and transfusion-related acute lung injury (TRALI), are serious. These adverse effects are associated with specific immunoglobulin preparations and individual differences. Performing an early assessment of risk factors, infusing at a slow rate, premedicating, and switching from intravenous immunoglobulin (IVIG) to subcutaneous immunoglobulin (SCIG) can minimize these adverse effects. Adverse effects are rarely disabling or fatal, treatment mainly involves supportive measures, and the majority of affected patients have a good prognosis.

Prevalence and Outcomes of Primary Immunodeficiency in Hospitalized Children in the United States

Primary immunodeficiency diseases (PIDDs) are rare yet life-threatening chronic conditions in children. The prevalence and outcomes of PIDDs in the pediatric population in the United States are not well understood. The objectives of this study were to (1) determine the epidemiology of children hospitalized with PIDD in the United States and (2) characterize the clinical outcomes of hospitalized children with PIDDs. Retrospective cohort analysis of the 2003-2012 Kids' Inpatient Database of children aged 2-18 years admitted with a primary or secondary diagnosis code of PIDD was performed. Secondary immunodeficiency diseases were excluded. There were 26,794 pediatric patients hospitalized with a diagnosis of a PIDD from 2003 to 2012. The national prevalence of all PIDDs per 100,000 was 66.6, 82.2, 97.4, and 126.8 in 2003, 2006, 2009, and 2012, respectively. The highest prevalence was in children 0-5 years of age (15,105 hospitalizations; 56%). There was no difference in prevalence between B-cell defects and T-cell defects. PIDDs affected all ethnic populations equally. Respiratory-related diagnoses were the most common comorbidity by an organ system. Overall mortality was 1.99%. Age was inversely correlated with clinical outcome. Children 0-5 years had higher mortality (424 deaths, 79.85%), mean hospital charges ($35,480), and length of stay (LOS) (5.6 days) compared with older age cohorts. The prevalence of PIDDs in the hospitalized pediatric population in the United States may have increased over time. Younger age is associated with higher mortality, hospital costs, and LOS. Further study is needed to determine cost-effective management strategies to improve outcomes in infants and young children with PIDD.

Improved outcomes on subcutaneous IgG in patients with humoral immunodeficiency and co-morbid bowel disease.

Immunoglobulin replacement can be life-saving for certain individuals with immunodeficiencies. Subcutaneous IgG (SCIG) is an increasingly used method of replacement over intravenous IgG (IVIG), with potential advantages including fewer systemic side effects, no need for IV access, patient-reported improved quality of life, and decreased cost. However, while patients with certain associated co-morbidities, such as protein-losing enteropathy, may demonstrate more stable IgG levels when on SCIG compared to IVIG, the clinical significance of these experiences is not well described. Using retrospective chart review, we examined three cases in which SCIG and IVIG was administered to patients with either common variable immunodeficiency (CVID) or secondary humoral immunodeficiency and protein-losing gastrointestinal co-morbid disease. Both outpatient and inpatient records were reviewed for data regarding treatment with IVIG versus SCIG, reported frequency and severity of infections, hospitalizations, and IgG levels. All three patients demonstrated improvement in infection rate, stability of IgG levels, and co-morbid disease when on SCIG as compared to IVIG. These findings suggest that the pharmacokinetics of SCIG may translate into more consistent serum IgG levels, contributing to clinical improvement in immunodeficient patients with protein-losing comorbidities when compared to IVIG. Limitations to this study are small patient numbers, retrospective design, and potential therapeutic bias. Further characterization of the effects of co-morbid conditions on immunoglobulin replacement is critical to providing improved and informed patient care.

The T-cell-dependent antibody response assay in nonclinical studies of pharmaceuticals and chemicals: Study design, data analysis, interpretation

The T-cell-dependent antibody response (TDAR) assay is a measure of immune function that is dependent upon the effectiveness of multiple immune processes, including antigen uptake and presentation, T cell help, B cell activation, and antibody production. It is used for risk and safety assessments, in conjunction with other toxicologic assessments, by the chemical and pharmaceutical industries, and research and regulatory agencies. It is also employed to evaluate investigational drug efficacy in animal pharmacology studies, provide evidence of biological impact in clinical trials, and evaluate immune function in patients with primary or secondary immunodeficiency diseases. Various immunization schemes, analytical methods, approaches to data analysis, and data interpretations are in use. This manuscript summarizes some recommended practices for the conduct and interpretation of the assay in animal studies.

Use of intravenous immunoglobulin in human disease: A review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology

Human immunoglobulin prepared for intravenous administration (IGIV) has a number of important uses in the treatment of disease. Some of these are in diseases for which acceptable treatment alternatives do not exist. In this review we have evaluated the evidence underlying a wide variety of IGIV uses and make specific recommendations on the basis of these data. Given the potential risks and inherent scarcity of IGIV, careful consideration of the indications for and administration of IGIV is warranted.

Safety monitoring of a polyvalent immunoglobulin preparation: documentation of 15,548 administrations

Between 1997 and 2002, a post-marketing surveillance study was conducted throughout Germany to evaluate Intraglobin F in a replacement therapy for primary and secondary immunodeficiency diseases. A total of 15,548 individual administrations in 1,705 patients were documented. The study was conducted as a multicenter project involving 72 outpatient and inpatient treatment centers in Germany. The study variables were recorded during the routine treatment of patients with congenital or acquired immunodeficiencies. No additional variables outside the normal routine were recorded as is mandatory in post-marketing surveillance studies. The rate of adverse drug reactions (ADR) was 0.064% in 15,548 administrations or 0.59% with reference to 1,705 treated patients; eight non-serious adverse events (AE) were considered to have a "probable" and one further AE a "possible" causal association with the use of Intraglobin F. Only one AE assessed as "serious" was classified as "probably" treatment-related. The efficacy of Intraglobin F was rated by the treating physicians as "very good" or "good" in 91.8% of the evaluated patients. This post-marketing surveillance study has demonstrated the safety of Intraglobin F. The statistical results obtained with the data are supported by the overall assessment of the treating physicians who rated the tolerability of Intraglobin F as "very good" or "good" in 98.5% of the patients. No new or unexpected risks were observed.

Non-ST Segment Elevation Myocardial Infarction Associated with IV Infusion of Immunoglobulin

INTRODUCTION IVimmunoglobulin (IVIG) is used in the treatment of a variety of disorders, including primary and secondary immunodeficiency diseases, Kawasaki disease, and idiopathic thrombocytopenia purpura.1 Although serious adverse cardiovascular reactions are rare, a recent article reviewed 28 published cases of thrombotic complications occurring in association with IVIG administration between 1986 and 2003.2 An additional 36 cases reported recently3-9 were not included in the review. This article describes 2 patients treated in the same month at the authors’ institution for non-ST segment elevation myocardial infarction possibly associated with IVIG administration. To the authors’ knowledge, case 1 represents the first reported case of a patient experiencing non-ST segment elevation myocardial infarction after each of 2 consecutive doses of IVIG.

Historical and current perspectives on bone marrow transplantation for prevention and treatment of immunodeficiencies and autoimmunities.

Primary immunodeficiency diseases often fully meet the definition of "experiments of nature." Much of the expanding understanding of the lymphoid systems and immunologic functions generated in recent years has been derived from studying patients with primary, generally genetically determined immunodeficiency diseases, as well as other relatively rare secondary immunodeficiency diseases. Increasing knowledge of immunologic defenses, their interacting cellular and molecular components, the evolving details of sequential stages of cellular differentiation, and the nature and control of the cellular and molecular interactions in immunity have now made it possible to define precisely many primary immunodeficiency diseases in full molecular genetic terms. With this wealth of scientific information based on experimental and clinical research, incredible advances have also been made in using bone marrow transplantation (BMT) often as a curative treatment for immunodeficiency, some 60 to 70 other diseases, leukemias, lymphomas, other cancers, and a rapidly expanding constellation of metabolic diseases or enzyme deficiencies. Also, progress in applying allogeneic BMT to prevent, treat, and cure complex autoimmune diseases, primary immunodeficiency diseases and certain forms of cancers, is considered. Further, mixed BMT (syngeneic plus allogeneic) that establishes a form of stable mixed chimerism has also been employed in animal experiments, which revealed that BMT can be used to treat not only immunodeficiency diseases, but also systemic and organ-specific autoimmune diseases, eg, diabetes and erythematous lupus-like diseases. Moreover, performing BMT in conjunction with organ allografts, eg, thymus or pancreatic transplants, has successfully prevented rejection of these allografts, sometimes without recourse to long-term irradiation or toxic chemical immunosuppressive agents. A crucial role for stromal cells in cellular engineering has now also been realized in animal models as a means of preventing graft rejection and promoting full and persistent reconstitution or correction of genetically-based diseases. With all of these achievements, BMT promises continued dramatic and impressive new approaches to clinical and scientific research and reveals an attractive strategy for the treatment and prevention of many currently intractable human diseases. If these achievements can be extended to larger outbred animals and humans, BMT may set the stage for induction of improved immunologic tolerance and for developing treatments for additional intractable human diseases in the 21st century.

Immunologic Disorders in Infants and Children,

A working knowledge of immunology is as important to pediatricians as is a working knowledge of biochemistry, genetics, pharmacology, or any of the other "basic sciences." For example, the primary immunodeficiency diseases are not nearly as uncommon as originally supposed; a new secondary immunodeficiency disease, acquired immunodeficiency syndrome, has touched nearly every practice. There is a growing appreciation that the immune system is important in the pathophysiology of a variety of pediatric illnesses. The third edition of this classic text successfully combines both basic and clinical immunology into one book and is the one immunology text pediatricians should have on their shelf. The book is divided into three sections. The first section covers basic immunology, with special attention paid to developmental aspects; the second section focuses on immunodeficiency diseases, both primary and secondary; and the third section is a review of immunologic aspects of pediatric illnesses. The first section on

Monoclonal gammopathies in children

Over a 10-year period sera of 4000 pediatric patients were subjected to agar gel electrophoresis and immunoelectrophoresis. Retrospective examination of the electrophoresis patterns indicated that single or multiple homogeneous immunoglobulin components were present in sera of 155 children (3.9%). They were most frequently found in patients suffering from primary and secondary immunodeficiency diseases, hematological malignancies, autoimmune diseases, and severe aplastic anemia. Follow-up analysis revealed that most of these monoclonal gammopathies were transient. The monoclonal gammopathies in the serum of 79 patients were identified by immunoblotting for class and light-chain isotypes. A marked absence of IgA monoclonal gammopathies and a predominance of monoclonal gammopathies of the lambda light-chain isotype were found. Most of the B-cell mono- or oligoclonal proliferations in children can probably develop due to a disturbance in the regulatory T-cell function.

The child with frequent infections

In this review, the normal immune system, primary and secondary immunodeficiency diseases, and nonimmunologic causes of recurrent infection have been described. With this information, any child with frequent infections can be evaluated in a sound and logical fashion. The history and physical examination are usually sufficient to rule out a significant immunodeficiency. For those in whom that is not the case, screening laboratory tests, most of which are readily available in hospitals and commercial laboratories, can and should be performed by the primary caretaker. These serve conclusively to rule in or rule out an immunodeficiency disorder in most patients and to establish the need for referral to an immunologist in the rare patient. With a few notable exceptions, the prognosis for children with immunodeficiency diseases has improved dramatically in the past two decades. This progress, fortunately, is certain to continue as the intricacies of the immune system and its genetic basis are gradually unraveled. However, the success of these new technologies depends on the ability of the primary pediatrician to identify these patients early, before permanent structural damage has occurred or a life-threatening viral infection been acquired.

Chronic Epstein-Barr virus infection.

The Epstein-Barr virus (EBV) has been associated with classic infectious mononucleosis, Burkitt's lymphoma, nasopharyngeal carcinoma, and B-cell lymphomas in primary and secondary immunodeficiency disease. The availability of specific serologic diagnosis of EBV, rather than dependence on heterophile antibody positivity, has broadened the scope of EBV-associated diseases. A chronic neuroasthenia syndrome accompanied by antibody titers to the viral capsid antigen and early antigen of EBV, which are higher than found in asymptomatic individuals, is one such additional EBV-associated syndrome. This paper describes the clinical and laboratory responses to EBV that are present in this chronic syndrome. It then discusses management of these patients and the difficulties in establishing a cause-and-effect relationship between EBV and chronic neuroasthenia along with recommendations for future studies.

Evaluation of lymphocyte differentiation in primary and secondary immunodeficiency diseases.

The differentiation status of T and B cells was evaluated in patients with common variable immunodeficiency (CVI), selective IgA deficiency (IgA), X-linked agammaglobulinemia (XLA), and the acquired immune deficiency syndrome (AIDS) with the use of conventional lymphocyte markers and four new monoclonal antibodies that identify lymphocyte subpopulations. These antibodies are HB 4, which identifies a subpopulation of resting B cells; HB 5, which identifies the C3d/EBV receptor on mature B cells; HB 7, which identifies immature B lymphocytes; and HB 10, which reacts with virgin but not activated or memory T cells. T and B cells from the IgA patients typically had normal phenotypic profiles, whereas diverse patterns of lymphocyte maturation were observed in CVI. In 11 of 16 CVI patients, B cells had normal antigenic phenotypes. Although B cells from four other CVI patients had normal frequencies of HB 5 and HB 7 antigen expression, few expressed the HB 4 antigen, suggesting that they were activated. In contrast, a large percentage of B cells from one CVI patient were of an immature phenotype. The expression of the HB 10 antigen by T cells in CVI patients was also variable, being normal in 10 of 16 patients, yet significantly decreased in six others. The vast majority of the limited numbers of IgM B cells from five XLA patients (greater than 100-fold reduction) has an immature phenotype (HB 4-5-7+). Interestingly, the circulating T cells in XLA patients were phenotypically similar to those in normal newborns, suggesting that T cell immaturity or defective T cell activation may occur in these B cell-deficient individuals. Circulating B cells from AIDS patients were mostly HB 7-, with variable expression of the HB 4 antigen and significantly decreased expression of the HB 5 antigen. Most of the T cells from AIDS patients were HB 10-, and thus appeared to be activated.

A subset of rheumatoid arthritis patients with a pattern of Epstein-Barr virus antibodies similar to that found in primary and secondary immunodeficiency diseases.

A subset of rheumatoid arthritis patients with a pattern of Epstein-Barr virus antibodies similar to that found in primary and secondary immunodeficiency diseases.

8 Thymic Hormones in Primary Immunodeficiency

The central role of the thymus gland in the development and maintenance of the immune system is recognized. Biochemically characterized thymic extracts are capable of differentiating human prethymic cells. The precise mechanism of differentiation by thymic factors is poorly defined. Thymosin fraction 5, thymostimulin, thymic humoral factor, thymopoietin and TP5 differentiate a subpopulation of isolated peripheral blood null lymphocytes (T cell rosette negative, surface immunoglobulin negative) from humans to form T cell rosettes. Bone marrow stem cells, isolated both from normal individuals and from some patients with primary immunodeficiency disease, can be differentiated to HTLA-positive, T cell rosetteforming cells. In some situations, T cell function as assessed by response to allogeneic cells or plant lectins is increased after incubation with thymic factors. Peripheral blood lymphocytes isolated from some children with primary or secondary immunodeficiency disease or from adults with autoimmune disease or malignancy have been incubated with thymic factors. Enhanced T cell rosette formation has occurred in a subgroup of these patients. Notably, children with severe combined immunodeficiency without stem cells have not had increased T cell rosette formation. The most important potential contribution of thymic factor research will be its precise application to the treatment of disease in humans. The understanding of the differentiation of human T cells is increasing and will allow us to define the pathogenesis of immunodeficiency disease in the human. Eventually, correlating disease pathogenesis with specific thymic factor effect(s) should allow for a logical approach to replacement therapy.