Immunoglobulin Substitution Therapy Research Articles

Case report: Persistent hypogammaglobulinemia and mixed chimerism after HLA class-II disparate-hematopoietic stem cell transplant

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for various hematological, immunological and metabolic diseases, replacing the patient’s hematopoietic system with donor-derived healthy hematopoietic stem cells. HSCT can be complicated by early and late events related to impaired immunological recovery such as prolonged hypogammaglobulinemia post-HSCT. We present a 16-year-old female patient with sickle-cell disease who underwent HSCT with stem cells from a human leukocyte antigen (HLA) class-II mismatched family donor. While cellular recovery was good post-HSCT, the patient developed mixed chimerism and suffered from cervical lymphadenopathy, recurrent airway infections and cutaneous SLE. She presented with hypogammaglobulinemia and was started on immunoglobulin substitution therapy and antibiotic prophylaxis. B-cell phenotyping showed that she had increased transitional and naïve mature B cells, reduced memory B cells, and diminished marginal zone/natural effector cells. In-depth immunophenotyping and B-cell receptor repertoire sequencing ruled out an intrinsic B-cell defect by expression of activation-induced cytidine deaminase (AID), presence of somatic hypermutations and differentiation into IgG- and IgA-producing plasma cells in vitro. Immunohistochemistry and flow cytometry of lymph node tissue showed a clear block in terminal B-cell differentiation. Chimerism analysis of sorted lymph node populations showed that exclusively patient-derived B cells populated germinal centers, while only a minor fraction of follicular helper T cells was patient-derived. Given this discrepancy, we deduced that the HLA class-II disparity between patient and donor likely hinders terminal B-cell differentiation in the lymph node. This case highlights that studying disturbed cognate T-B interactions in the secondary lymphoid organs can provide unique insights when deciphering prolonged hypogammaglobulinemia post-HSCT.

Immunoglobulin-Substitutionstherapie bei hämatologischen Patienten mit sekundärem Antikörpermangel

Immunglobulin Substitution Therapy in Hematological Patients with secondary Antibody Deficiency Abstract. Hematological malignancies and immunochemotherapy are frequently associated with secondary cellular and humoral immunodeficiencies. Due to the growing application of effective therapeutic antibodies, and cellular therapies specifically targeting and hence depleting antibody producing cells (B- and plasma cells) the incidence of secondary antibody deficiencies in the daily practice is increasing. This article will provide a short overview of the etiology of secondary antibody deficiencies in hematological patients. Then, it will discuss the efficacy and indication of immunoglobulin substitution therapy in these patients and finally address the choice of the respective preparation.

Impaired memory B‐cell development and antibody maturation with a skewing toward IgE in patients with STAT3 hyper‐IgE syndrome

Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is caused by heterozygous mutations in the STAT3 gene and is associated with eczema, elevated serum IgE, and recurrent infections resembling severe atopic dermatitis, while clinically relevant specific IgE is almost absent. To investigate the impact of STAT3 signaling on B-cell responses, we assessed lymph node and bone marrow, blood B and plasma cell subsets, somatic hypermutations in Ig genes, and in vitro proliferation and antibody production in STAT3-HIES patients and healthy controls. Lymph nodes of STAT3-HIES patients showed normal germinal center architecture and CD138+ plasma cells residing in the paracortex, which expressed IgE, IgG, and IgM but not IgA. IgE+ plasma cells were abundantly present in STAT3-HIES bone marrow. Proliferation of naive B cells upon stimulation with CD40L and IL-4 was similar in patients and controls, while patient cells showed reduced responses to IL-21. IgE, IgG1, IgG3 and IgA1 transcripts showed reduced somatic hypermutations. Peripheral blood IgE+ memory B-cell frequencies were increased in STAT3-HIES, while other memory B-cell frequencies except for IgG4+ cells were decreased. Despite impaired STAT3 signaling, STAT3-HIES patients can mount in vivo T-cell-dependent B-cell responses, while circulating memory B cells, except for those expressing IgG4 and IgE, were reduced. Reduced molecular maturation demonstrated the critical need of STAT3 signaling for optimal affinity maturation and B-cell differentiation, supporting the need for immunoglobulin substitution therapy and explaining the high IgE serum level in the majority with absent allergic symptoms.

Fcγ-receptor polymorphisms associated with clinical symptoms in patients with immunoglobulin G subclass deficiency

Background: Immunoglobulin G subclass deficiencies (IgGsd) are associated with recurrent respiratory tract infections. Immunoglobulin substitution therapy may be needed to prevent chronic lung tissue damage but tools for identifying the patients that will benefit from this treatment are still insufficient. Some FcγR polymorphisms seem to predispose for an increased risk for infections. In this study we wanted to evaluate if the FcγR-profile differs between individuals with IgGsd and a control population.Methods: Single nucleotide polymorphisms (SNPs) of FcγRIIa, FcγRIIIa and FcγRIIc in 36 IgGsd patients and 192 controls with similar sex and geographical distribution were analyzed by TaqMan allelic discrimination assay or Sanger sequencing.Results: In the IgGsd-group, homozygous frequency for FcγRIIa-R/R131 (low-binding capacity isoform) was higher (p = .03) as well as for non-classical FcγRIIc-ORF (p = .03) and classical FcγRIIc-ORF tended (p = .07) to be more common compared to the controls. There was no difference between the groups regarding FcγRIIIa.Conclusion: The gene for classical FcγRIIc-ORF tended to be more frequent in individuals with immunoglobulin G subclass deficiency and the genes for non-classical FcγRIIc-ORF as well as low-binding capacity receptor FcγRIIa-R/R131 were more frequent. Further studies on the FcγR polymorphisms may pave way for identifying individuals that will benefit from immunoglobulin substitution.

Antibodies against Pneumococcal Capsular Polysaccharides and Natural Anti-Galactosyl (Alpha-Gal) in Patients with Humoral Immunodeficiencies.

Humoral deficiencies represent a broad group of disorders. The aim of the study was to compare the levels of antibodies against pneumococcal capsular polysaccharides (anti-PCP) and natural anti-galactosyl (anti-Gal) antibodies in (1) patients with chronic lymphocytic leukaemia (CLL), (2) patients with common variable immunodeficiency (CVID), and (3) a healthy population and to explore their diagnostic and prognostic potential. Serum immunoglobulin levels and levels of anti-Gal IgG, IgA, and IgM and anti-PCP IgG and IgG2 were determined in 59 CLL patients, 30 CVID patients, and 67 healthy controls. Levels of IgG, IgA, IgM, anti-Gal IgA, anti-Gal IgM, and anti-PCP IgA were lower in CLL and CVID patients than in healthy controls (p value for all parameters < 0.0001). Decrease in the levels of IgA, IgM, anti-Gal IgA, and anti-PCP IgA was less pronounced in the CLL group than in the CVID group. IgA decline, anti-Gal IgA, anti-PCP IgA, and anti-PCP IgG2 were negatively correlated with CLL stage. We devise the evaluation of anti-Gal antibodies to be a routine test in humoral immunodeficiency diagnostics, even in cases of immunoglobulin substitution therapy. Significant reductions, mainly in anti-Gal IgA, IgM, and anti-PCP IgA levels, may have prognostic importance in CLL patients.

Clinical Heterogeneity of Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is the most common, clinically relevant, primary immunodeficiency (PID). In the western world the incidence of this disease is about 1:50000. CVID is characterized by hypogammaglobulinemia which involves in all cases immunoglobulin G (IgG), in about 70-80% of cases immunoglobulin A (IgA) and in about 50% of cases immunoglobulin M (IgM). Additionally, patients with CVID develop weak or no immunization responses against polysaccharide (mainly) and protein antigens. Clinical manifestations of CVID may present either early in childhood or late in adulthood, usually between the third and fourth decade of life. The range of CVID clinical manifestations is broad. Underlying CVID should be considered mainly in cases of patients who present with recurrent or persistent bacterial infections of the upper or lower respiratory tract. The possibility of underlying CVID has also to be examined during laboratory investigation of various clinical syndromes, such as lymphadenopathy, hepatosplenomegaly, chronic diarrhea, or malabsorption, and also of autoimmune cytopenias such as idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia. It is noteworthy, that autoimmune diseases and malignancies in the form of lymphoma and neoplasm of the gastrointestinal tract occur with increased incidence in CVID patients in comparison to the general population. Treatment strategy of CVID patients should not be limited to immunoglobulin substitution therapy (administered either intravenously or subcutaneously), but it also has to target effective management of infections and early diagnosis of occurring malignancies (lymphomas and gastrointestinal tumors) through systematic patient monitoring. With regard to life expectancy of CVID patients, two recently published large retrospective studies showed that CVID patients suffering only from infections had prolonged overall survival compared to those who presented with other CVID clinical manifestations. Exclusion of all potential causes of secondary hypogammaglobulinemia is mandatory for establishing the diagnosis of CVID. Also, in some CVID cases, differential diagnosis from other PID may be required, such as X-linked agammaglobulinemia (XLA), antibody deficiency with increased IgM (Hyper-IgM syndrome), and X-linked lymphoproliferative syndrome (XLP).

Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency

The clinical and immunologic features of CD27 deficiency remain obscure because only a few patients have been identified to date. We sought to identify novel mutations in TNFRSF7/CD27 and to provide an overview of clinical, immunologic, and laboratory phenotypes in patients with CD27 deficiency. Review of the medical records and molecular, genetic, and flow cytometric analyses of the patients and family members were performed. Treatment outcomes of previously described patients were followed up. In addition to the previously reported homozygous mutations c.G24A/p.W8X (n= 2) and c.G158A/p.C53Y (n= 8), 4novel mutations were identified: homozygous missense c.G287A/p.C96Y (n= 4), homozygous missense c.C232T/p.R78W (n= 1), heterozygous nonsense c.C30A/p.C10X (n= 1), and compound heterozygous c.C319T/p.R107C-c.G24A/p.W8X (n= 1). EBV-associated lymphoproliferative disease/hemophagocytic lymphohistiocytosis, Hodgkin lymphoma, uveitis, and recurrent infections were the predominant clinical features. Expression of cell-surface and soluble CD27 was significantly reduced in patients and heterozygous family members. Immunoglobulin substitution therapy was administered in 5 of the newly diagnosed cases. CD27 deficiency is potentially fatal and should be excluded in all cases of severe EBV infections to minimize diagnostic delay. Flow cytometric immunophenotyping offers a reliable initial test for CD27 deficiency. Determining the precise role of CD27 in immunity against EBV might provide a framework for new therapeutic concepts.

Analysis of specific IgG titers against tick-borne encephalitis in patients with primary antibody deficiency under immunoglobulin substitution therapy: impact of plasma donor origin.

Immunoglobulin (Ig) replacement therapy is effective in reducing infections in patients with primary antibody deficiency (PAD). Diversity of specific antibodies is achieved by pooling plasma from over 1000 donors usually of a given geographic region. However, there is no agreement with regard to an optimal vaccination schedule for plasma donors. Especially for tick-borne encephalitis (TBE), regional vaccination rates differ widely among populations due to the epidemiology of the disease. We analyzed specific antibody titers against TBE in comparison to total IgG levels in 162 serum samples collected from 110 PAD patients substituted with polyvalent intravenous IgG or subcutaneous IgG. Some patients received different IgG products over time leading to a total number of 122 different patient-IgG product combinations. Positive TBE-specific IgG levels were detected in 35 cases when measured by standard ELISA and could be confirmed by demonstration of neutralizing antibodies in 31 cases. The detection of specific antibody levels correlated with the geographic origin of the IgG preparations. No titers were detectable in patients substituted with IgG products from North-American donors, whereas variable degrees of anti-TBE titers were observed in patients receiving products from different European countries. We suggest considering the patients’ personal risk for TBE when selecting an appropriate Ig preparation. These data support regional plasma donation in order to address the diverse local infection profile.

Common variable immunodeficiency unmasked by treatment of immune thrombocytopenic purpura with Rituximab

BackgroundHypogammaglobulinemia may be part of several different immunological or malignant conditions, and its origin is not always obvious. Furthermore, although autoimmune cytopenias are known to be associated with common variable immunodeficiency (CVID) and even may precede signs of immunodeficiency, this is not always recognized. Despite novel insight into the molecular immunology of common variable immunodeficiency, several areas of uncertainty remain. In addition, the full spectrum of immunological effects of the B cell depleting anti-CD20 antibody Rituximab has not been fully explored. To our knowledge this is the first report of development of CVID in a patient with normal immunoglobulin prior to Rituximab treatment.Case presentationHere we describe the highly unusual clinical presentation of a 34-year old Caucasian male with treatment refractory immune thrombocytopenic purpura and persistent lymphadenopathy, who was splenectomized and received multiple courses of high-dose corticosteroid before treatment with Rituximab resulted in a sustained response. However, in the setting of severe pneumococcal meningitis, hypogammaglobulinemia was diagnosed. An extensive immunological investigation was performed in order to characterize his immune status, and to distinguish between a primary immunodeficiency and a side effect of Rituximab treatment. We provide an extensive presentation and discussion of the literature on the basic immunology of CVID, the mechanism of action of Rituximab, and the immunopathogenesis of hypogammaglobulinemia observed in this patient.ConclusionsWe suggest that CVID should be ruled out in any patient with immune cytopenias in order to avoid diagnostic delay. Likewise, we stress the importance of monitoring immunoglobulin levels before, during, and after Rituximab therapy to identify patients with hypogammaglobulinemia to ensure initiation of immunoglobulin replacement therapy in order to avoid life-threatening invasive bacterial infections. Recent reports indicate that Rituximab is not contra-indicated for the treatment of CVID-associated thrombocytopenia, however concomitant immunoglobulin substitution therapy is of fundamental importance to minimize the risk of infections. Therefore, lessons can be learned from this case report by clinicians caring for patients with immunodeficiencies, haematological diseases or other autoimmune disorders, particularly, when Rituximab treatment may be considered.

Vaccination against tick-borne encephalitis virus tests specific IgG production ability in patients under immunoglobulin substitution therapy

To assess B-cell function in patients under immunoglobulin (IgG)-replacement therapy, the non-licensed artificial bacteriophage (ΦX174)-neo-antigen may be used despite limited availability and experience. Active immunization against tick-borne encephalitis (TBE) is performed in few European countries. To test the feasibility of using licensed TBE vaccination as (neo-)antigen to determine residual or restored B-cell function in patients under regular IgG substitution, TBE-IgG levels were analyzed in 18 patients with ≥1–2 years of regular intravenous or subcutaneous IgG substitution and in pharmaceutical IgG-preparations ( n = 21 batches, 10 products). Six individuals were boosted against TBE. Although TBE-specific IgG was detectable in concentrates (281–57,100 VieU/0.5 μL), levels were only borderline in patient sera ( n = 31, 18 individuals; median 132 VieU; positive >155). Thus, TBE vaccination may be used to test B-cell function under IgG replacement therapy because IgG substitution appears insufficient to yield protective TBE-specific antibody levels in children.

Optimization of Immunoglobulin Substitution Therapy by a Stochastic Immune Response Model

BackgroundThe immune system is a complex adaptive system of cells and molecules that are interwoven in a highly organized communication network. Primary immune deficiencies are disorders in which essential parts of the immune system are absent or do not function according to plan. X-linked agammaglobulinemia is a B-lymphocyte maturation disorder in which the production of immunoglobulin is prohibited by a genetic defect. Patients have to be put on life-long immunoglobulin substitution therapy in order to prevent recurrent and persistent opportunistic infections.MethodologyWe formulate an immune response model in terms of stochastic differential equations and perform a systematic analysis of empirical therapy protocols that differ in the treatment frequency. The model accounts for the immunoglobulin reduction by natural degradation and by antigenic consumption, as well as for the periodic immunoglobulin replenishment that gives rise to an inhomogeneous distribution of immunoglobulin specificities in the shape space. Results are obtained from computer simulations and from analytical calculations within the framework of the Fokker-Planck formalism, which enables us to derive closed expressions for undetermined model parameters such as the infection clearance rate.ConclusionsWe find that the critical value of the clearance rate, below which a chronic infection develops, is strongly dependent on the strength of fluctuations in the administered immunoglobulin dose per treatment and is an increasing function of the treatment frequency. The comparative analysis of therapy protocols with regard to the treatment frequency yields quantitative predictions of therapeutic relevance, where the choice of the optimal treatment frequency reveals a conflict of competing interests: In order to diminish immunomodulatory effects and to make good economic sense, therapeutic immunoglobulin levels should be kept close to physiological levels, implying high treatment frequencies. However, clearing infections without additional medication is more reliably achieved by substitution therapies with low treatment frequencies. Our immune response model predicts that the compromise solution of immunoglobulin substitution therapy has a treatment frequency in the range from one infusion per week to one infusion per two weeks.

Common Variable Immunodeficiency Disorders in Children: Delayed Diagnosis Despite Typical Clinical Presentation

To characterize common variable immunodeficiency disorder (CVID) in childhood. We retrospectively investigated clinical findings in 32 children with primary CVID by questionnaire and file review. Clinical presentation included recurrent or chronic respiratory tract infections (88%), sinusitis (78%), otitis media (78%), and intestinal tract infections (34%), mainly with encapsulated bacteria. Meningitis was found in 25%, sepsis in 16%, and pyelonephritis in 16% of patients. Poliomyelitis after vaccination occurred in 2 patients and opportunistic infections occasionally. Allergic disorders were present in 38%, and autoimmune disease in 31% of patients. Eighty percent of the patients underwent surgical procedures because of recurrent infections. Growth retardation was seen in 28% of patients, and 16% showed retarded mental development. Bronchiectasis developed in 34%, and lymphoid proliferative disease in 13%. Incidence of allergic and autoimmune diseases was increased in first-degree relatives with normal immunologic findings. Mean time between symptoms and induction of immunoglobulin substitution therapy was 5.8 years (0.2-14.3). CVID in children presents with comparable symptoms and disorders as in adults. We found a significant influence on growth and development. The marked delay of diagnosis may be due to overlap with common pediatric disorders, while also reflecting insufficient awareness of these disorders.

Common variable immune deficiency and lung transplantation

We report on a male patient with bronchiectasis secondary to common variable immune deficiency (CVID) receiving lung transplantation. The patient had been diagnosed with CVID many y prior to right-sided single lung transplantation and was receiving appropriate immunoglobulin substitution therapy. He received antithymocyte globulin induction and maintenance triple therapy with cyclosporine, azathioprine and prednisolone. The early post-operative course was complicated by the development of severe acute cellular rejection and organizing pneumonia. Despite immunoglobulin replacement and antifungal prophylaxis and treatment, Aspergillus fumigatus was repeatedly cultured from bronchoalveolar lavage fluid, 18 months after transplantation. The patient died following a protracted period of repeated hospital admissions, 46 months after transplantation. A review of the literature suggests that many CVID patients appear to have had a complicated post-operative course after lung- and other solid-organ transplantation, and highlights the need for the establishment of international registries for transplanted patients with uncommon conditions.

Pharmacoeconomic evaluation of immunoglobulin treatment in patients with antibody deficiencies from the perspective of the German statutory health insurance.

Primary antibody deficiencies are the most common forms of primary immunodeficiencies. Substitution therapy with polyvalent immunoglobulins has been established as the standard therapy for antibody deficiencies for several decades. Until now mainly intravenous immunoglobulins (IVIG) have been used in Germany, and the majority of patients receive treatment in hospital outpatient clinics. In recent years subcutaneous administration of immunoglobulins (SCIG) has been developed which is administered as home self-infusion. Studies indicate no significant differences in immunoglobulin substitution therapy between SCIG and IVIG concerning outcome. We carried out a cost-minimization analysis to compare the two treatment alternatives in Germany. Under base case assumptions the treatment with SCIG is cost saving from the perspective of the German statutory health insurance. The main cost drivers are IVIG and SCIG; the incremental cost of SCIG compared to IVIG is most sensitive to changes in the immunoglobulin price and changes in the body weight of the patient.

Clinical, Immunological, and Molecular Analysis in a Large Cohort of Patients with X-Linked Agammaglobulinemia: An Italian Multicenter Study

A questionnaire-based retrospective clinical and immunological survey was conducted in 73 males with a definite diagnosis of X-linked agammaglobulinemia based on BTK sequence analysis. Forty-four were sporadic and 29 familial cases. At December 2000, the patients' ages ranged from 2 to 33 years; mean age at diagnosis and mean duration of follow-up were 3.5 and 10 years respectively. After the mid-1980s all but 2 were on intravenous immunoglobulin (IVIG) substitution therapy, with residual IgG >500 mg/dl in 94% of the patients at the time of enrollment. Respiratory infections were the most frequent manifestation both prior to diagnosis and over follow-up. Chronic lung disease (CLD) was present in 24 patients, in 15 already at diagnosis and in 9 more by 2000. The cumulative risk to present at diagnosis with CLD increased from 0.17 to 0.40 and 0.78 when the diagnosis was made at the ages of 5, 10, and 15 years respectively. For the 9 patients who developed CLD during follow-up, the duration of follow-up, rather than age at diagnosis; previous administration of intramuscular immunoglobulin; and residual IgG levels had a significant effect on the development of CLD. Chronic sinusitis was present in 35 patients (48%), in 15 already at diagnosis and in 20 by 2000. Sistemic infections such as sepsis and meningitis/meningoencephalitis decreased over follow-up, probably due to optimal protection provided by high circulating IgG levels reached with IVIG.

Early B cell defects.

The development of B lineage cells from haematopoietic stem cells in the bone marrow to mature antibody-secreting plasma cells in peripheral lymphoid tissues is a complex and tightly regulated process. The proliferation and maturation of these cells occurs in response to numerous signals from the bone marrow microenvironment, soluble cytokines, interaction with antigen and T lymphocytes and the expression of specific gene products. Lymphocyte development, in both T and B lineages, begins with the commitment of multipotent progenitors to the lymphoid lineage. It is likely that these early stages are in part dependent upon extracellular and stromal signals, though the exact mechanisms of early lymphoid commitment are not well defined. The transcription factor Ikaros appears to play an important role in these initial stages, since mice with targeted deletions of the Ikaros gene lack T, B and natural killer cell development [1]. By contrast, the transcription factors E2A and EBF appear to be more B cell-specific, in that mice that are unable to express these genes have normal numbers of T cells and myeloid cells but few if any B lineage cells [2–4]. The earliest stages of normal B cell development are antigen-independent and occur in the bone marrow in response to stromal cell contact and cytokines. From the pre-B cell stage onwards, B cell development is dependent upon the successful assembly, and functional signalling through, pre-B and B cell receptor complexes. Central to this process is expression of the individual components of the receptor and also the molecules that transduce signals from the receptor to initiate cellular events. This is diagrammatically represented in Fig. 1. The understanding of this highly organized developmental pathway comes not only from in vitro data and the generation of transgenic mice but also from the study of naturally occurring human gene abnormalities. In this review we will outline the major gene defects that result in early B lymphocyte maturation arrest and detail the clinical manifestations and the molecular pathogenesis of these conditions. Considerable emphasis will be devoted to X-linked agammaglobulinaemia (XLA), since this is the most common abnormality of B cell development. Fig. 1 The stages of B lymphocyte development in the bone marrow and periphery are outlined. The most significant B cell developmental block most commonly seen in individuals with X-linked agammaglobulinaemia (XLA) is shown by a dashed line at the pro B cell ... X-linked agammaglobulinaemia Clinical manifestations XLA was the first human immunodeficiency described for which the clinical and laboratory findings dictated effective therapy. In 1952 Bruton reported the case of an 8-year-old boy who had suffered from recurrent infections and in whom analysis of serum by protein electrophoresis revealed no demonstrable gammaglobulin fraction [5]. The boy was treated with monthly intramuscular injections of human gamma globulin with significant clinical improvement. Although there was no family history in this initial case, subsequent cases revealed a similar clinical phenotype with an X-linked pedigree [6,7]. The phenotype of XLA is characterized in its classical form by the almost complete absence of immunoglobulin of all isotypes and the profound reduction of B lymphocytes in the peripheral cir‐culation. As a result the majority of affected boys are prone to recurrent bacterial infection from the age of approximately 4–12 months following the disappearance of maternal immunoglobulin [8]. However, in a significant number of cases (21% in a survey of 44 patients) onset of infections may occur later at 3–5 years of age [9]. The infections are usually caused by pyogenic bacteria, with Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas being the most common species [8], although mycoplasmas are a significant cause of arthritis [10,11]. The site of infection varies considerably, with sinusitis, otitis media and lower respiratory tract infections being the most common [8,9]. Resistance to viral infection remains predominantly intact except for a susceptibility to enteroviral infection which most commonly results in chronic meningoencephalitis or poliomyelitis in a significant number of cases [12]. Indeed, the major cause of mortality in the series reported by Hermaszewski & Webster [9] was as a result of enteroviral meningoencephalitis. The incidence of enteroviral disease in current populations of XLA patients appears to be less frequent, a finding which may be a result of improved clinical monitoring of patients and optimal immunoglobulin substitution therapy. The disease has always been considered to be confined to the B lymphocyte compartment; however, up to 25% of patients with XLA have profound neutropenia at the time of diagnosis [13]. This may be due to endotoxaemia following severe infections experienced by these patients, or it may be a reflection of the need for the XLA gene product in myeloid cells in situations of stress.

Immunoglobulin deficiency and determination of pneumococcal antibody titers in patients with therapy-refractory recurrent rhinosinusitis.

We examined 245 patients with chronic rhinosinusitis not responding to prolonged antibiotic treatment and tested each patient for humoral antibody deficiencies. Low immunoglobulin levels were found in 22 patients. Five of them had defects of two or more immunoglobulin isotypes that were diagnosed as common variable immunodeficiency (CVI). Seventeen had an IgG-subclass deficiency. Before and after immunization with pneumococcal vaccine, serotype-specific pneumococcal antibody levels were determined to further evaluate the relevance of the underlying deficiency. Significantly reduced antibody titers of pneumococcal serotypes were found in CVI patients (n = 5), while immunization of 17 patients with IgG-subclass deficiency gave different results. Three of the 17 patients responded poorly to pneumococcal immunization and were prone to a polysaccharide specific immunodeficiency. Patients with CVI or IgG-subclass deficiency failing to produce protective antibody levels in more than five serotypes were chosen for antibiotic and/or immunoglobulin substitution therapy. Since recurrent sinusitis in these patients did not resolve with adequate conservative therapy, endonasal microsurgery was then performed and was seen to be a valuable therapeutic option. Our study suggests that an IgG-subclass deficiency may be the first sign of a basic immunological change, resulting in persisting sinus infections.

Tumor Necrosis Factor and Intravenous Gammaglobulins in Common Variable Immunodeficiency

Common variable immunodeficiency (CVI) patients require regular intravenous immunoglobulin substitution therapy (IVGG). We studied eight patients; four of whom had adverse reactions to IVGG, and found that those coincided with elevated tumor necrosis factor-α (TNF-α) levels daring infusion. Those reactions and TNF production were abolished by switching from one IVGG preparation to another in two patients. Reappearance of adverse reactions after switching preparation was preceded by a progressive rise in peak TNF levels in one patient.

Immunological Abnormalities in Pediatric Aids

HIV infection of a fetus from an infected mother has severe immunological implications because it destroys still immature immune system. The abnormalities observed are precocious in the infants. When the infection occurs in perinatal period, clinical and immunological manifestations can present themselves at the age of 2-5 years. Two patterns of HIV infection can be distinguished. Humoral immunodeficiency is present in a high proportion of patients and leads to repeated bacterial infections and progression of the disease. Immunoglobulin substitution therapy improves clinical manifestations and can help to avoid viral replication.

Immunoglobulin G subclass deficiencies.

Low levels of single or multiple serum immunoglobulin G (IgG) subclasses is a common finding among patients with increased susceptibility to infections. In this investigation we summarize data from studies of 503 subclass-deficient individuals. Low IgG2 levels was the most common deficiency among children, and boys were more often deficient than girls. From the age of 16, females dominated, and the most frequent finding was low IgG3 levels. In vitro T or B lymphocyte dysfunction was demonstrated in 75% of the individuals, suggesting that low subclass levels may be indicators of an underlying defect at the B cell or possibly T cell level. Vaccinations and mucosal biopsies were performed to evaluate which patients may be helped by immunoglobulin substitution therapy.