Immunoglobulin Treatment for Primary Antibody Deficiencies

Adults and children with primary antibody deficiencies are prone to bacterial infections affecting the respiratory tract and gastrointestinal canal. To prevent or alleviate infections, replacement therapy with IgG is needed, usually on a lifelong basis. The IgG can be administered intramuscularly, intravenously, or subcutaneously. Subcutaneous IgG (SCIG) therapy, using small portable pumps for once-per-week self infusions, has shown many advantages compared with the two other routes of administration. This review highlights findings from international studies and demonstrates that: (i) SCIG therapy is safe, with very few adverse effects; (ii) the therapy can be used for patients with previous adverse effects to intravenous administration of IgG; (iii) the therapy leads to high serum IgG levels and good protection against infections; (iv) the therapy facilitates home therapy, as the infusion technique is easy for children, adults and elderly people to learn and there is no need for venous access; (v) SCIG home therapy leads to significantly improved life situations for the patients; (vi) the SCIG home therapy regimen in particular reduces the costs of treatment.     

Pathogenesis,Diagnosis, and Management of Primary Antibody Deficiencies and Infections

Summary: Primary antibody deficiencies are the most common primary immunodeficiency diseases. They are a heterogeneous group of disorders with various degrees of dysfunctional antibody production resulting from a disruption of B-cell differentiation at different stages. While there has been tremendous recent progress in the understanding of some of these disorders, the etiology remains unknown for the majority of patients. As there is a large spectrum of underlying defects, the age at presentation varies widely, and the clinical manifestations range from an almost complete absence of B cells and serum immunoglobulins to selectively impaired antibody responses to specific antigens with normal total serum immunoglobulin concentrations. However, all of these disorders share an increased susceptibility to infections, affecting predominantly the respiratory tract. A delay of appropriate treatment for some diseases can result in serious complications related to infections, while timely diagnosis and adequate therapy can significantly decrease morbidity and increase life expectancy and quality of life.     

喉鳞状细胞癌的表观遗传学研究进展

喉癌是来源于喉粘膜上皮组织的恶性肿瘤.尽管临床应用喉癌分子标记物筛查已取得重要进展,但迄今特异性标记物在喉癌筛查及随访治疗方面仍差强人意.近年来表观遗传学在恶性肿瘤生物学行为研究领域方兴未艾.表观遗传学改变涉及基因失调,主要的表观遗传学改变包括DNA甲基化失衡,组蛋白修饰和smallRNA失调.总的表观遗传学改变已被认为是恶性肿瘤的一种分子特征,而基于具体的表观遗传学模式,可确定癌症的行为和特征.本文综述了喉癌的表观遗传学改变,这对于更深入的认识与了解喉癌在表观遗传学水平上的发生和发展,促进相关成果临床应用转化具有重要意义.     

Home-Based Subcutaneous Immunoglobulin Versus Hospital-Based Intravenous Immunoglobulin in Treatment of Primary Antibody Deficiencies: Systematic Review and Meta Analysis

Immunoglobulin replacement by the subcutaneous route (SCIg) for the prophylactic treatment of primary or secondary antibody deficient patients has been introduced as an alternative to conventional intravenous administration (IVIg). This is a systematic review of all eligible studies comparing efficacy and safety of IVIg and SCIg. Retrospective and prospective cohort studies and randomized, controlled trials comparing SCIg to IVIg were identified from MEDLINE, EMBASE, CINAHL, AMED, CSR, ISI and Cochrane Database without restriction on publication date and language. If possible, meta-analysis was performed by using the Review Manager software. A total of 47 articles with 1,484 compared cases were reviewed. Subcutaneous immunoglobulin replacement achieved acceptable IgG trough level, low incidence of side effects, efficacy similar to IVIg infusions, better health related quality of life and treatment satisfaction, and faster functional recovery with less time off work. Because of the heterogeneity of the reports, meta-analysis had to be performed by random effect method for IgG trough levels [OR (odds ratio)?=?1.00, range?=?0.84–1.15; p?<?0.01], infection rates (OR?=?0.59, range?=?0.36–0.97; p?=?0.04), and adverse events (OR?=?0.09, range?=?0.07–0.11; p?<?0.001), which showed significant preference of SCIg over IVIg. Based on the analysis of published reports, changing immunoglobulin replacement therapy from IVIg to SCIg may be of benefit to qualified patients with primary immunodeficiency. These advantages, having been demonstrated in numerous studies,make medical, practical and economic sense to consider switching patients with antibody deficiency from IVIg to SCIg.     

New Genetic Discoveries and Primary Immune Deficiencies

The field of immunology has undergone recent discoveries of genetic causes for many primary immunodeficiency diseases (PIDD). The ever-expanding knowledge has led to increased understanding behind the pathophysiology of these diseases. Since these diseases are rare, the patients are frequently misdiagnosed early in the presentation of their illnesses. The identification of new genes has increased our opportunities for recognizing and making the diagnosis in patients with PIDD before they succumb to infections that may result secondary to their PIDD. Some mutations lead to a variety of presentations of severe combined immunodeficiency (SCID). The myriad and ever-growing genetic mutations which lead to SCID phenotypes have been identified in recent years. Other mutations associated with some genetic syndromes have associated immunodeficiency and are important for making the diagnosis of primary immunodeficiency in patients with some syndromes, who may otherwise be missed within the larger context of their syndromes. A variety of mutations also lead to increased susceptibility to infections due to particular organisms. These patterns of infections due to specific organisms are important keys in properly identifying the part of the immune system which is affected in these patients. This review will discuss recent genetic discoveries that enhance our understanding of these complex diseases.     

Effectiveness of Immunoglobulin Replacement Therapy on Clinical Outcome in Patients with Primary Antibody Deficiencies: Results from a Multicenter Prospective Cohort Study

A 5-years multicenter prospective study on 201 patients with common variable immunodeficiencies and 101 patients with X-linked agammaglobulinemia over a cumulative follow-up period of 1,365 patient-years was conducted to identify prognostic markers and risk factors for associated clinical co-morbidities, the effects of long-term immunoglobulin treatment and the IgG trough level to be maintained over time required to minimise infection risk. Overall, 21% of the patients with common variable immunodeficiencies and 24% of patients with X-linked agammaglobulinemia remained infection free during the study. A reduction of pneumonia episodes has been observed after initiation of Ig replacement. During the observation time, pneumonia incidence remained low and constant over time. Patients with pneumonia did not have significant lower IgG trough levels than patients without pneumonia, with the exception of patients whose IgG trough levels were persistently <400 mg/dL. In X-linked agammaglobulinemia, the only co-morbidity risk factor identified for pneumonia by the final multivariable model was the presence of bronchiectasis. In common variable immunodeficiencies, our data allowed us to identify a clinical phenotype characterised by a high pneumonia risk: patients with low IgG and IgA levels at diagnosis; patients who had IgA level <7 mg/dL and who had bronchiectasis. The effect of therapy with immunoglobulins at replacement dosage for non-infectious co-morbidities (autoimmunity, lymphocytic hyperplasia and enteropathy) remains to be established. A unique general protective trough IgG level in antibody deficiency patients will remain undefined because of the major role played by the progression of lung disease in X-linked agammaglobulinemia and in a subset of patients with common variable immunodeficiencies.     

Increased Prevalence of Gastrointestinal Viruses and Diminished Secretory Immunoglobulin a Levels in Antibody Deficiencies

Purpose

Gastrointestinal disease occurs frequently in antibody deficiencies. This study aims to explore the relation between gastrointestinal infections and mucosal homeostasis in patients with antibody deficiencies.

Methods

We performed an observational study including 54 pediatric antibody deficient patients (48 % CVID, 41 % CVID-like, 11 % XLA) and 66 healthy controls. Clinical symptom scores and stool samples were collected prospectively. Stool samples were evaluated for bacteria, parasites, viruses, secretory IgA- and for calprotectin levels. Results were compared between patients and controls.

Results

24 % of antibody deficient patients versus 9 % of healthy controls tested positive for gastrointestinal viruses (p?=?0.028). Fecal calprotectin levels were significantly higher in virus positive patients compared to virus negative patients (p?=?0.002). However, in controls, fecal calprotectin levels were similar between virus positive and virus negative controls. Moreover, gastrointestinal virus positive patients had low serum IgA levels in 13/14 cases (94 %) versus 40/62 (62 %) patients in the virus negative patient group (p?=?0.04). The virus positive patient group also displayed significantly lower secretory IgA levels in stool (median 13 ug/ml) than patients without gastrointestinal viruses detected or healthy controls (median 155 ug/ml) (p?=?0.046).

Conclusion

We here report an increased prevalence of gastrointestinal viruses and gastrointestinal complaints in antibody deficient patients. Patients that tested positive for gastrointestinal viruses showed diminished serum- and secretory IgA levels, and only in patients, virus positivity was associated with signs of mucosal inflammation. These findings suggest that particularly patients with low IgA are at risk for longstanding replication of gastrointestinal viruses, which may eventually result in CVID-related enteropathy.     

Historical Perspectives in the Diagnosis and Treatment of Primary Immune Deficiencies

The field of Primary Immune Deficiency Disorders (PIDD) has advanced rapidly over the past several years with over 200 different gene mutations defined. With the recent institution of newborn screening for T cell deficiencies in many states and earlier recognition of the signs and symptoms of patients with immune deficiency, it is now apparent that PIDD is not as “rare” as was originally thought several decades ago. With the earlier recognition of patients with recurrent infections and various immune perturbations, advancements in the treatment of these immune deficiency disorders have led to enhanced survival and quality of life. In this issue, the diagnosis of PIDD through laboratory testing and skin manifestations is reviewed. The more recently described cellular immune deficiencies, selective immune deficiencies, and advances in the use of bone marrow transplantation in the correction of some of these immune deficiencies are discussed.     

Dysregulation of Circulating Tfr/Tfh Ratio in Primary biliary cholangitis

Follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells are critical for the development and maintenance of germinal centre (GC) and humoral immune responses. Accumulating evidence has demonstrated that the dysregulation of either Tfh cells or Tfr cells contributes to the pathogenesis of autoimmune diseases. We aim to investigate the roles of circulating Tfh cells and circulating Tfr cells in the pathogenesis of primary biliary cholangitis (PBC). A total of 34 patients with PBC and 27 health individuals were enrolled in this study. Flow cytometry revealed that circulating Tfh (CD4⁺CXCR5⁺CD127^hiCD25^lo) cells were increased, but Tfr (CD4⁺CXCR5⁺CD127^loCD25^hi) cells and ratio of Tfr/Tfh were dramatically decreased in PBC patients compared with healthy controls. The Tfr/Tfh ratio was negatively correlated with level of serum IgM. Meanwhile, we also observed effector memory (CCR7^loPD‐1^hi) Tfh cells and Tfr cells were dramatically increased, but central memory (CCR7^hiPD‐1^lo) Tfh cells and Tfr cells were decreased in PBC patients compared with healthy controls. Effector memory Tfr cells were positively correlated with level of serum ALP. These results indicate that an imbalance of circulating Tfr cells and Tfh cells may be involved in the immunopathogenesis of PBC and may provide novel insight for the development of PBC therapies.     

Simple Method To Distinguish between Primary and Secondary C3 Deficiencies

Due to the increasing numbers of reported clinical cases of complement deficiency in medical centers, clinicians are now more aware of the role of the complement system in the protection against infections caused by microorganisms. Therefore, clinical laboratories are now prepared to perform a number of diagnostic tests of the complement system other than the standard 50% hemolytic component assay. Deficiencies of alternative complement pathway proteins are related to severe and recurrent infections; and the application of easy, reliable, and low-cost methods for their detection and distinction are always welcome, notably in developing countries. When activation of the alternative complement pathway is evaluated in hemolytic agarose plates, some but not all human sera cross-react to form a late linear lysis. Since the formation of this linear lysis is dependent on C3 and factor B, it is possible to use late linear lysis to routinely screen for the presence of deficiencies of alternative human complement pathway proteins such as factor B. Furthermore, since linear lysis is observed between normal human serum and primary C3-deficient serum but not between normal human serum and secondary C3-deficient serum caused by the lack of factor H or factor I, this assay may also be used to discriminate between primary and secondary C3 deficiencies.     

Secondary Antibody Deficiency in Glucocorticoid Therapy Clearly Differs from Primary Antibody Deficiency

Purpose

The aim of this study was to identify characteristics of hypogammaglobulinemia secondary to glucocorticoid therapy and their value in the differential diagnosis to primary forms of antibody deficiency.

Methods

We investigated prevalence and character of hypogammaglobulinemia in a cohort of 36 patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) on glucocorticoid therapy in comparison to a gender- and age-matched cohort of hospital controls. We therefore determined serum immunoglobulin levels as well as B- and T cell-subsets in the peripheral blood of all participants. In addition, prior serum immunoglobulin levels and clinical data of the GCA and PMR patients were extracted from the electronic patient data-base.

Results

21/36 GCA/PMR patients on glucocorticoid treatment developed antibody deficiency. In 19 patients this included IgG and in 13 patients IgG was the only affected isotype. The reduction of IgG was persistent in nearly 50 % of these patients during the observed period. GCA/PMR patients had reduced circulating naive and transitional B cells (p = 0.0043 and p = 0.0002 respectively) while IgM, IgG and IgA memory B cells were preserved. Amongst T-cell subsets, we found a reduction of CD4 memory T cells (p < 0.0001), CD4 regulatory T cells (p = 0.0002) and few CD8 memory T-cell subtypes.

Conclusion

Persistent humoral immunodeficiency occurs in about a quarter of GCA/PMR patients under glucocorticoid therapy. Because most patients have isolated IgG deficiency, preserved IgA production and class-switched memory B cells, by these markers this form of secondary hypogammaglobulinemia can be clearly distinguished from common variable immunodeficiency (CVID).

     

Primary Immune Deficiencies Presenting in Adults: Seven Years of Experience from Iran

Primary immunodeficiencies (PIDs) are not solely diseases of childhood. We describe the clinical presentation and outcome for 55 adult patients with previously unrecognized PIDs. This series provides unique data regarding PIDs presenting in adulthood, and serves as a timely reminder that physicians must consider the diagnosis of PIDs in their adult patients. Using the experience gained from these patients, we outline key “warning signs” suggestive of an underlying PID. Only through increased physician awareness will patients with PIDs receive timely diagnosis and optimal management.     

原发性胆汁性胆管炎抗体及肝外疾病研究

原发性胆汁性胆管炎（PBC）是一种以胆汁淤积为特点的慢性自身免疫性肝病,可发展至肝硬化甚至肝衰竭,早期诊断PBC十分重要。PBC患者多数合并自身免疫性相关肝外疾病,包括干燥综合征、系统性硬化症、甲状腺疾病等。本文总结了PBC相关抗体及相关肝外疾病的研究,帮助临床医生对PBC的诊断及治疗。     

Quality of Life in Children with Primary Antibody Deficiency

Primary antibody deficiency disorders (PADs) can have an excellent outlook if diagnosed early and treated appropriately, but require lifelong treatment with immunoglobulin replacement. Some carry risks of inflammatory complications even with optimal treatment. Quality of life (QoL) and the psychological impact of PADs has been relatively little studied, particularly in children. The purpose of this study was to evaluate QoL and psychological impact in a large group of children affected by a range of PADs, as well as a group with transient hypogammaglobulinemia of infancy (THI). Both parental and, where appropriate, child ratings, were collected using standardised questionnaires (PedsQL and SDQ). Higher rates of psychological difficulties, particularly emotional and peer-relationship difficulties were found in children with PAD when compared with healthy controls. Quality of life was poorer than in healthy controls, and also worse than in children affected by diabetes mellitus. Variations in QoL and the degree of psychological difficulties were found between specific diagnostic groups, with children affected by THI being amongst those with the lowest scores for QoL. Further studies are needed to corroborate and extend these findings, but this study confirms previous findings that primary antibody deficiency has a significant impact on quality of life and psychological well-being, and additionally suggests that the impact varies according to severity of the underlying condition. For those with significant difficulties psychological intervention at an early stage may be beneficial.