Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus.

OBJECTIVES: Secondary antibody deficiency (SAD), associated with severe, recurrent or persistent infections, is common in patients with haematological malignancies (HM), but unifying guidance on immunoglobulin replacement therapy (IgRT) in these patients is lacking. We aimed to develop consensus statements for the use of IgRT in patients with HM. METHODS: A Delphi exercise was employed to test the level of agreement on statements developed by a Task Force based on available data and their clinical experience. In Round 1, an Expert Panel, comprising specialist EU physicians caring for patients with HM, helped to refine the statements. In Round 2, experts rated their agreement with the statements. In Round 3, experts who had scored their agreement as ≤4 were invited to review their agreement based on the overall feedback. RESULTS: Three definitions and 20 statements were formulated and tested for consensus, covering measurement of IgG levels, initiation and discontinuation of IgRT, dosing, and the use of subcutaneous IgG. Consensus (agreement ≥70% on Likert-type scale) was reached for all three definitions and 18 statements. CONCLUSIONS: Recommendations have been developed with the aim of providing guidance for the use of IgRT to prevent severe, recurrent or persistent infections in patients with HM and SAD.

From Dysgammaglobulinemia to Autosomal-Dominant Activation-Induced Cytidine Deaminase Deficiency: Unraveling an Inherited Immunodeficiency after 50 Years.

The genetic investigation of a family presenting with a dominant form of hyper IgM syndrome published in 1963 and 1975 revealed a R190X nonsense mutation in activation-induced cytidine deaminase. This report illustrates the progress made over 6 decades in the characterization of primary immunodeficiencies, from immunochemistry to whole-exome sequencing.

Tolerability and safety of long-term rituximab treatment in systemic inflammatory and autoimmune diseases.

Rituximab, an anti-CD20 monoclonal antibody causing selective B-cell depletion, is used for various systemic inflammatory and autoimmune diseases (SIADs). Long-term safety data on rituximab are limited. The objectives of this study were to evaluate the long-term safety and tolerability of rituximab treatment for SIADs. A retrospective, single-center observational study including all patients ≥ 16 years treated with rituximab for SIADs was performed. The electronic medical records were reviewed, and data concerning indication and duration of rituximab treatment, prior and concurrent immunosuppressive therapy, and adverse events such as infections requiring hospitalization, dysgammaglobulinemia and end organ damage, were collected. A total of 70 patients were included, with a median treatment duration of 54 months, ranging 30-138 months. The most common indications for rituximab treatment were granulomatosis with polyangiitis (22.9%), primary Sjögren's syndrome (20.0%) and systemic lupus erythematosus (14.3%). Infections and persistent dysgammaglobulinemia were the most common adverse events, occurring in 34.3% and 25.7%, respectively. A total of 64 infections were observed in 24 (34.3%) patients, including 1 case of fatal infection. Seventeen patients performed B-cell quantitation during the first 2 years following discontinuation, of which only four (19.0%) demonstrated B-cell reconstitution. End organ damage occurred in two patients, presenting as pyoderma gangrenosum and interstitial pneumonitis. No opportunistic infections were observed. Three patients died during the observational period, of which one was due to lethal infection. This study presents observational data with long treatment duration. It demonstrates that long-term rituximab treatment is relatively well tolerated, and that no cumulative side effects were observed.

Recurrent Septic Shock and Syncope: An Unusual Combination.

Immunoglobulin G (IgG) deficiency disorder is a form of dysgammaglobulinemia, where proportional levels of immunoglobulin G isotype is reduced as compared to other immunoglobulin isotypes. Common clinical presentations of IgG deficiency disorder are recurrent sinusitis and/or lower respiratory infections. However, IgG deficiency manifesting as recurrent septic shock in absence of upper and lower respiratory infection has never been reported, in our search for literature from world over. With this rare case, we highlight the importance of investigating IgG levels in clinical scenarios of recurrent sepsis with no known or traceable infective focus.

Falsely low immunoglobulin (Ig)G4 in routine analysis: how not to miss IgG4 disease.

Immunoglobulin (Ig)G4 disease can have apparently 'normal' levels of IgG4 due to antigen excess conditions. IgG4 measurement therefore appears falsely low. UK National External Quality Assurance Scheme (UK NEQAS) data and other reports have suggested that this problem occurred despite pre-existing antigen excess detection steps. To determine the clinical relevance of the problem, we examined the prevalence and characteristics of prozoning in our laboratory and patient cohorts. We establish that the prevalence of raised IgG4 in routine IgG4 analysis is low (< 1%) using one of the two routine methods in use in the United Kingdom. We show that subsequent assay modification appears to have reduced the likelihood of misleading readings. However, the original version of the assay prozoned to low levels (below 0·64 g/l) in 41% of high IgG4 samples in our patients. This may explain the previous reports of low sensitivity of raised IgG4 for IgG4RD, and predictive values should be re-evaluated in this disease using modified prozone-resistant protocols. All laboratories providing IgG4 measurements should verify that their assays are fit for the clinical quality requirement of detection raised IgG4 levels and must verify the upper limit of their reference ranges and freedom from prozoning.

A prospective ten-year follow-up of patients with chronic urticaria.

BACKGROUND: Chronic urticaria can be the initial clinical presentation of a number of different diseases. The objective of the present study was to report the associated diseases during a ten-year clinical-laboratory follow-up in patients with an initial diagnosis of chronic spontaneous urticaria (CSU) of unknown cause. METHODS: A prospective, longitudinal cohort study with a ten-year clinical-laboratory follow-up was conducted. Patients with a history of urticarial plaques of over six weeks presenting as the only clinical symptom were selected. Individuals with other clinical conditions, urticaria of known causes or chronic physical urticaria were excluded. The following tests were initially performed: haemogram, urine type I, stool parasite exam and sedimentation rate. The following exams were ordered during follow-up: PPD; urine culture; serology tests; antithyroid and antinuclear antibodies, rheumatoid factor, lupus anticoagulant; thyroid hormones; serum immunoglobulin; paranasal sinus and thorax radiographs; testing for BK and Helicobacter pylori; and prick tests. RESULTS: Infections were diagnosed in 29% of patients (syphilis, parasitosis, H. pylori, urinary infection, tuberculosis, hepatitis B and C); autoimmune diseases in 21% (thyroiditis, rheumatoid arthritis and antiphospholipid antibody syndrome); primary immunodeficiencies in 4% (IgA and IgG2 deficiencies); and chronic myeloid leukaemia in 1%. At ten-years of follow-up, the urticaria diagnosis was CSU of unknown cause in 45% of the cases. CONCLUSION: This ten-year clinical-laboratory follow-up of 100 individuals with chronic urticaria as the initial diagnosis revealed the presence of associated diseases in over half of the cases. The most prevalent diseases were infections and autoimmune diseases besides primary immunodeficiencies and blood diseases.

Immunoglobulin deficiency in patients with chronic rhinosinusitis: Systematic review of the literature and meta-analysis.

BACKGROUND: Several studies have shown a high prevalence of immunoglobulin deficiencies in patients with chronic rhinosinusitis (CRS). OBJECTIVE: We sought to perform a systematic review and meta-analysis to estimate this prevalence more precisely and to identify patients who need substitution treatment. METHODS: All case series published after 1990 describing patients with CRS, which was defined as symptomatic rhinosinusitis for more than 12 weeks and documented immunoglobulin deficiencies (including deficiencies of IgG with subclasses, IgA, and IgM; specific antibody deficiencies; and potential common variable immunodeficiency), were retrieved. A meta-analysis of the proportion of any combination of common variable immunodeficiency, IgG deficiency, IgA deficiency, and IgM deficiency in patients with CRS was performed by using logit transformation of the prevalence. Recurrent CRS was defined as rhinosinusitis not controlled by appropriate conservative management for 4 months, and difficult-to-treat CRS was defined as noncontrollable rhinosinusitis despite successful sinus surgery and appropriate conservative management for at least 1 year. RESULTS: The meta-analysis revealed a prevalence of pooled IgG, IgA, and IgM deficiencies in 13% of patients with recurrent CRS and 23% of patients with difficult-to-treat CRS. The prevalence of IgG subclass deficiency (5% to 50%) and specific antibody deficiency (8% to 34%) was increased in patients with CRS, as was the prevalence of respiratory allergies in patients with recurrent CRS (31% to 72%). CONCLUSION: Immunoglobulin deficiency is a frequent condition in patients with CRS. An even higher prevalence of atopy was observed in patients with recurrent CRS. Therefore immunoglobulin titers and accurate allergy diagnostic workups are strongly recommended in these patients to provide specific treatments for symptom alleviation. However, there is a need for larger prospective studies addressing the effect of specific therapeutic interventions for CRS.

Symptomatic Primary Selective IgM Immunodeficiency - B Lymphoid Cell Defect in Adult Man with Secondary HLH Syndrome.

Selective immunoglobulin M deficiency(sIgMD) is a rare form of dysgammaglobulinaemia characterized by an isolated low level of serum immunoglobulin M (IgM). It was an incidence of less than 0.03% in the general population and 1% in hospitalized patients. sIgMD may occur as a primary or secondary condition. sIgMD is much more common than primary .Hemophagocytic lymphohistiocytosis (HLH) is also a rare but potentially fatal disease of normal but overactive histiocytes and lymphocytes and can be primary or secondary, characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and hematologic alterations. We report an adult case of primary sIgMD with absent B lymphoid cells and secondary HLH syndrome who presented with recurrent infections, fever and pancytopenia.

Immunologic assessment and KMT2D mutation detection in Kabuki syndrome.

Kabuki or Niikawa-Kuroki syndrome (KS) is a rare disorder with multiple malformations and recurrent infections, especially otitis media. This study aimed to investigate the genetic defects in Kabuki syndrome and determine if immune status is related to recurrent otitis media. Fourteen patients from 12 unrelated families were enrolled in the 9-year study period (2005-2013). All had Kabuki faces, cleft palate, developmental delay, mental retardation, and the short fifth finger. Recurrent otitis media (12/14) and hearing impairment (8/14) were also more common features. Immunologic analysis revealed lower memory CD19+ cells (11/13), lower memory CD4+ cells (8/13), undetectable anti-HBs antibodies (7/13), and antibody deficiency (7/13), including lower IgA (4), IgG (2), and IgG2 (1). Naïve emigrant lymphocytes, lymphocyte proliferation function, complement activity, and superoxide production in polymorphonuclear cells were all normal. All the patients had KMT2D mutations and 10 novel mutations of R1252X, R1757X,Y1998C, P2550R fs2604X, Q4013X, G5379X, E5425K, R5432X, R5432W, and R5500W. Resembling the phenotype of common variable immunodeficiency, KS patients with antibody deficiency, decreased memory cells, and poor vaccine response increased susceptibility to recurrent otitis media. Large-scale prospective studies are warranted to determine if regular immunoglobulin supplementation decreases the frequency of otitis media and severity of hearing impairment.

Increased serum IgM, immunodeficiency, and autoimmunity: A clinical series.

BACKGROUND: Primary immunodeficiencies (PIDs) are generally characterized by recurrent infections; however they may be complicated by other clinical disorders such as allergy, autoimmunity, and lymphoproliferation. In particular, autoimmunity may be the first manifestation of the disease in patients with low serum immunoglobulins (Ig) levels. Here we describe a group of patients that share features of immunodeficiency and autoimmunity. MATERIALS AND METHODS: All patients went through a complete T and B cell subset characterization and a B cell function analysis in the peripheral blood by flow-cytometry. B cell proliferation and plasma cell differentiation was measured, in vitro, after CpG stimulation for 7 days as previously described. Semi-quantitative PCR analysis for AID and UNG expression as well as serum levels of BAFF were carried out in order to better define the diagnosis. RESULTS: Immunological and molecular analysis did not lead to the identification of known molecular defect typical of Hyper IgM syndrome. A comparative study of the peripheral blood B cell subsets between patients and healthy donors showed that in patients with autoimmune manifestations all circulating B cells expressed high amounts of surface IgM. CONCLUSIONS: These results suggest that the increased IgM expression on circulating B cells, reflecting B cell activation, might identify a clinical condition characterized by hyper IgM serum levels of unknown molecular defects, associated with susceptibility to infections and autoimmunity.

Dysgammaglobulinemia Associated With Glu349del, a Hypomorphic XIAP Mutation.

BACKGROUND: X-linked lymphoproliferative syndrome type 2 is a rare hereditary immunodeficiency caused by mutations in the XIAP gene. This immunodeficiency frequently results in hemophagocytic lymphohistiocytosis, although hypogammaglobulinemia and dysgammaglobulinemia are also common. OBJECTIVE: We identified 17 patients from 12 Japanese families with mutations in XIAP. The Glu349del mutation was observed in 3 patients, each from a different family. Interestingly, these patients exhibited dysgammaglobulinemia but not hemophagocytic lymphohistiocytosis. We conducted an immunological study of patients carrying Glu349del and other mutations to elucidate the pathogenic mechanisms of dysgammaglobulinemia in patients with mutations in the XIAP gene. PATIENTS AND METHODS: We performed an immunological study of 2 patients carrying the Glu349del mutation and 8 patients with other mutations. RESULTS: Flow cytometry showed that the percentage of memory B cells in patients with a mutation in XIAP was lower than that observed in the healthy controls. The patients with the Glu349del mutation had a lower percentage of memory B cells than those with other mutations. Ig production was reduced in patients with the Glu349del mutation. Increased susceptibility to apoptosis was observed in the patients with other mutations. Susceptibility to apoptosis was normal in patients with Glu349del. Microarray analysis indicated that expression of Ig-related genes was reduced in patients with the Glu349del mutation and that the pattern was different from that observed in the healthy controls or patients with other mutations in XIAP. CONCLUSIONS: Patients carrying the Glu349del mutation in the XIAP gene may have a clinically and immunologically distinct phenotype from patients with other XIAP mutations. The Glu349del mutation may be associated with dysgammaglobulinemia.

Selective IgE deficiency and cardiovascular diseases.

Selective immunoglobulin E (IgE) deficiency (IgED) is defined as serum levels of IgE more than or equal to 2 kIU/L and is associated with immune dysregulation and autoimmunity. This study aimed to investigate a prevalence of atherosclerotic cardiovascular disease (ASCVD) in population with IgED. Within the electronic patient record (EPR) database of Leumit Health Care Services (LHS) in Israel, data capture was performed using IBM Cognos 10.1.1 BI Report Studio software. The case samples were drawn from the full study population (n = 18,487), having any allergy-related symptoms and/or those requesting antiallergy medications and performed serum total IgE measurement during 2012 at LHS. All subjects aged more than or equal to 40 years old, with serum total IgE less than 2 kIU/L were included in case group. Control group was randomly sampled from the remained subjects, with a case-control ratio of 10 controls for each case (1:10). The comorbid cardiovascular diseases during less than or equal to 10 years before serum total IgE testing were identified and retrieved using specific International Classification of Diseases, 9th Revision, Clinical Modification diagnostic codes. There were 103 in case and 1030 subjects in control group. Compared with control group patients, the case group had significantly more arterial hypertension [34 (37.7%) versus 187 (18.2%), p < 0.001], ischemic heart disease (IHD) [26 (25.2%) versus 87 (8.4%), p < 0.001], carotid stenosis [5 (4.9%) versus 7 (0.7%), p = 0.003], cerebrovascular disease (CVD) [3 (2.9%) versus 5 (0.5%), p = 0.029], and peripheral vascular disease (PVD) [4 (3.9%) versus 9 (0.9%), p = 0.024]. IgED is associated with higher prevalence of arterial hypertension and ASCVD.

Recurrent respiratory infections, specific antibody deficiencies, and memory B cells.

OBJECTIVES: To investigate the immunological phenotypes detected in children with recurrent upper and lower respiratory infections that have normal total immunoglobulin concentrations. METHODS: A cohort of over 60 children with recurrent respiration infections was evaluated for specific antibody deficiencies (SAD) and for memory B-cell abnormalities. A control group of children without recurrent infections was also evaluated. Evaluation included a detailed history of immunizations with pneumococcal vaccines; determination of IgM, IgG, IgA, and IgE concentrations; measurement of anti-pneumococcal polysaccharide antibody levels by ELISA and expression of CD27, IgD, and IgM on peripheral CD19(+)B cells by flow cytometry to determine the proportions of naive, IgM-memory B cells, and class-switched memory B cells. RESULTS: Patients were classified as having a SAD to either pure polysaccharides (PPV-SAD) or to conjugate polysaccharides (PCV-SAD) based on the number of polysaccharides to which they developed an adequate antibody response. A normal response to only 2 or fewer of 7 PCV or PPV serotypes was considered as evidence of SAD. Forty-one patients without SAD and 26 with SAD were identified. IgM-memory B cells were low in 3 of 41 patients without SAD; in 3 of 5 PPV-SAD patients; and in 10 of 21 PCV-SAD patients. Class-switched memory B cells were low in 19 of 41 patients without SAD; in all 5 patients with PPV-SAD; and in 11 of 21PCV-SAD patients. CONCLUSIONS: Patients with recurrent infection with or without SAD may have low IgM- and/or class-switched memory B cells. Ongoing research aims to determine the prognostic implications of these differences in patients with SAD.

Significant differences in B-cell subpopulations characterize patients with chronic graft-versus-host disease-associated dysgammaglobulinemia.

Manifestations of chronic graft-versus-host disease (cGVHD) can resemble those seen in immunodeficiency states and autoimmune disorders. Reports by us and others suggest an involvement of B cells in the pathogenesis of cGVHD. We investigated B-lymphocyte subpopulations in cGVHD cohorts defined by serum immunoglobulin G (IgG) levels to characterize novel biomarkers for impairment of humoral immunity after allogeneic hematopoietic stem cell transplantation. Seventy-six patients were enrolled a median of 46 months after hematopoietic stem cell transplantation. The hypogammaglobulinemia group had significantly diminished CD19(+) B cells (165 vs 454 vs 417 × 106L) with elevated CD19(+)CD21(low) immature (16.5%, 7.7%, and 9.1%) and CD19(+)CD21(int-high)CD38(high)IgM(high) transitional (10.5% vs 4.2% vs 6.3%) B-cell proportions compared with the normogammaglobulinemia and hypergammaglobulinemia groups. CD19(+)CD10(-)CD27(-)CD21(high) naive B cells were highly elevated in all patients with cGVHD. CD19(+)CD27(+)IgD(+) non-class-switched (4 vs 12 vs 11 × 106/L) and class-switched (7 vs 35 vs 42 × 106/L) memory B cells were significantly lower in the hypogammaglobulinemia group compared with the others. Besides significantly higher B-cell activation factor/B-cell ratios, significantly more cGVHD patients with hypergammaglobulinemia had autoantibodies compared with the hypogammaglobulinemia subgroup (68% vs 24%, P = .024). In conclusion, B-cell subpopulations can serve as novel cellular biomarkers for immunodeficiency and autoimmunity indicating different pathogenetic mechanisms of cGVHD and encouraging future prospective longitudinal studies.

Poor specific antibody response immunodeficiency (dysgammaglobulinemia) predates systemic lupus erythematosus.

Poor specific antibody response is a well-known primary immunodeficiency that is related to hypogammaglobulinemia or common variable immunodeficiency (CVID). The co-existence of CVID or hypogammaglobulinemia and systemic lupus erythematosus (SLE) has been rarely described. In all reported cases, the diagnosis of SLE antedates CVID. We report a 15-year-old Saudi girl who was diagnosed with poor specific antibody response at age 6 years in the form of poor or no antibody response and dysgammaglobulinemia. She developed SLE with musculoskeletal and hematological manifestations, positive antinuclear antibody and high anti-dsDNA nine years later. She was treated with rituximab with good response.

Immunoparesis and monoclonal gammopathy of undetermined significance are disassociated in advanced age.

Immunoparesis and a skewed serum free light chain (FLC) ratio are indicators of immune dysfunction predictive of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). Previous studies have reported increased prevalence of MGUS by age, but no study has examined the relationship between immunoparesis and abnormal FLC ratios in the elderly. We screened 453 older adults (median age, 80 years; range, 65-96) to characterize the patterns of immunoparesis and abnormal FLC ratio in relation to MGUS. We defined MGUS in 4.4% of the subjects; the prevalence was 12.5% among individuals of >90 years. In MGUS (vs. non-MGUS) cases, immunoparesis and abnormal FLC ratios were detected in 70.0% (vs. 49.0%; P = 0.07) and 50.0% (vs. 12.9%; P = 0.0001), respectively. Based on small numbers, MGUS patients with abnormal FLC ratio were borderline (P = 0.07) more likely to have immunoparesis. Overall, the prevalence of immunoparesis varied in a nonlinear fashion, with lowest frequencies in the youngest and oldest groups. Our observed disassociation between MGUS prevalence and impaired immunoglobulin production suggests that separate mechanisms are involved in the development of MGUS and immunoparesis in advanced age. These findings emphasize the need for molecularly defined methods to characterize myeloma precursor states and better predict progression to MM.