IgG Hypogammaglobulinemia Research Articles

Secondary Hypogammaglobulinemia

Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to extrinsic causes, such as a medication or an acquired disease process, resulting in decreased immunoglobulin production or increased immunoglobulin loss. Most published reports of SHG refer to IgG hypogammaglobulinemia and data on isolated IgA or IgM hypogammaglobulinemia is limited. The common causes of SHG include medications, hematological malignancies, and conditions associated with protein loss. Hypogammaglobulinemia can increase the risk of infection, morbidity and mortality, particularly in patients who may already be immunocompromised due to their associated condition or use of immunosuppressive therapies. With growing use of immunosuppressive or immunomodulatory treatments that affect B-cells, it is increasingly important to assess and monitor for SHG. Treatment of the underlying condition or removal of the extrinsic factor often results in resolution of the SHG. A subset of patients presenting with autoimmune or malignant conditions can have a primary immunodeficiency (PID) or primary immune regulatory disorder. It is therefore important to consider both primary and secondary causes when assessing hypogammaglobulinemia. This article will review these common causes and discuss an approach to assessment and management of SHG.

Hypogammaglobulinemia and Infection Risk in an Ocrelizumab-treated Multiple Sclerosis Cohort.

Ocrelizumab is an effective anti-CD20 therapy approved for Relapsing Remitting (RRMS) and Primary Progressive Multiple Sclerosis (PPMS). In clinical trials, a proportion of patients developed hypogammaglobulinemia which could contribute to infection risk. This study aimed to identify hypogammaglobulinemia and its risk factors and evaluate potentially associated serious infection risk in a real-world cohort of patients. All MS patients treated with ocrelizumab in a Quebec City MS clinic from January 2017 to August 2021 were included and detailed patient characteristics were collected by chart review. Levels of immunoglobulins (IgM, IgA and IgG) were assessed prior to each treatment. Serious infection was defined as an infection requiring hospitalization or emergency room treatment. Association between hypogammaglobulinemia and serious infection was analyzed. A total of 266 patients (average follow-up 2.05 years) were included (87% RRMS). After 6 infusions, 32.8%, 3.5% and 4.2% of patients had at least one IgM, IgA and IgG hypogammaglobulinemia event respectively. Aside from pre-treatment hypogammaglobulinemia, there were no variables associated with on-treatment hypogammaglobulinemia. There was a total of 21 serious infections (3.36 and 12.33 per 100-person-years in RRMS and PPMS). Developing hypogammaglobulinemia during treatment was not associated with serious infection. A regression analysis did not show associations between serious infection and key disease characteristics. Similar to ocrelizumab extension studies, our cohort demonstrated a significant rate of hypogammaglobulinemia over time, mostly with IgM. No association was found between hypogammaglobulinemia and serious infection.

B cell subsets reconstitution and immunoglobulin levels in children and adolescents with B non-Hodgkin lymphoma after treatment with single anti CD20 agent dose included in chemotherapeutic protocols: single center experience and review of the literature.

RTX, an anti-CD20 monoclonal antibody, added to chemotherapy has proven to be effective in children and adolescents with high-grade, high-risk and matured non-Hodgkin lymphoma. RTX leads to prompt CD19+ B lymphocyte depletion. However, despite preserved immunoglobulin production by long-lived plasmablasts after treatment, patients remain at risk of prolonged hypogammaglobulinemia. Further, there are few general guidelines for immunology laboratories and clinical feature monitoring after B cell-targeted therapies. The aim of this paper is to describe B cell reconstitution and immunoglobulin levels after pediatric B-NHL protocols, that included a single RTX dose and to review the literature. A retrospective single-center study on the impact of a single RTX dose included in a chemotherapeutic pediatric B Non-Hodgkin Lymphoma (B-NHL) treatment protocols. Immunology laboratory and clinical features were evaluated over an eight hundred days follow-up (FU) period, after completing B-NHL treatment. Nineteen patients (fifteen Burkitt lymphoma, three Diffuse large B cell lymphoma, and one Marginal zone B cell lymphoma) fulfilled the inclusion criteria. Initiation of B cell subset reconstitution occurred a median of three months after B-NHL treatment. Naïve and transitional B cells declined over the FU in contrast to the marginal zone and the switched memory B cell increase. The percentage of patients with IgG, IgA, and IgM hypogammaglobulinemia declined consistently over the FU. Prolonged IgG hypogammaglobulinemia was detectable in 9%, IgM in 13%, and IgA in 25%. All revaccinated patients responded to protein-based vaccines by specific IgG antibody production increase. Following antibiotic prophylaxes, none of the patients with hypogammaglobulinemia manifested with either a severe or opportunistic infection course. The addition of a single RTX dose to the chemotherapeutic treatment protocols was not shown to increase the risk of developing secondary antibody deficiency in B-NHL pediatric patients. Observed prolonged hypogammaglobulinemia remained clinically silent. However interdisciplinary agreement on regular long-term immunology FU after anti-CD20 agent treatment is required.

216.14: Validating a Cut-off of IgG Hypogammaglobulinemia as a Risk Factor of Severe Infection in Solid Organ Transplantation

Backgound and aims: Severe infection is a leading cause of morbidity and mortality in solid organ transplantation. IgG hypogammaglobulinemia has been previously investigated in single and multicenter studies in distinct solid organ transplantations as a predictor of infection. We aimed to validate the IgG cut-off of 600 mg/dl as a risk factor of severe infection in solid organ transplantation. The potential utility of this biomarker is that this can be modulated by therapeutic intervention. Materials and Methods: 538 heart, liver or kidney recipients were analysed in a prospective study performed in 2 centers. During a follow-up during the first 6 months after solid organ transplantation 298 (55.4%) patients developed at least one episode of severe infection the majority of which were bacterial infections. As a secondary outcome we retrospectively analysed the impact of IgG hypogammaglobulinemia early after transplantation on the rate of death. Survival analysis was performed by Kaplan-Meier. Risk for development of severe infection was also performed by logistic regression analysis. Results: The rate of decrease of IgG after transplantation was similar in both participating centers. Cumulative survival without severe infection during the first 6 months after transplantation was lower in solid organ transplantation recipients with IgG hypogammaglobulinemia defined as IgG < 600 mg/dl at days 7 or 30 after transplantation (Log Rank 5.22, p=0.022). IgG hypogammaglobulinemia was associated with higher rates of death after solid organ transplantation (Log Rank 5.75, p=0.017). In logistic regression analysis IgG hypogammaglobulinemia was significantly associated with risk of severe infection (OR 1.635, p=0.040, 95%CI 1.022-2.615). IgG hypogammaglobulinemia was a risk factor of death (OR 1.078, p= 0.011, 95%CI 1.180 – 3.668). We performed an immunological score for development of severe infection composed of pre transplant monocytes < 7% (2 points), IgG hypogammaglobulinemia (2 points), CD4 <400 cells/uL at day 30 (2 points), C3 < 60 mg/dl at day 30 (2 points) and CRP > 3 mg/dl at day 30 (2 points). In those patients with 4 or more points, OR for development of infection was 2.89 (95% CI 1.641 – 5.123; p<0.001). Conclusion: IgG hypogammaglobulinemia (defined as IgG < 600 mg/dL early after transplantation) is associated with risk of severe infection in solid organ transplantation. This cut-off should be taken into account in future clinical trials that evaluate the impact of the modification of this risk factor by adding intravenous immunoglobulin to these patients to prevent severe infection. An immunological score combining IgG hypogammaglobulinemia and other innate and acquired immunity parameters could be a better way to identify the risk for development of severe infection in solid organ recipients.

424.11: A 5-Dose IVIG Protocol Decreases the Risk of Reinfection in Solid Organ Transplant Patients With Secondary Antibody Immunodeficiency: Results of a Multicenter Randomized Clinical Trial

Introduction: Infection is a leading cause of morbidity and health spending after solid organ transplantation (SOT). Secondary antibody deficiency (SAD), defined as IgG hypogammaglobulinemia, is frequently observed after SOT. In single center, multicenter and metanalysis, IgG hypogammaglobulinemia has been demostrated as a risk factor of severe infection in all SOT. Reinfection is more common among patients with SAD after SOT. Intravenous immunoglobulins (IVIG) are used for replacement therapy in primary and secondary immunodeficiencies. In primary immunodeficiency the protocols are well established. However, in SAD, the doses, number of doses and, above all, the time of therapy are not well defined. In a multicenter randomized clinical trial we evaluated the safety and efficacy of a 5-dose IVIG protocol to decrease the rate of reinfection in SOT with severe infections and SAD. Materials and Methods: Distribution: Heart 20, Lung 15, Kidney 5, Liver transplantation 4 were randomized. Patients with post transplant severe infections and SAD (IgG < 600 mg/dL) were included. IVIG protocol: Two doses of 15 grams (interval between doses 7-15 days) followed by another 3 doses of 20 grams (interval between doses 15-30 days) of a 5% IVIG product. 39 patients that completed the protocol were analysed [IVIG in combination with conventional antimicrobial therapy (n=21) versus conventional antimicrobial therapy alone (n=18)]. Specific antibodies were tested at inclusion in the clinical trial (visit 1, V1) and 30-45 days after last IVIG dose (last-visit, V7) in a subgroup of patients performed at the coordinating center in Madrid (Gregorio Marañon Hospital). Results: The primary outcome measure (rate of reinfection) was lower in patients randomized to receive IVIG as compared with patients receiving only conventional antimicrobial therapy (28.6 vs 66.7%, chi-square test, p=0.017). Reconstitution of IgG between V1 and V7 was higher in IVIG group as compared with non IVIG group (361±223 vs 255±275 mg/dL, p=0.038). Higher levels of specific IgG anti-cytomegalovirus, IgG anticlostridium difficile toxins A and B and IgG1 anti-tetanus toxoid antibodies was demonstrated at V7 in IVIG-recipients as compared with patients that were treated with antimicrobial therapy alone. A significant increase of specific antibodies between V1 and V7 was only observed in IVIG group. A significant decrease of serum BAFF levels was demostrated in IVIG group. 16 SAE were reported in 13 patients (6/21 IVIG treated patients (28.57%) and 7/18 non-IVIG patients (38.88%), p=0.496). None of SAE was considered to be related with study drug. Conclusions: We have demonstrated that IVIG is associated with lower rate of reinfection in SOT with severe infection and SAD. Reconstitution of specific antibodies and immunemodulation of serum BAFF was only observed in IVIG-treated patients. We believe that this way of administering IVIG can be validated in future clinical trials with a larger number of patients.

Long-term Effectiveness and Safety of Rituximab in Neuromyelitis Optica Spectrum Disorder and MOG Antibody Disease.

Rituximab is used widely for relapse prevention in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease (MOGAD); however, data regarding the effectiveness and safety of long-term rituximab use in these conditions are limited. In this study, we sought to evaluate long-term clinical outcomes in patients with aquaporin-4 IgG-seropositive (AQP4-IgG+) NMOSD and MOGAD treated with rituximab. We performed a retrospective chart review of patients with AQP4-IgG+ NMOSD or MOGAD followed at the Johns Hopkins Neuromyelitis Optica Clinic and included patients who had received at least 1 dose of rituximab. We identified 111 patients with NMOSD and 23 patients with MOGAD who fulfilled the inclusion criteria. The median duration of rituximab treatment for the patients with NMOSD was 3.7 years (range: 0.5-13.2 years) and for the patients with MOGAD was 2.1 years (range: 0.5-7.0 years). The annualized relapse rate (ARR) decreased after rituximab initiation in both NMOSD (median ARR: pretreatment 1.1, posttreatment 0; p < 0.001) and MOGAD (median ARR: pretreatment 1.9, posttreatment 0.3; p = 0.002). Relapses on rituximab occurred in 31 patients with NMOSD (28%) and 14 patients with MOGAD (61%). The majority of NMOSD treatment failures (37/48 relapses; 77%) occurred either within the initial 6 months after starting rituximab (n = 13 relapses) or in the setting of delayed/missed rituximab doses and/or peripheral B-cell reconstitution (n = 24 relapses), whereas in MOGAD, these circumstances were present in a smaller proportion of treatment failures (19/35 relapses; 54%). The risk of relapse on rituximab was greater for patients with MOGAD compared with patients with NMOSD (hazard ratio: 2.8, 95% CI: 1.5-5.2, p = 0.001). Infections requiring hospitalization occurred in 13% and immunoglobulin G (IgG) hypogammaglobulinemia in 17% of patients. The median rituximab treatment duration before IgG hypogammaglobulinemia onset was 5.4 years (interquartile range: 3.8-7.7 years). Rituximab treatment is associated with the reduced annualized relapse rate in AQP4-IgG-seropositive NMOSD, especially in the absence of gaps in treatment and/or B-cell reconstitution. In MOGAD, although a reduction in relapses was observed after initiation of rituximab, this association appeared to be less robust than in AQP4-IgG-seropositive NMOSD. Severe infections and hypogammaglobulinemia occurred in a significant proportion of patients, highlighting the need for close monitoring of infectious complications. This study provides Class IV evidence that rituximab decreases the annualized relapse rate in AQP4-IgG-seropositive NMOSD and MOGAD.

Intravenous Immunoglobulin is Associated with Lower Rates of Reinfection in Solid Organ Recipients with Infection and Secondary Antibody Deficiency: A Multicenter Randomized Clinical Trial

<h3>Purpose</h3> In a multicenter randomized clinical trial we evaluated the safety and efficacy of an intravenous immunoglobulin (IVIG) protocol to decrease the rate of reinfection in solid organ recipients with severe infections and secondary antibody deficiency. <h3>Methods</h3> Distribution: Heart 20, Lung 15, Kidney 5, Liver transplantation 4 were randomized. Patients with post transplant severe infections and secondary antibody deficiency (defined as IgG < 600 mg/dL) were included. IVIG protocol: Two doses of 15 grams (interval between doses 7-15 days) followed by another 3 doses of 20 grams (interval between doses 15-30 days) of a 5% IVIG product. 39 patients that completed the protocol were analysed [IVIG in combination with conventional antimicrobial therapy (n=21) versus conventional antimicrobial therapy alone (n=18)]. Specific antibodies were tested at inclusion in the clinical trial (V1) and 30-45 days after last IVIG dose (last-visit, V7) in a subgroup of patients to assess the kinetics of humoral immunity reconstitution. <h3>Results</h3> The primary outcome measure (rate of reinfection) was significantly lower in patients randomized to receive IVIG as compared with patients receiving only conventional antimicrobial therapy (28.6 vs 66.7%, chi-square test, p=0.017). Mean number of reinfections tended to be lower in IVIG group (0.47, interval 1-3, versus 0.89, interval 1-4, Mann-Whitney test, p=0.056). IVIG recipients tended to have lower IgG levels in V1 but disclosed significantly higher IgG concentrations at distinct visits during follow-up. Significantly higher levels of specific IgG anti-cytomegalovirus, IgG anti-clostridium difficile toxins A and B and IgG1 anti-tetanus toxoid antibodies was demonstrated at V7 in patients who received IVIG as compared with patient that were treated with antimicrobial therapy alone. A significant decrease of serum IL6 and BAFF levels (V1 versus V7) was demostrated in IVIG treated patients. IVIG infusions were well tolerated. <h3>Conclusion</h3> In a multicenter randomized clinical trial we have demonstrated that IVIG is associated with a lower rate of reinfection in solid organ transplantation with severe infection and secondary IgG hypogammaglobulinemia.

Immunologic Abnormalities Associated With Health Status of Heart Recipients Long Term After Transplantation

With improvements in survival rates, health-related quality of life is an important outcome parameter to evaluate the effectiveness of transplantation. We aimed to identify potential immunologic abnormalities as factors associated with poorer health-related quality of life at distinct scales of the 36-Item Short Form Health Survey in heart transplant recipients long term after transplantation. One hundred heart transplant recipients were evaluated in a single center. Short-form 36 questionnaires were sent by mail to participants. All patients were clinically and immunologically evaluated after the first year of heart transplantation. A high prevalence of several immunologic abnormalities persisted even after the first year of transplantation, including IgG hypogammaglobulinemia, low IgG-specific antipneumococcal antibodies, C4 hypocomplementemia, CD8 T-cell lymphocytopenia, and CD19 B-cell lymphocytopenia. Older recipients (>55 years), posttransplant diabetes, digestive complications, and posttransplant infections were associated with lower physical functioning scores (scale < 60). Older recipients (>55 years), pretransplant diabetes, pretransplant arterial hypertension, posttransplant digestive complications, and lower CD8 counts were associated with lower physical role scores (scale <25). In a single center study, lower CD8 cell counts were found to be associated with poorer health status in heart recipients after the first year of transplantation.

Long-Term Follow-up of a Prospective Clinical Trial of Carfilzomib, Rituximab and Dexamethasone (CaRD) in Waldenstrom's Macroglobulinemia

The proteasome-inhibitor bortezomib is active in Waldenstrom's macroglobulinemia (WM) though is associated with considerable peripheral neuropathy (PN) that results in frequent dose reduction and treatment discontinuation. We therefore examined the efficacy and safety of carfilzomib, a neuropathy-sparing proteasome-inhibitor, along with rituximab, and dexamethasone (CaRD) in 31 proteasome inhibitor-naive and rituximab-naive symptomatic WM patients. The preliminary findings of this study were previously published (Treon et al, Blood 2014), and herein we provide a long-term update of this study. The median baseline characteristics for patients enrolled on this prospective clinical trial were as follows: Age 61 (range 47-75 years), prior therapies 0 (range 0-1), hematocrit 32.3%, serum IgM 3,375 mg/dL, serum B2M 3.6 mg/L, and bone marrow disease involvement 60%. Therapy consisted of IV carfilzomib 20mg/m2 (cycle 1) and 36mg/m2 (cycles 2 and beyond) along with IV dexamethasone 20 mg on days 1, 2, 8, 9. Rituximab 375 mg/m2 was administered on days 2, 9 of each 21-day cycle. Treatment consisted of six 21-day induction cycles, followed by maintenance therapy that was given every 8 weeks for eight cycles and consisted of carfilzomib 36 mg/m2 and IV dexamethasone 20 mg on days 1, 2. Rituximab was given at 375 mg/m2 on day 2 of each maintenance cycle. Following protocol therapy, the median serum IgM levels declined to 561 mg/dL at best response (p<0.00001). Median hematocrit rose to 41.9% (p<0.00001). Thirty patients completed induction therapy, with reduction in bone marrow tumor burden from a median of 60% to 7.5% at end of induction (p<0.0001). Twenty patients completed maintenance therapy and had a bone marrow tumor burden reduction to 2.5% at end of maintenance treatment (p<0.0001 versus pre-treatment baseline; p=0.0088 versus end of induction). The best overall response was 80.64% (1 CR, 11 VGPR, 10 PR, 3 MR), and major response rate was 71%. Median time to response (MR or better) was 2.1 months. As shown in Figure 1A, the median progression-free survival (PFS) for all patients was reached at 46 months (range 2-63 months). PFS was associated with depth of response. Patients who achieved at least a VGPR have not reached median PFS, whereas the median PFS was 52 months for those who attained a PR, and 4 months for those with less than a PR (Figure 1B; Chi-square 35.5, p<0.0001). All patients are alive, and 14 patients remain in follow-up without a progression event.Grade >2 treatment-related toxicities included elevated lipase (12.9%), steroid-related hyperglycemia (6.45%), neutropenia (9.67%), and reversible cardiomyopathy in a patient with multiple risk factors (3.22%). Only one grade 2 PN (3.2%), and no grade 3/4 PN events occurred. At baseline, the median serum IgA level was 47 mg/dL, versus 46 mg/dL at last follow-up (p=0.11). Conversely, median serum IgG levels declined from 715 mg/dL at baseline to 372 mg/dL at last follow-up (p=0.0004). Treatment related IgG hypogammaglobulinemia was associated with recurring sino-bronchial infections, and necessitated IVIG treatment in 6 (19.4%) patients. Discontinuation of protocol therapy occurred for non-response (n=8), hypogammaglobulinemia associated with infections (n=2), grade 2 PN (n=1), cardiomyopathy (n=1), progressive disease (n=1), and prolonged hold of protocol therapy for an unrelated procedure (n=1). The long-term results of this study show that CaRD is an active, PN-sparing regimen that is associated with durable responses in symptomatic patients with WM. PFS is impacted by depth of response, and IgG hypogammaglobulinemia is commonly encountered with this regimen. [Display omitted] DisclosuresCastillo:Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Treon:Pharmacyclics: Consultancy, Research Funding.

Rituximab-induced hypogammaglobulinemia and infection risk in pediatric patients

Rituximab is a B-cell depleting agent used in B-cell malignancies and autoimmune diseases. A subset of adult patients may develop prolonged and symptomatic hypogammaglobulinemia following rituximab treatment. However, this phenomenon has not been well delineated in the pediatric population. This study sought to determine the prevalence, risk factors, and clinical significance of hypogammaglobulinemia following rituximab therapy in children. This was a multicenter, retrospective cohort study that extracted clinical and immunological data from pediatric patients who received rituximab. The cohort comprised 207 patients (median age, 12.0 years). Compared to baseline values, there was a significant increase in hypogammaglobulinemia post-rituximab therapy, with an increase in prevalence of hypo-IgG (28.7%-42.6%; P= .009), hypo-IgA (11.1%-20.4%; P= .02), and hypo-IgM (20.0%-62.0%; P< .0001). Additionally, low IgG levels at any time post-rituximab therapy were associated with a higher risk of serious infections (34.4% vs 18.9%; odds ratio, 2.3; 95% CI, 1.1-4.8; P= .03). Persistent IgG hypogammaglobulinemia was observed in 27 of 101 evaluable patients (26.7%). Significant risk factors for persistent IgG hypogammaglobulinemia included low IgG and IgA levels pre-rituximab therapy. Nine patients (4.3%) within the study were subsequently diagnosed with a primary immunodeficiency, 7 of which received rituximab for autoimmune cytopenias. Hypogammaglobulinemia post-rituximab treatment is frequently diagnosed within the pediatric population. Low IgG levels are associated with a significant increase in serious infections, and underlying primary immunodeficiencies are relatively common in children receiving rituximab, thus highlighting the importance of immunologic monitoring both before and after rituximab therapy.

Secondary antibody deficiency is associated with development of infection in kidney transplantation: Results of a multicenter study.

We performed a multicenter study to assess the association between secondary antibody deficiency (immunoglobulin G [IgG] hypogammaglobulinemia combined with low levels of specific antibodies) and development of infection in kidney transplantation. We prospectively analyzed 250 adult kidney recipients at four centers. The assessment points were before transplantation and 7 and 30days after transplantation. The immune parameters were as follows: IgG, IgA, and IgM and complement factors C3 and C4 tested by nephelometry; specific IgG antibodies to cytomegalovirus (CMV) and IgG and IgG2 antibodies to pneumococcal polysaccharide (anti-PPS) determined using enzyme-linked immunosorbent assay. The clinical follow-up period lasted 6months. The clinical outcomes were CMV disease and recurrent bacterial infections requiring antimicrobial therapy. Multivariate logistic regression. At day 7, IgG hypogammaglobulinemia (IgG levels<700mg/dL) combined with low IgG anti-CMV antibody titers (defined as levels<10000 units) was present in 12% of kidney recipients. IgG hypogammaglobulinemia combined with low IgG anti-PPS antibody titers (defined as levels<10mg/dL) at 1month after kidney transplantation were recorded in 16% of patients. At day 7 the combination of IgG hypogammaglobulinemia and low anti-CMV titers was independently associated with the development of CMV disease (odds ratio [OR], 6.95; 95% confidence interval [CI], 1.17-41.31; P=.033). At day 30 after transplantation, the combination of IgG<700mg/dL and IgG anti-PPS<10mg/dL, was independently associated with recurrent bacterial infection (OR, 5.942; 95% CI, 1.943-18.172; P=.002). In a prospective multicenter study, early immunologic monitoring of secondary antibody deficiency proved useful for the identification of kidney recipients who developed severe infection.

Incidence and prognostic significance of serum immunoglobulins and paraproteins in patients with chronic lymphocytic leukaemia: another valuable piece of the puzzle.

In this issue of the journal, Corbigni et al. present a large retrospective multicentric study evaluating serum immunogloblins and paraproteins in patients (pts) with newly diagnosed chronic lymphocytic leukaemia (CLL).1 This study is so far the largest (n = 1505) published on this topic. Its main findings include: hypogammaglobulinaemia of any class was detected in 13·2% of patients, while IgM and IgG paraproteins were present in 4·8 and 10%. Presence of IgM paraprotein significantly correlated with more advanced clinical stages, TP53 aberrations, and inferior treatment-free survival (TFS). Likewise, pts with decreased IgG or paraprotein of the same class experienced shorter TFS. Using receiver operator curve analysis for identification of an optimal threshold, serum concentration of IgA ≤ 0·82 g/l was also associated with inferior TFS. Complex perturbation of the immune system including both humoral and cellular mechanisms has long been recognized as one of the hallmarks of CLL.2 Hypogammaglobulinaemia, or decreased serum concentrations of immunoglobulins (Ig), is by far the most studied phenomenon of immune dysfunction in CLL, with first publications appearing more than 50 years ago.3, 4 Even these early studies in limited numbers of pts noted a significantly higher occurrence of infections in connection with hypogammaglobulinaemia. Results of studies published between 1975 and 2010 have been often conflicting regarding the frequency of hypogammaglobulinaemia at diagnosis (IgG, 5–39%, IgA, 3–37%, IgM, 4–64%) and its prognostic significance, most likely due to relatively small (usually n < 100) patient groups, heterogeneous proportion of early stages, different thresholds for hypogammaglobulinaemia, variable duration of follow-up and selection bias.5-9 After 2010, there have been four major publications dealing with the topic.10-14 Despite inevitable heterogeneity, some recurring patterns could be identified in the literature, namely, association of lower Ig concentrations with advancing disease or antileukaemic therapy and the unfavourable prognostic value of IgA hypogammaglobulinaemia in terms of shorter treatment-free and/or overall survival. From the clinical point of view, combination of significant IgG hypogammaglobulinaemia (the arbitrary cut-off is usually set to ≤ 5g/l) and repeated or severe bacterial infections represents a generally accepted indication for Ig replacement therapy15, 16 in the form of intravenous infusion (IVIG) or more recently, subcutaneous injection (SCIG) which is more cost-effective, more convenient for the patient and yields comparable results.16, 17 The research of monoclonal immunoglobulins/paraproteins in CLL has attracted much less attention than that of hypogammaglobulinaemia. First publications emerged at the end of 1970s and during the 1980s,18, 19 Pangalis et al. 1988,20 and several larger studies reported the frequency of paraproteins in newly diagnosed CLL pts between 7 and 35%;21-23 results regarding their prognostic value of were again inconclusive. In a recent Italian study, the presence of IgG or IgM paraproteins was linked with several unfavourable prognostic factors such as unmutated IGHV genes or TP53 aberrations and correlated with shorter TFS.22 The present study by Corbigni et al. seems to confirm some of the previously published findings, namely association of IgM paraprotein with advanced clinical stages and TP53 abnormalities, as well as significantly shorter TFS in pts with paraprotein or IgG/IgA deficiency (including multivariate analysis). None of these parameters was significant for shorter overall survival in the multivariate analysis; probably due to recent developments of the therapeutic armamentarium, namely novel targeted oral inhibitors such as ibrutinib, idelalisib, and venetoclax, whose introduction has led to marked survival improvement especially in pts with relapsed/refractory CLL. Finally, it is important to point out that the present study has several limitations: first, incidence and severity of infectious complications was not recorded; furthermore, there is no information on the cause of death (infection versus CLL progression versus other); subclasses of IgG and IgA have not been tested; also data regarding Ig replacement therapy is not available. Despite these constraints, the study by Corbigni et al. adds another valuable piece to the puzzle of the area investigating humoral immune dysfunction in CLL. Supported by programme PROGRES Q40/08 and by DRO (UHHK, 00179906). I declare no conflict of interest related to this publication.

Contraceptive vaccination for mares and its effects on cyclicity and estrous behavior

New biomarkers are necessary to improve detection of the risk of infection in heart transplantation. We performed a multicenter study to evaluate humoral immunity profiles that could better enable us to identify heart recipients at risk of severe infections.We prospectively analyzed 170 adult heart recipients at 8 centers in Spain. Study points were before transplantation and 7 and 30 days after transplantation. Immune parameters included IgG, IgM, IgA and complement factors C3 and C4, and titers of specific antibody to pneumococcal polysaccharide antigens (anti-PPS) and to cytomegalovirus (CMV). To evaluate potential immunologic mechanisms leading to IgG hypogammaglobulinemia, before heart transplantation we assessed serum B-cell activating factor (BAFF) levels using enzyme-linked immunoassay. The clinical follow-up period lasted 6 months. Clinical outcome was need for intravenous anti-microbials for therapy of infection.During follow-up, 53 patients (31.2%) developed at least 1 severe infection. We confirmed that IgG hypogammaglobulinemia at Day 7 (defined as IgG <600 mg/dl) is a risk factor for infection in general, bacterial infections in particular, and CMV disease. At Day 7 after transplantation, the combination of IgG <600 mg/dl + C3 <80 mg/dl was more strongly associated with the outcome (adjusted odds ratio 7.40; 95% confidence interval 1.48 to 37.03; p = 0.014). We found that quantification of anti-CMV antibody titers and lower anti-PPS antibody concentrations were independent predictors of CMV disease and bacterial infections, respectively. Higher pre-transplant BAFF levels were a risk factor of acute cellular rejection.Early immunologic monitoring of humoral immunity profiles proved useful for the identification of heart recipients who are at risk of severe infection.

IgG Hypogammaglobulinemia is a Risk Factor of Cytomegalovirus Infection in a Multicenter Study in Kidney Transplantation

IgG Hypogammaglobulinemia is a Risk Factor of Cytomegalovirus Infection in a Multicenter Study in Kidney Transplantation

Intravenous Immunoglobulin Replacement Therapy in Solid Organ Transplantation with Severe Infections and Secondary Antibody Deficiency

Background Secondary antibody deficiency is a risk factor of severe infection in solid organ transplantation. Very few studies have previously evaluated the potential role of IgG replacement in solid organ recipients with IgG hypogammaglobulinemia (HGG) at the time of a severe infectious complication. We evaluated the impact of therapeutic intervention of intravenous immunoglobulin (IVIG) in solid organ recipients with severe infections and HGG on clinical outcomes. Methods Retrospective analysis of prospectively collected data of 60 patients in a single center. All patients were hospitalized because of severe infections or developed a severe infection during a hospitalization in the post-transplantation period (June 2015-June 2017) and were found to have HGG (serum IgG<600 mg/dL). 32 patients received non-specific 5% IVIG in addition to conventional antimicrobial therapy with the aims of contributing to control of infection, secondary prevention of re-infection and normalization of IgG (IgG>750 mg/dL) and 28 patients were treated with only conventional antimicrobial therapy. IVIG was administered at a dose of 300-400 mg/kg/month. Clinical outcome was the incidence of new infectious complications and deadly infections during a 6-month follow up. Results Distribution of solid organ recipients was as follows: Heart 37, liver 10, kidney 13. The incidente of re-infection was significantly higher in patients with HGG that were not treated with IVIG as compared with IVIG-treated patients (78.6% vs 28.1%, two-sided chi-square test p<0.001). Size effect (No IVIG vs IVIG) was an odds-ratio 9.40 (95%CI 2.86-30.71, p<0.001). The incidence of deadly infections was also significantly higher in patients with HGG that were not treated with IVIG (35.7% vs 12.5%, p<0.034, odds ratio 8, 95%CI 1.7-38.5, p=0.009). Conclusions IVIG replacement therapy in solid organ recipients with severe infections and HGG is associated with a lower rate of re-infection and deadly infections. A randomized clinical trial is warranted to further evaluate this potential effect of IVIG in solid organ transplantation. Instituto de Salud Carlos III. Project FIS Clinical Trial EC11084. With participation of FEDER funds. A way of making Europe.

Defining Secondary Antibody Deficiency After Heart Transplantation

Post transplant severe hypogammaglobulinemia (defined as IgG < 400 mg/dL) has been found to be a risk factor of bacterial, viral and fungal infection in solid organ transplantation according to single center, multicenter and metanalysis studies. In the present study we report on the concentrations of different specific antimicrobial antibodies in heart recipients that were found to have severe hypogammaglobulinemia after heart transplantation to further characterize secondary antibody deficiency in these patients as a potential indication of intravenous immunoglobulin therapy. In a prospective single center follow-up study we evaluated in 131 heart recipients the kinetics of total IgG and of specific antibody concentrations at baseline (pre-transplant) and day 7 and 30 after transplantation. IgG was performed by nephelometry. Specific antibodies included: IgG, IgA and IgM anti-pneumococcal polysaccharide (whole 23 serotypes), IgG anti-CMV, IgG anti-HBs, IgG anti- tetanus toxoid, IgG anti-varicella zoster, IgG anti-salmonella typhi and IgG anti-haemophilus influenzae type B antibodies. All specific antibodies were tested by ELISA tests. During follow-up, 17 (12.9%) patients developed severe IgG hypogammaglobulinemia at least in one study point after transplantation. These patients were found to have significantly lower concentrations of IgG anti-pneumococcal polysaccharide antibodies [at day 7, p=0.002, day 30, p=0.010], IgG anti-HBs [day 7, p=0.001], IgG anti-CMV [day 7, p=0.046], IgG anti-varicella zoster [day 7, p=0.042], as compared with patients without severe hypogammaglobuliemia. Severe hypogammaglobulinemia was a risk factor of severe infection (OR 6.20, 95% confidence interval 2.09-18.39, p=0.0010) and a risk factor of death (OR 4.86, 95% confidence interval 1.39-16.89, p=0.01). Secondary severe IgG hypogammaglobulinemia early after heart transplantation is associated with specific antibody deficiency that could further explain why these patients are at a higher risk of developing severe infections. The association of this secondary antibody deficiency status with higher rates of death is a rationale for considering the role of immune replacement therapy in this setting. Instituto de Salud Carlos III. Project FIS 1501472. With participation of FEDER funds. A way of making Europe.

Monitoring of early humoral immunity to identify lung recipients at risk for development of serious infections: A multicenter prospective study.

Infection is still a leading cause of death during the first year after lung transplantation. We performed a multicenter study among teaching hospitals to assess monitoring of early humoral immunity as a means of identifying lung recipients at risk of serious infections. We prospectively analyzed 82 adult lung recipients at 5 centers in Spain. Data were collected before transplantation and at 7 and 30 days after transplantation. Biomarkers included IgG, IgM, IgA, complement factors C3 and C4, titers of antibodies to pneumococcal polysaccharide antigens (IgG, IgA, IgM) and antibodies to cytomegalovirus (IgG), and serum B-cell activating factor (BAFF) levels. The clinical follow-up period lasted 6 months. Clinical outcomes were bacterial infections requiring intravenous anti-microbial agents, cytomegalovirus (CMV) disease, and fungal infections requiring therapy. We found that 33 patients (40.2%) developed at least 1 serious bacterial infection, 8 patients (9.8%) had CMV disease, and 10 patients (12.2%) had fungal infections. Lower IgM antibody levels against pneumococcal polysaccharide antigens at Day 7 (defined as <5 mg/dl) were a risk factor for serious bacterial infection (adjusted odds ratio [OR] 3.96; 95%confidence interval [CI] 1.39 to 11.26; p = 0.0099). At Day 7 after transplantation, IgG hypogammaglobulinemia (defined as IgG <600 mg/dl) was associated with a higher risk of CMV disease (after adjustment for CMV mismatch: OR 8.15; 95% CI 1.27 to 52.55; p = 0.028) and fungal infection (adjusted OR 8.03, 95% CI 1.51 to 42.72; p = 0.015). Higher BAFF levels before transplantation were associated with a higher rate of development of serious bacterial infection and acute cellular rejection. Early monitoring of specific humoral immunity parameters proved useful for the identification of lung recipients who are at risk of serious infections.

Evaluation of humoral immunity profiles to identify heart recipients at risk for development of severe infections: A multicenter prospective study

New biomarkers are necessary to improve detection of the risk of infection in heart transplantation. We performed a multicenter study to evaluate humoral immunity profiles that could better enable us to identify heart recipients at risk of severe infections. We prospectively analyzed 170 adult heart recipients at 8 centers in Spain. Study points were before transplantation and 7 and 30 days after transplantation. Immune parameters included IgG, IgM, IgA and complement factors C3 and C4, and titers of specific antibody to pneumococcal polysaccharide antigens (anti-PPS) and to cytomegalovirus (CMV). To evaluate potential immunologic mechanisms leading to IgG hypogammaglobulinemia, before heart transplantation we assessed serum B-cell activating factor (BAFF) levels using enzyme-linked immunoassay. The clinical follow-up period lasted 6 months. Clinical outcome was need for intravenous anti-microbials for therapy of infection. During follow-up, 53 patients (31.2%) developed at least 1 severe infection. We confirmed that IgG hypogammaglobulinemia at Day 7 (defined as IgG <600 mg/dl) is a risk factor for infection in general, bacterial infections in particular, and CMV disease. At Day 7 after transplantation, the combination of IgG <600 mg/dl + C3 <80 mg/dl was more strongly associated with the outcome (adjusted odds ratio 7.40; 95% confidence interval 1.48 to 37.03; p = 0.014). We found that quantification of anti-CMV antibody titers and lower anti-PPS antibody concentrations were independent predictors of CMV disease and bacterial infections, respectively. Higher pre-transplant BAFF levels were a risk factor of acute cellular rejection. Early immunologic monitoring of humoral immunity profiles proved useful for the identification of heart recipients who are at risk of severe infection.

Hypogammaglobulinemia and risk of severe infection in kidney transplant recipients.

Recent data have outlined a link between hypogammaglobulinemia (HGG) and infection risk and suggested that HGG correction may decrease post-transplant infections. We analyzed the risk factors of HGG and the relationship between HGG and the risk of severe infection in a cohort of 318 kidney transplant recipients (KTR) who were transplanted between 2003 and 2013. Immunoglobulin (Ig) concentration was measured prospectively at day 15 (D15), month 6 (M6), month 12 (M12), and month 24 (M24) post transplant. The prevalence of IgG HGG was 56% and 36.8% at D15 and M6, respectively. Age was the sole identified risk factors for D15 IgG HGG (odds ratio [OR] 1.02, P = 0.019). Risk factors for M6 IgG HGG were the presence of D15 IgG HGG (OR 6.41, P < 0.001) and treatment of acute rejection (OR 2.63, P = 0.014). Most infections occurred between D15 and M6 post transplant. Only age (hazard ratio 1.03, P < 0.001) was identified as a risk factor of infection between D15 and M6 post transplant. Survival free of infection (overall infections and bacterial or viral infections) did not differ significantly between patients with or without D15 IgG HGG. Only septicemia occurring between M6 and M12 post transplant was more frequently observed in patients with HGG. The low prevalence of severe HGG (<400 mg/dL) did not allow conclusions on the infectious risk associated with this patient subgroup. This study does not support the existence of a strong link between post-transplant HGG and the risk of severe infections in KTR. Correction of HGG to minimize the risk of severe infections in KTR is thus questionable and needs to be reevaluated in prospective studies.

Treatment of adult hyper-IgD syndrome with canakinumab

Hyper-IgD and periodic fever syndrome (HIDS) is a rare, autosomal-recessive autoinflammatory disease characterized by lifelong recurrent episodes of systemic inflammation. HIDS frequently presents in infancy with intermittent fevers lasting from 4 to 7 days, recurring every 4 to 6 weeks. Febrile episodes may be unprovoked or precipitated by factors including infections, vaccinations, or stress. Associated symptoms may include abdominal pain, diarrhea, rashes, arthralgias, aphthous ulcers, and lymphadenopathy. During acute attacks, patients may exhibit leukocytosis, elevations in acute-phase reactants, and elevated levels of proinflammatory cytokines such as IL-1, IL-6, and TNF-a. At baseline, affected individuals may have elevated IgD levels; however, increases in IgD levels are not universal, particularly in very young patients. If clinical suspicion is high, HIDS should be considered despite normal serum IgD levels. Patients with HIDS may exhibit increased rates of infection, particularly with S pneumoniae; this may be secondary to infrequent IgG hypogammaglobulinemia or host conditions that may be permissive for persistence of this organism. HIDS is part of a clinical spectrum caused by decreased activity of mevalonate kinase, an enzyme involved in isoprenoid biosynthesis. Four mutations in MVK, the gene encoding mevalonate kinase (V377I, I268T, H20P/N, and P167L), account for more than 70% of the cases associated with HIDS. Lack of isoprenoid end products due to abnormal metabolism increases IL-1b secretion from mevalonate kinaseedeficient PBMCs, making IL-1 signaling a promising therapeutic target. Previous studies have shown inconsistent benefits of treatments including colchicine, cyclosporine, and statins. Many patients respond well to oral steroids, but the frequency of exacerbations makes a steroid-sparing therapy desirable. Biologic therapies have been successful in the treatment of other periodic fever syndromes. The cryopyrin-associated periodic syndromes are a group of fever disorders including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). These conditions are also mediated through excessive IL-1b production. Canakinumab, a fully human antie IL-1b mAb, has been shown to induce rapid remission of symptoms in patients with cryopyrin-associated periodic syndromes and is approved by the Food and Drug Administration for the treatment of FCAS and MWS. Biologics including etanercept, adalimumab, and anakinra have all been shown to decrease the frequency and severity of febrile episodes in patients with HIDS. Small numbers of patients with HIDS treated with canakinumab have also shown clinical improvement. Here, we describe the case of a patient with HIDS who had significant clinical improvement with initiation of canakinumab therapy.