A Retrospective Analysis of Rituximab Treatment for B Cell Depletion in Different Pediatric Indications

Background: Rituximab (RTX) is used in cancer therapy as well as in the treatment of autoimmune diseases and alloimmune responses after transplantation. It depletes the disease-causing B cells by binding to the CD (cluster of differentiation) 20 antigen. We evaluate different pediatric treatment protocols (via fixed treatment schedule, B cell- or symptom-controlled) and their therapeutic effects.Methods: Demographic information, clinical and laboratory characteristics, and special laboratory values such as immunoglobulin G (IgG), CD19 positive B cells and Epstein-Barr viral load were retrospectively analyzed in children treated with RTX between 2008 and 2016.Results: Seventy-six patients aged 1 to 19 (median 13) years were treated with 259 RTX infusions. The spectrum of diseases was very heterogeneous. RTX led to a complete depletion of the B cells. The reconstitution time varied between patients and was dependent on the application schedule (median 11.8 months). Fourteen out of 27 (52%) patients developed hypogammaglobulinaemia. The risk of IgG deficiency was 2.6 times higher in children under 4 years of age than in olderones. In the last group IgG deficiency developed in only 38% of the cases (n = 8). Recurrent and severe infections were observed each in 11/72 (15%) patients. Treatment-related reactions occurred in 24/76 (32%) cases; however, treatment had to be discontinued in only 1 case. In 16/25 (76%), the Epstein-Barr viral load dropped below the detection limit after the first RTX infusion.Conclusion: RTX is an effective and well-tolerated drug for the treatment of oncological diseases as well as autoimmune and alloimmune conditions in children. B cell depletion and reconstitution varies both intra- und interindividually, suggesting that symptom-oriented and B cell-controlled therapy may be favorable. Treatment-related reactions, IgG deficiency and infections must be taken into account.

Assessment of COVID-19 Incidence and the Ability to Synthesise Anti-SARS-CoV-2 Antibodies of Paediatric Patients with Primary Immunodeficiency

Background: Data regarding the course of SARS-CoV-2 infection in children with primary immunodeficiency (PID) is insufficient. The purpose of the study was to evaluate the morbidity and clinical course of COVID-19 and the ability to produce anti-SARS-CoV-2 IgG antibodies in children with PID. Methods: In this retrospective study, medical records of 99 patients aged 0–18 were evaluated. The patients were divided into three groups: PID group (68.69%), control group (19.19%) and patients with ongoing or previous paediatric inflammatory multisystem syndrome (12.12%). Data such as morbidity, clinical outcome, and IgG anti-SARS-CoV-2 antibody titres were assessed. Results: A confirmed diagnosis of SARS-CoV-2 infection has been established in 26.47% of patients with PID. Among patients with PID infected with SARS-CoV-2, only three cases were hospitalised. Mortality in the PID group was 0%. Throughout an observation period of 1 year, 47.06% of patients with PID were tested positive for the anti-SARS-CoV-2 antibody. Conclusion: In the study group, in most cases the disease had a mild and self-limiting course. Remarkably, even though IgG deficiency was the most prevalent form of PID in the study group, the patients were able to respond satisfactorily to the infection in terms of anti-SARS-CoV-2 IgG.

Association of mannose-binding lectin, ficolin-2 and immunoglobulin concentrations with future exacerbations in patients with chronic obstructive pulmonary disease: secondary analysis of the randomized controlled REDUCE trial

Background The innate and adaptive immune system is involved in the airway inflammation associated with acute exacerbations in patients with chronic obstructive pulmonary disease (COPD). We evaluated the association of mannose-binding lectin (MBL), immunoglobulin (Ig) and ficolin-2 concentrations with COPD exacerbations and according to the glucocorticoid treatment duration for an index exacerbation. Methods Post-hoc analysis of the randomized, double-blind, placebo-controlled REDUCE trial of 5 vs. 14 days of glucocorticoid treatment for an index exacerbation. MBL, ficolin-2 and total IgG/IgA and subclass concentrations were determined in stored samples drawn (n = 178) 30 days after the index exacerbation and associated with the risk of re-exacerbation during a 180-day follow-up period. Results IgG and subclass concentrations were significantly lower after 14 days vs. 5 days of glucocorticoid treatment. Patients with higher MBL concentrations were more likely to suffer from a future exacerbation (multivariable hazard ratio 1.03 per 200 ng/ml increase (95% confidence interval (CI) 1.00–1.06), p = 0.048), whereas ficolin-2 and IgG deficiency were not associated. The risk was most pronounced in patients with high MBL concentrations, IgG deficiency and 14 days of glucocorticoid treatment pointing towards an interactive effect of MBL and IgG deficiency in the presence of prolonged glucocorticoid treatment duration [Relative excess risk due to interaction 2.13 (95% CI − 0.41–4.66, p = 0.10)]. IgG concentrations were significantly lower in patients with frequent re-exacerbations (IgG, 7.81 g/L vs. 9.53 g/L, p = 0.03). Conclusions MBL modified the short-term exacerbation risk after a recent acute exacerbation of COPD, particularly in the setting of concurrent IgG deficiency and recent prolonged systemic glucocorticoid treatment. Ficolin-2 did not emerge as a predictor of a future exacerbation risk.

Immunoglobulin Deficiency as an Indicator of Disease Severity in Patients with COVID-19

Despite the pandemic status of COVID-19, there is limited information about host risk factors and treatment beyond supportive care. Immunoglobulin G (IgG) could be a potential treatment target. Our aim was to determine the incidence of IgG deficiency and associated risk factors in a cohort of 62 critical ill COVID-19 patients admitted to two German ICUs (72.6% male, median age: 61 years). 13 (21.0%) of the patients displayed IgG deficiency (IgG <7 g/L) at baseline (predominant for the IgG1, IgG2, and IgG4 subclasses). IgG-deficient patients had worse measures of clinical disease severity than those with normal IgG levels (shorter duration from disease onset to ICU admission, lower ratio of PaO2 to FiO2, higher Sequential Organ Failure Assessment score, and higher levels of ferritin, neutrophil-to-lymphocyte ratio and serum creatinine). IgG-deficient patients were also more likely to have sustained lower levels of lymphocyte counts and higher levels of ferritin throughout the hospital stay. Furthermore, IgG-deficient patients compared to those with normal IgG levels displayed higher rates of acute kidney injury (76.9% vs. 26.5%; p=0.005) and death (46.2% vs. 14.3%; p=0.012), longer ICU (28 [6-48] vs. 12 [3-18] days; p=0.012) and hospital length of stay (30 [22-50] vs. 18 [9-24] days; p=0.004). Multivariable logistic regression showed increasing odds of 90-day overall mortality associated with IgG-deficiency (OR 12.8, 95% CI 1.5-108.4; p=0.019). IgG deficiency might be common in critically ill COVID-19 patients, and warrants investigation as both a marker of disease severity as well as a potential therapeutic target.

Administration of intravenous immunoglobulin in patients with chronic lymphocytic leukemia and infectious complications

Background. Chronic lymphocytic leukemia (CLL) is one of the most frequent malignant blood disorders in adult patients. For the last several decades treatment of CLL made its way from simple chemotherapy agents (chlorambucil, cyclophosphamide, fludarabine) to highly technological innovative medications (monoclonal antibodies, targeted agents, CAR T-cell therapy). Despite quite high rate of remissions induced by the novel treatment methods significant proportion of the patients develop infectious mostly bacterial complications in the long term. Various infections often become the cause of mortality in CLL patients in remission. They develop in about 70 % of the patients and become severe in about 30 % of them (requiring inpatient hospitalization and/or intravenous antibacterial treatment). Novel agents for treatment of CLL influencing the immune B-cells lead to immune suppression (secondary hypogammaglobulinemia, immunoglobulin G (IgG) deficiency), distribution and severity of infectious complications. Substitutive treatment with intravenous IgG changed clinical course of the secondary hypoimmunoglobulinemia reducing significantly incidence of the infectious events in CLL patients as well as in patients undergoing immunochemotherapy (ICT) and immunosuppressive treatment. Objective. To determine the necessity for immunocorrection in patients with CLL requiring ICT. Materials and methods. Patients with the diagnosis of CLL undergoing ICT within hematology department developing infectious complications were observed. Results and discussion. Patients with CLL undergoing ICT were tested and analyzed and according to the results in 31 of these patients hypogammaglobulinemia and reduced levels of IgG were revealed. In 8 of the patients reduction of IgG was detected already at the primary diagnosis of CLL (Binet stages B and C). Depending on the performed treatment of CLL frequency of infectious complications differed and was the highest in subjects with progressive course of leukemia and in those who were treated with RFC (rituximab, fludarabine and cyclophosphamide) ICT. Levels of IgG ranged from 0.86 to 5.55 g/L (median – 3.49 g/L, lower-upper quartile – 2.62-4.76 g/L). Levels of hypogammaglobulinemia in the whole group ranged from 4.49 to 16.87 g/L (median – 12.11 g/L, lower-upper quartile – 11.44-12.88 g/L). Patients underwent the substitutive treatment with intravenous immunoglobulin with the dose of 0.4 g/kg every month. The medication was administered according to standard recommendations. There were no side effects registered within 24 h of infusion. Additionally, patients with infectious complications were treated with antibacterial, antifungal and antiviral agents. After application of intravenous immunoglobulin general condition of the patients improved, body temperature normalization and reduction of recurrent infectious events were observed. The mean time from the diagnosis of persistent hypogammaglobulinemia to complete resolution of infectious complications was 12.5 months (ranging from 3.6 to 27 months). Our results suggested that patients with IgG deficiency without signs of infection responded better to this treatment. Levels of IgG increased from 6.57 to 13.5 g/L (median – 9.35 g/L, lower-upper quartile – 7.57-10.70 g/L) and levels of γ-globulin grew from 14.4 to 17.69 g/L (median – 16.70 g/L, lower-upper quartile – 15.96-17.30 g/L). Conclusions. Secondary hypogammaglobulinemia and deficiency of the serum IgG often develop in patients with blood malignancies, especially in those involving clonal proliferation of the B-cells, like in CLL. According to our study immunocorrection by intravenous immunoglobulin resulted in resolution of infectious complications in all cases of confirmed immunodeficiency. In order to prevent severe infections in CLL patients it is expedient to perform screening of the humoral immunity status before initiation of ICT and in case of development of febrile conditions.

ATOPIC DERMATITIS – ASSOCIATED IMMUNE DYSFUNCTION

The immune system shows a complex role to defend the body in response to “non-self” antigens, respond abnormally to antigens allergens (hypersensitivity and autoimmunity) and shows immune tolerance by lack of reactivity to its own structures (self).Aim. The aim of this study is to demonstrate that in atopic dermatitis immune deficiency influences the development of atopy, disease severity and comorbidities. Material and methods. Following medical record review, 135 cases diagnosed with AD were included in the study. Statistical analysis was performed using SPSS v20 for determining the frequency and testing the hypotheses, for p < 0.05, by t tests and One-Way ANOVA. Results. Of the 135 cases, 51.9% were male children and 48.1% female children aged 1 month to 127 months with a mean of 26.21. According to total serum IgE level, 64.4% of patients had elevated IgE levels, 35.6% normal levels. According to the SCORAD, children had mild AD in 20.7% of cases, moderate in 70.4%, and severe in 8.9%. IgA deficiency was found for 48.1% of cases, and for 51.9% normal. IgG deficiency was found in 38.5% of cases. The independent samples t tests showed statistical significant demonstrating correlations between IgE level and IgA immune deficiency, between SCORAD and IgG and IgA immune deficiency. Atopic march is influenced by elevated IgE, IgA and IgG immune deficiency, p <0.05. Conclusions. Atopy in AD can be influenced by complex factors, both internal and environmental, but this remains a controversial topic. External factors acting on a background genetically predisposed to atopy trigger the manifestation of AD.