Facilitated Subcutaneous Immunoglobulin Treatment Increases the Quality of Life and Decreases the Number of Infections and Hospitalizations in Children with Primary Immunodeficiencies.

INTRODUCTION: Immunoglobulin replacement therapy is an effective lifelong treatment modality used in patients with primary immunodeficiency to prevent and/or reduce the incidence of serious infections. Facilitated subcutaneous immunoglobulin (fSCIG) was developed to combine the advantages of intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) and is the latest method of immunoglobulin G (IgG) administration. In this study, switching to fSCIG administration in primary immunodeficiency patients receiving regular IVIG or SCIG therapy was evaluated, and serum IgG trough levels, frequency of infections, frequency and duration of hospitalizations, duration of absence from school/work, and quality of life were determined. METHODS: In this study, fifteen patients with primary immunodeficiency who were previously receiving IVIG or SCIG treatment, followed by fSCIG, were evaluated retrospectively. Age, diagnosis, current complications, mean IgG value, frequency of infection, frequency of hospitalization, and duration of absenteeism from school and work were recorded during and before fSCIG treatment. At the beginning of fSCIG treatment, at 6th and 12th months, "The Quality of Life Scale" was also evaluated in patients and parents. RESULTS: The most common indications for initiation of fSCIG treatment were the difficulty of access to the hospital and the long transfusion periods. No systemic adverse reactions were reported except for redness, swelling, and mild pain on the injection site. The median IgG values for the last 1 year were 529.6 mg/dL for IVIG (n = 9), 876.2 mg/dL for SCIG (n = 6) and 856.7 mg/dL for fSCIG (n = 15, all patients) treatment. The frequency of infections and the number of hospitalizations decreased significantly in the fSCIG group compared to both previous treatment modalities. There was a significant increase in the quality of life score of the patients and their families when compared with previous treatment modalities. CONCLUSION: fSCIG is an effective treatment method and is well tolerated in patients with immunodeficiency. It provides stable immunoglobulin levels and excellent protection against infections and offers the patients the possibility of home-based therapy.

Current genetic defects in common variable immunodeficiency patients on the geography between Europe and Asia: a single-center experience.

Identification of the causes of monogenetic common variable immunodeficiency (CVID) patients has rapidly increased in the last years by means of worldwide availability of appropriate genetic diagnostic methods. However, up to date, very limited numbers of reports demonstrating the role of geography, ethnicity, and consanguinity have been published. Here, we reported the first study of Turkish CVID patients and compared them with the results of three countries from America, Europe, and Asia. A total of 100 children diagnosed as CVID according to the criteria of European Society for Immunodeficiencies were enrolled, and they were genetically analyzed by using targeted next-generation sequencing and whole-exome sequencing. The median age of our patients was 5.8 years (range, 3.0-16.0 years) at clinical diagnosis and 9.0 years (range, 4.8-21.0 years) at the time of genetic diagnosis. The consanguinity rate was 24%. Disease-causing pathogenic variants were defined in 40% of patients in a total of 17 different genes. Sixteen of 40 identified pathogenic variants were novel (40%). We determined 18 surface molecular defects, 10 cytosolic defects, 9 nuclear defects, and 3 others. In our cohort, the most common gene was TACI (15/40 in pathogenic variant identified cases and 15/100 in all cases) followed by the others such as PLCÒ¯2, LRBA, TCF3, and STAT1. In contrast to our expectations, our results were more similar to American and European population rather than Asians, although we also have high consanguinity rates and live on the geography between Europe and Asia. Genetic investigation is a great challenge, because of the complexity and heterogeneity of the disease, and each country has to know their own current genetic landscape in CVID for a better and successful management of the patients.

Autoimmune Cytopenias Are Highly Associated with Inborn Errors of Immunity and They May Be the Initial Presentations in Cases without Severe Infections.

INTRODUCTION: Inborn errors of immunity (IEIs) are inherited disorders that present with increased susceptibility to infections as well as noninfectious complications. Due to the aberrant immune functions of patients with IEI, autoimmune cytopenia (AIC) may be the initial finding, which makes diagnosis a challenge. We aimed to evaluate the clinical course, laboratory findings, and treatment response of AIC in children with IEI. METHODS: Data of children with autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenic purpura (ITP) were obtained from a retrospective chart review of IEI patients diagnosed and followed in our center. Demographic and clinical features and therapeutic outcomes were evaluated. Immunologic findings were compared between patients with AIHA, ITP, and Evans syndrome (ES). The patients were also divided into two subgroups based on the presence or absence of immune dysregulation diseases (IDDs), and all data were compared between these two groups. RESULTS: Out of 562 patients with IEI, 6% (n: 34) had AIC which were ITP (23.5%), AIHA (35.5%), and ES (41.2%). AIC was the initial finding in 50% of these 34 patients. Patients with ES had a higher mean percentage of CD8+ T lymphocytes than ITP patients (40.77 ± 20.21% vs. 22.33 ± 12.48%, p = 0.011). Patients with IDDs were more likely to develop ES (p = 0.004), lymphoproliferation (p = 0.005), and resistance to first-line therapy (p = 0.021) than other IEI groups. CONCLUSION: This study shows that AIC may be the initial finding of IEI, particularly when lymphoproliferation and resistance to first-line therapy co-occur. Therefore, detailed investigation should be offered to all patients to avoid diagnostic delay.

Dual Diagnosis of Trichohepatoenteric Syndrome and Lipoid Proteinosis in a Turkish Child.

Introduction: Trichohepatoenteric syndrome (THES) is caused by pathogenic mutations in TTC37 and SKIV2L genes and characterized by intractable diarrhea, facial dysmorphism, hair abnormality, immunodeficiency, and skin abnormalities. Lipoid proteinosis is caused by pathogenic mutations in ECM1 gene and characterized by deposition of hyaline-like material in various tissues resulting in heterogenous clinical findings. Case Presentation: Four years after the diagnosis and management of THES, due to new clinical findings, another reason for underlying features of the patient was considered. WES was performed and a homozygous c.507delT (p.Arg171GlyfsTer7) mutation in the ECM1 gene was detected. Conclusion: This case provides an example of co-existence of multiple genetic defects in a single patient born to consanguineous parents.

An Extraordinary Case of Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) Syndrome Misdiagnosed as Juvenile Idiopathic Arthritis on Admission.

Background: APECED is a syndrome characterized by autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy. The most observed clinical findings are chronic mucocutaneous candidiasis, hypoparathyroidism, and autoimmune adrenal insufficiency. Case Presentation. A three-year-old male patient was admitted with classical signs of juvenile idiopathic arthritis and treated with nonsteroidal anti-inflammatory drugs. During follow-up, signs of autoimmunity, candidiasis, nail dystrophy, and onychomycosis were observed. The parents were consanguineous, and targeted next-generation sequencing was performed. A homozygous mutation in the AIRE gene SAND domain (c.769C > T, p.Arg257Ter) was detected, and the patient was diagnosed with APECED syndrome. Conclusion: Inflammatory arthritis is rarely described in association with APECED and is often misdiagnosed as juvenile idiopathic arthritis. In APECED cases, nonclassical symptoms such as arthritis may occur before developing classical symptoms and considering the diagnosis of APECED in patients with CMC and arthritis is useful for early diagnosis before development of complications and management of disease.

Successful treatment of post-pericardiotomy syndrome via C1 inhibitor replacement therapy in a hereditary angioedema patient with Marfan syndrome.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (HAE-C1INH) is caused by dysfunctional C1-INH protein due to mutations in the SERPING1 gene encoding C1-INH. Marfan syndrome is a genetic connective tissue disease that affects the cardiovascular and ocular systems along with the skeletal system. In this case, we present the successful treatment of post-pericardiotomy syndrome unresponsive to classical therapy, which has not been described in the literature. The syndrome developed in a patient with hereditary angioedema (HAE) who underwent open heart surgery due to cardiac involvement in Marfan syndrome. CASE: A nine-year-old male HAE-C1INH patient underwent open heart surgery secondary to cardiac involvement caused by Marfan syndrome. To prevent HAE attacks, 1000 units of C1 inhibitor concentrate therapy were given 2 hours before and 24 hours after the operation. Post-pericardiotomy syndrome was diagnosed on the postoperative second day and ibuprofen 15 mg/kg/day (3 weeks) was started. Since there was no response to classical treatment on the 21st postoperative day, C1 inhibitor concentrate treatment was planned as 1000 units/ dose for 2 days a week considering a prolonged hereditary angioedema attack. In the second week of treatment, complete recovery was achieved for pericardial effusion with a total of 4 doses. CONCLUSIONS: We emphasize that in patients with hereditary angioedema undergoing this treatment, care should be taken in terms of complications that may be associated with the disease even if short-term prophylaxis is given before operations and that longer-term use of C1 inhibitor concentrate has a place in treatment.

Alterations in B and NK cells highly correlate with disease severity in children with COVID-19.

Background/aim: Children with coronavirus disease 2019 (COVID-19) present milder symptoms than adults and are at lower risk of hospitalization and life-threatening complications. However, the kinetics of lymphocyte subsets and serum immunoglobulins in the peripheral blood during COVID-19 infection remains unclear. In this study, it was aimed to determine the changes in hematological and immunological parameters, especially in the lymphocyte subsets, in the peripheral blood of children with different COVID-19 disease severity. Materials and methods: The study was planned as a prospective cohort and included 68 children aged 0-18 years who were admitted to Ege University Faculty of Medicine Department of Pediatrics and diagnosed with COVID-19 infection between May 2020 and December 2021. In addition to demographic characteristics, clinical findings, and severity criteria, hematological, biochemical, and immunological laboratory (T/B lymphocyte subgroups, serum immunoglobulins) results were noted and examined if there were some correlations between disease severity and the laboratory values. Results: In the study group, while 60.6% (n = 40) of the patients received treatment in the hospital, 10.6% (n = 7) needed intensive care treatment. Lymphopenia (35.3%) was more common than neutropenia (14.7%) in the COVID-19-infected children. CD19+ B cells were low in a very high percentage of patients (26.5%), and 16.2% had low levels of NK cells. Significant correlation between disease severity and CD19+lymphocytes, CD19+CD38+IgMlow lymphocytes, CD19+CD38+CD27highIgMhigh lymphocytes, CD19+CD81+ lymphocytes (p = 0.001, p = 0.008, p = 0.014, p = 0.025, and rs = 0.394, rs = 0.326, rs = 0.303, rs = 0.280, respectively), significant inverse correlation between disease severity and absolute lymphocytes counts and CD3-CD16+CD56+ lymphocytes (p = 0.004, 0.014, and rs = -0.353, rs = -0.304, respectively) were observed. The percentage of hospitalized patients with low CD3 levels (15%) was significantly higher than that of the outpatients with low CD3 levels. Conclusion: As the severity of the disease increased, the CD19+, CD19+CD38+IgMlow, CD19+CD38+CD27highIgMhigh, and CD19+CD81+ lymphocytes percentages increased, while the lymphocyte count and NK cell percentage decreased. Therefore, detecting these prognostic immunobiomarkers related to the severity of the disease may contribute considerably to management of the illness.

Effectiveness and adverse reactions to subcutaneous immunotherapy in children with allergic rhinitis/asthma.

OBJECTIVE: Adverse reactions, which are mostly local and rarely systemic, can be seen during subcutaneous immunotherapy (SCIT). It was not possible to continue SCIT at times due to systemic reactions. The purpose of the present study was to identify the incidence and risk factors associated with adverse reactions during subcutaneous allergen-specific immunotherapy (AIT). METHODS: A total number of 344 patients under 18 years old with allergic rhinitis and/or asthma who underwent SCIT between 2005 and 2021 were included in the study. Demographic characteristics of the patients, laboratory findings [Total Immunglobulin E(IgE), aeroallergen prick test, inhaler, and allergen specific IgE(sIgE) and eosinophil counts], and adverse events observed during AIT were recorded retrospectively. Descriptive and univariate/multivariate logistic regression analyses were used to identify risk factors for adverse events. RESULTS: Among 344 patients, 33.4% (n = 115) were female, mean age was 133.1 ± 41.0 months, and 42.2% (n = 145) were >12 years old. One hundred-thirty eight (40.1%) of the patients were mono-sensitized, 47 (13.7%) had asthma, 207 (60.2%) allergic rhinitis, and 90 (26.2%) asthma and allergic rhinitis. Single allergen content was administered to 187 (54.4%) patients (62 mite, 114 grass mix, 11 olea), and multiple allergens to 157 (45.6%) patients (121 pollen mix, 36 other (mite/alternaria)]. A total number of 33.008 injections were administered. 840 adverse reactions (262 (31.1%) at up-dosing phase, 578 (68.8%) at maintenance phase) in 195 (56.7%) patients were observed. Among the adverse reactions, 632 (75.2%) were local, 160 (19%) large local, and 48 (5.7%) (39 at maintenance, 9 at up-dosing) (in 31 patients) were systemic (28 Grade 1, 12 Grade 2, 8 Grade 3). Adrenalin was administered to 8 patients with Grade 3 systemic reaction (8/33008; %0.024). Adverse reactions, especially local ones, were seen more frequently in children under 12 years old (p < 0.001). Patients sensitized with grass pollen (p:0.01) and mite (p:0.004), and those who had received SCIT with pollen mixture had more adverse reactions than the others. More adverse reactions were observed in SCIT containing calcium-phosphate as adjuvant (p: 0.01). Local reactions were risk factors for large local (OR = 3.591, %95 CI:2.064-6.247, p < 0.001) and systemic (OR = 2.190, %95 CI:1.005-4.722 p = 0.046) reactions at univariate analyses. Total nasal symptom scores, Visual Analog Scale and asthma symptom control test decreased after one year of treatment (p < 0.01). CONCLUSION: SCIT is a safe and effective treatment method in childhood that leads to improvements in all nasal symptoms and asthma after one year of treatment.

A Novel BLNK Gene Mutation in a Four-Year-Old Child Who Presented with Late Onset of Severe Infections and High IgM Levels and Diagnosed and Followed as X-Linked Agammaglobulinemia for Two Years.

Agammaglobulinemia is a rare inherited immunodeficiency disorder. Mutations in the BLNK gene cause low levels of mature B lymphocytes in the peripheral blood leading to recurrent infections. We present a four-year-old Turkish boy who had recurrent respiratory tract infections in the last six months. He had very low IgG (81 mg/dl) and IgA levels (<5 mg/dl) with high IgM (258 mg/dl). Flow cytometric analysis of lymphocyte subsets showed low CD19+ B cells (0.05%). Homozygous c.790C > T (p.Gln264Ter) mutation was detected in the BLNK gene with Targeted Next Generation Sequencing (TNGS) gene analysis. Agammaglobulinemia may be due to different genetic etiologies together with complex genetic events. Although the first diagnosis to be considered in male patients is Bruton's agammaglobulinemia, patients with normal BTK sequence and/or expression should be investigated with a large genetic study such as TNGS in the early period to reach a definitive diagnosis. This male case of agammaglobulinemia highlights the necessity of considering BLNK mutations in children with B cell deficiency, even though they are known to be rare causes of agammaglobulinemia. Our case is also remarkable with high IgM levels before intravenous immunoglobulin replacement therapy and with late-onset severe infections.

Could Age and Oral Challenge Outcomes Identify High-Risk Patients During Cow's Milk Oral Immunotherapy?

Objective: Severe immunglobuline E (IgE)-mediated reactions during oral immunotherapy (OIT) are major obstacles to treatment. The present study aimed to evaluate and identify clinical and laboratory biomarkers of adverse events during OIT among children with cow's milk (CM) allergy. Study Design: Eighty-six children older than 36 months who had undergone OIT with milk were enrolled. Clinical data, oral food challenge (OFC) test results, and laboratory data were recorded retrospectively. Results: The median duration of the build-up phase of OIT was 19 weeks (min 10-max 40) and the duration of the maintenance phase was 86.5 (min 1-max 132) months. A total of 11,767 CM doses were administered during the build-up phase and adverse reactions were seen in 62 (73.8%) patients with reactions registered for 157 doses among 11,767 (1/75 doses). The number of reactions during the maintenance phase was 41 (47.6%) in 24 (27.9%) patients. There was a significant reduction in the number of reactions (P = 0.000) between the build-up phase and maintenance phase. Adverse reactions and anaphylaxis were higher for patients who had cough during OFC (P = 0.003, P = 0.002, respectively) during the build-up phase and also during the maintenance phase too (P = 0.000). Evaluation for all reactions and anaphylaxis (during build-up and maintenance) with Kaplan-Meier and Cox regression analysis showed class IV-VI of CM-specific immunoglobulin E (sIgE), casein-sIgE and cough during OFC were significantly associated with increased probability of reaction and anaphylaxis. Younger age at onset of OIT was associated with risk reduction (0.017). Conclusion: Laboratory data and reactions during the OFC (especially cough) can help to identify high-risk patients during OIT.

Erratum: X-linked agammaglobulinemia: investigation of clinical and laboratory findings, novel gene mutations and prevention of infective complications in long-term follow-up.

[This corrects the article on p. 37 in vol. 10, PMID: 33815962.].

Four diseases, PLAID, APLAID, FCAS3 and CVID and one gene (PHOSPHOLIPASE C, GAMMA-2; PLCG2): Striking clinical phenotypic overlap and difference.

We suggest PLAID, APLAID, and FCAS3 have to be considered as different aspects of the same underlying condition, because of our long-term clinical and genetical experiences. Some CVID patients have the same disease-causing mutations in PLCG2 gene, so it may be better to define all of them as "PLCG2deficiency."

Consensus Middle East and North Africa Registry on Inborn Errors of Immunity.

BACKGROUND: Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. METHODS: We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. RESULTS: We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). CONCLUSIONS: This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation.

X-linked agammaglobulinemia: investigation of clinical and laboratory findings, novel gene mutations and prevention of infective complications in long-term follow-up.

Introduction-Objective: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease predominantly with antibody deficiency and characterized by recurrent pyogenic infections, absence of B cells and agammaglobulinemia. In this study, it is aimed to review the demographic data of our XLA patients and examine the frequency of severe bacterial and mild infections and benefits of immunoglobulin replacement therapies to reduce the rate of infections. In addition, correlations between genotypic results and clinical and laboratory findings were searched. PATIENTS AND METHODS: In this study, 20 patients who were followed-up between 1995-2019 and diagnosed with XLA by flow cytometric and genetic tests were included. Demographic data, symptoms at admission and follow-up, laboratory data and radiologic imaging findings, previous infections, immunoglobulin replacement treatments, and genetic analysis results of the patients were recorded. RESULTS: All patients in the study were male and the mean age of onset of symptoms was 60 months. The mean age at diagnosis was 72 months. A total of 19 different mutations were identified in the Bruton-tyrosine kinase gene, six of them were novel. Our eldest patient was 34 years old and the longest follow-up period was 24 years. Respiratory tract infections were the most common in the patients, only 35% of the causative agents were found in sputum cultures and H. influenzae type b (57.8%) was isolated most frequently. Both intravenous and subcutaneous immunoglobulin replacement therapies significantly reduced the number of severe bacterial infections and other mild infections. CONCLUSION: XLA is a rare pediatric primary immunodeficiency disease and affected individuals require lifelong immunoglobulin replacement therapy. Immunoglobulin replacement prevents life-threatening infections and dramatically increases survival rates. The patients with regular treatment and follow-up, reach adulthood and has a high quality of life.

A Novel Homozygous TRNT1 Mutation in a Child With an Early Diagnosis of Common Variable Immunodeficiency Leading to Mild Hypogammaglobulinemia and Hemolytic Anemia.

Although sideroblastic anemias (SAs) may be associated with different etiologies, deterioration of mitochondrial heme biosynthesis in bone marrow erythroid cells is a general abnormality. Congenital SA associated with immunodeficiency, periodic fever, and developmental delay is because of loss-of-function mutations in the TRNT1 gene. We report a patient with a novel homozygous mutation in the TRNT1 gene presenting with anemia with siderocytes, hypogammaglobulinemia, hepatosplenomegaly, and brittle hair but without periodic fever or developmental delay. The patient was presented to emphasize the power of reverse phenotyping in the differential diagnosis of primary immunodeficiency patients with atypical features and to raise awareness for TRNT1 disease in case of coexistent SA and hypogammaglobulinemia.