Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease.

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

Genetic Evaluation of the Patients with Clinically Diagnosed Inborn Errors of Immunity by Whole Exome Sequencing: Results from a Specialized Research Center for Immunodeficiency in Türkiye.

Molecular diagnosis of inborn errors of immunity (IEI) plays a critical role in determining patients' long-term prognosis, treatment options, and genetic counseling. Over the past decade, the broader utilization of next-generation sequencing (NGS) techniques in both research and clinical settings has facilitated the evaluation of a significant proportion of patients for gene variants associated with IEI. In addition to its role in diagnosing known gene defects, the application of high-throughput techniques such as targeted, exome, and genome sequencing has led to the identification of novel disease-causing genes. However, the results obtained from these different methods can vary depending on disease phenotypes or patient characteristics. In this study, we conducted whole-exome sequencing (WES) in a sizable cohort of IEI patients, consisting of 303 individuals from 21 different clinical immunology centers in Türkiye. Our analysis resulted in likely genetic diagnoses for 41.1% of the patients (122 out of 297), revealing 52 novel variants and uncovering potential new IEI genes in six patients. The significance of understanding outcomes across various IEI cohorts cannot be overstated, and we believe that our findings will make a valuable contribution to the existing literature and foster collaborative research between clinicians and basic science researchers.

Therapeutic modalities and clinical outcomes in a large cohort with LRBA deficiency and CTLA4 insufficiency.

BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency (LRBA-/-) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) insufficiency (CTLA4+/-) are mechanistically overlapped diseases presenting with recurrent infections and autoimmunity. The effectiveness of different treatment regimens remains unknown. OBJECTIVE: Our aim was to determine the comparative efficacy and long-term outcome of therapy with immunosuppressants, CTLA4-immunoglobulin (abatacept), and hematopoietic stem cell transplantation (HSCT) in a single-country multicenter cohort of 98 patients with a 5-year median follow-up. METHODS: The 98 patients (63 LRBA-/- and 35 CTLA4+/-) were followed and evaluated at baseline and every 6 months for clinical manifestations and response to the respective therapies. RESULTS: The LRBA-/- patients exhibited a more severe disease course than did the CTLA4+/- patients, requiring more immunosuppressants, abatacept, and HSCT to control their symptoms. Among the 58 patients who received abatacept as either a primary or rescue therapy, sustained complete control was achieved in 46 (79.3%) without severe side effects. In contrast, most patients who received immunosuppressants as primary therapy (n = 61) showed either partial or no disease control (72.1%), necessitating additional immunosuppressants, abatacept, or transplantation. Patients with partial or no response to abatacept (n = 12) had longer disease activity before abatacept therapy, with higher organ involvement and poorer disease outcomes than those with a complete response. HSCT was performed in 14 LRBA-/- patients; 9 patients (64.2%) showed complete remission, and 3 (21.3%) continued to receive immunosuppressants after transplantation. HSCT and abatacept therapy gave rise to similar probabilities of survival. CONCLUSIONS: Abatacept is superior to immunosuppressants in controlling disease manifestations over the long term, especially when started early, and it may provide a safe and effective therapeutic alternative to transplantation.

Clinical phenotypes of childhood food allergies based on immune mechanisms: A multicenter study.

Background: Food allergies (FA) are an important public health concern that place a major burden on the lives of children and their families. The complex pathogenesis of FAs results in multisystemic and heterogenous clinical presentations. Objective: To evaluate, according to immune mechanisms, the characteristics and risk factors of childhood FA in Turkey. Methods: This descriptive multicenter study included 1248 children with FA, aged < 18 years,, who were evaluated by pediatric allergists in 26 different centers. Results: Immune mechanisms of FA were immunoglobulin E (IgE) mediated in 71.8%, non-IgE mediated in 15.5%, and mixed IgE/non-IgE mediated in 12.7% of the patients. An episode of anaphylaxis had occurred in 17.6% of IgE-mediated FA. The most common food allergens were classified into five categories (in order of decreasing frequency): cow's milk, egg, tree nuts and/or peanut, wheat, and seafood. Allergies to cow's milk and egg declined significantly with age, whereas tree nuts and/or peanut allergies increased with age. The 0-2 year age group accounted for 62.5% of the cases. The most frequent cause of FA and food anaphylaxis was cow's milk before age 13 years and tree nuts and/or peanut during adolescence (ages 13-18 years). Compared with other phenotypes, male sex (odds ratio [OR] 1.486; p = 0.032), sibling(s) (OR 1.581; p = 0.021), and maternal atopy (OR 1.531; p = 0.045) increased the likelihood of IgE-mediated FA, whereas high household income (OR 1.862; p = 0.026) increased the likelihood of non-IgE-mediated FA in multivariate regression analysis. Conclusion: This study showed that the clinical findings of FA were highly variable, depending on age and underlying immune mechanism. Knowing the population characteristics will enable better management of FA in children.

Hematopoietic stem cell transplantation in CD40 ligand deficiency: A single-center experience.

Deficiency of the CD40L, expressed on the surface of T lymphocytes, is caused by mutations in the glycoprotein CD40L (CD154) gene. Resulting defective humoral and cellular responses cause a clinical presentation that includes recurrent sinopulmonary bacterial infections, opportunistic infections, sclerosing cholangitis, neutropenia, and autoimmune manifestations. HSCT represents the only curative treatment modality. However, the therapeutic decision to use HSCT proves challenging in many cases, mainly due to the lack of a phenotype-genotype correlation. We retrospectively reviewed patients with CD40L deficiency who were transplanted in Antalya and Göztepe MedicalPark Pediatric HSCT units from 2014 to 2019 and followed by Akdeniz University School of Medicine Department of Pediatric Immunology. The records of eight male cases, including one set of twins, were evaluated retrospectively. As two transplants each were performed on the twins, a total of ten transplants were evaluated. Conditioning regimens were predominantly based on myeloablative protocols, except for the twins, who received a non-myeloablative regimen for their first transplantation. Median neutrophil and platelet engraftment days were 13 (range 10-19) and 14 (range 10-42) days, respectively. In seven of ten transplants, a CMV reactivation was developed without morbidity. None of the patients developed GVHD, except for one mild case of acute GVHD. All patients survived, and the median follow-up was 852 days. Our data show that HSCT for patients with CD40 ligand deficiency is a potentially effective treatment for long-term disease control.

Mutational landscape of severe combined immunodeficiency patients from Turkey.

Severe combined immunodeficiency (SCID) has a diverse genetic aetiology, where a clinical phenotype, caused by single and/or multiple gene variants, can give rise to multiple presentations. The advent of next-generation sequencing (NGS) has recently enabled rapid identification of the molecular aetiology of SCID, which is crucial for prognosis and treatment strategies. We sought to identify the genetic aetiology of various phenotypes of SCIDs and assessed both clinical and immunologic characteristics associated with gene variants. An amplicon-based targeted NGS panel, which contained 18 most common SCID-related genes, was contumely made to screen the patients (n = 38) with typical SCID, atypical SCID or OMENN syndrome. Allelic segregations were confirmed for the detected gene variants within the families. In total, 24 disease-causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1). The overall success rate of our custom-made NGS panel was 60% (39.3% for NK+ SCID and 100% for NK- SCID). Incidence of autosomal-recessive inherited genes is more frequently found in our cohort than the previously reported populations probably due to the high consanguineous marriages in Turkey. In conclusion, the custom-made sequencing panel was able to identify and confirm the previously known and novel disease-causing variants with high accuracy.

Hematopoietic Stem Cell Transplantation From Unrelated Donors in 2 Cases of Interleukin-10 Receptor Deficiency: Is Surgery Not a Requirement?

Mutations in interleukin-10 and its receptors cause infantile inflammatory bowel disease (IBD), a hyperinflammatory disorder characterized by severe, treatment-refractory colitis, multiple abscesses, and enterocutaneous fistulas. Patients with infantile IBD often require several surgical interventions, including complete colectomy, and hematopoietic stem cell transplantation is currently the only known medical therapy. Traditionally, operative management has been preferred before stem cell transplantation because of the latter's increased susceptibility to procedural complications; however, surgical intervention could be delayed, and possibly reconsidered, because our 2 patients with infantile IBD demonstrated a rapid response to treatment via engraftment.

Immune Reconstitution Inflammatory Syndrome After DLI in a SCID Patient After Hematopoetic Stem Cell Transplantation.

Immune reconstitution inflammatory syndrome (IRIS) is a clinical condition emerging after immune recovery of an immunocompromised status, mostly in human immunodeficiency virus infected patients but also in several other settings, such as the recovery from the severe combined immunodeficiency status after hematopoietic stem cell transplantation. Herein, we report a patient transplanted for severe combined immunodeficiency who developed IRIS for 2 times, namely shortly after transplantation and after donor lymphocyte infusion. Pediatric transplant teams need to be aware of the previous IRIS phenomenon of BCG-adenitis while making the decision of donor lymphocyte infusions.

Hematopoietic stem cell transplantation from unrelated donors in children with DOCK8 deficiency.

DIDS is a unique form of combined immune deficiency characterized by an unusual susceptibility to cutaneous viral infections, severe allergies with eosinophilia and elevated immunoglobulin E titers, autoimmunity, and cancer. HSCT is considered the standard of care for this deadly disease. We have retrospectively analyzed the outcome of allogeneic HSCT from unrelated donors in patients with DIDS. Data from four patients, with five transplants, are presented. All patients received transplants from unrelated donors' BM, except for one patient who received a cord blood transplant. The conditioning regimens were based on myeloablative protocols for BM derived transplants; a NM regimen was pursued for the patient who received a cord blood transplant, which resulted in graft rejection. Although recurrent pneumonia and skin infections resolved immediately after transplantation, all patients subsequently developed human herpesvirus infection, including cutaneous herpetic lesions, cytomegalovirus reactivation, and zona zoster, which could be attributed to the use of ATG. Despite the presence of serious morbidities prior to transplantation, all patients recovered successfully. DIDS can be successfully treated with allogeneic HSCT from unrelated donors following a myeloablative conditioning regimen, with a reasonable safety profile.

In vitro interferon γ improves the oxidative burst activity of neutrophils in patients with chronic granulomatous disease with a subtype of gp91phox deficiency.

AIM OF THIS STUDY: Chronic granulomatous disease (CGD) is a genetically heterogeneous primary immunodeficiency caused by a defect in phagocyte production of oxygen metabolites, and resulting in infections produced by catalase-positive microorganisms and fungi. Interferon γ (IFN-γ) has a multitude of effects on the immune system. Although preliminary studies with CGD patients on treatment with IFN-γ showed that it enhanced phagocytosis and superoxide production, ongoing studies did not reveal a significant increase of this function. Here we investigated the oxidative capacity of phagocytes in different subtypes of CGD patients on treatment with IFN-γ in vitro. MATERIAL AND METHODS: Fifty-seven patients with CGD from 14 immunology centres were enrolled to our multi-centre study. Twenty-one patients were studied as controls. Oxidative burst assay with dihydrorhodamine 123 (DHR) was used and the stimulation index (SI) was calculated with respect to CGD subtypes in both neutrophils and monocytes before, and then one and 24 hours after adding IFN-γ. RESULTS: Upon comparison of the SIs of the patients' neutrophils before in vitro IFN-γ at hour 0, and after adding IFN-γ at hour 1 and 24 were compared, and the differences were determined between hours 0-24 and hours 1-24. This difference was especially apparent between hours 1-24. In CGD subtypes, particularly in gp91phox subtype, it was seen that, following in vitro IFN-γ, SIs of neutrophils began to increase after hour 1, and that increase became more apparent at hour 24. CONCLUSIONS: Our study showed that IFN-γ treatment may increase the oxidative bursting activity by increasing the superoxide production in neutrophils, particularly in gp91phox subtype.

Cutaneous leukocytoclastic vasculitis due to Salmonella enteritidis in a child with interleukin-12 receptor beta-1 deficiency.

Defects in the interleukin 12 (IL-12)/interferon gamma (IFN-γ) pathway result in Mendelian susceptibility to mycobacterial disease (MSMD). IL-12 receptor beta 1 (IL-12Rß1) deficiency, the most common form of MSMD, is associated with weakly virulent mycobacteria and salmonella. Infections in patients with this deficiency are extraintestinal, or septicemic, recurrent infections with nontyphoid salmonellae. Here we report a case of an IL-12Rß1 deficiency with cutaneous leukocytoclastic vasculitis due to Salmonella enteritidis.

Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation.

BACKGROUND: Inherited deficiencies of IL-10 or IL-10 receptor (IL-10R) lead to immune dysregulation with life-threatening early-onset enterocolitis. OBJECTIVES: We sought to gather clinical data of IL-10/IL-10R-deficient patients and devise guidelines for diagnosis and management, including hematopoietic stem cell transplantation (HSCT). METHODS: We enrolled 40 patients with early-onset enterocolitis and screened for mutations in IL10/IL10R using genetic studies, functional studies, or both of the IL-10 signaling pathway. Medical records of IL-10/IL-10R-deficient patients were reviewed and compiled. RESULTS: Of 40 patients, we identified 7 with novel mutations, predominantly in consanguineous families with more than 1 affected member. IL-10/IL-10R-deficient patients had intractable enterocolitis, perianal disease, and fistula formation. HSCT was carried out in 2 patients with IL-10 deficiency and 1 patient with IL-10R α chain deficiency and proved to be an effective therapy, leading to rapid improvement of clinical symptoms and quality of life. CONCLUSION: Because the defect in patients with IL-10/IL-10R deficiency resides in hematopoietic lineage cells and their colitis is resistant to standard immunosuppressive therapy, HSCT should be considered early as a potentially curative therapeutic option.

Is It Possible to Use Inflammatory Markers as Potential Biomarkers for Chronic Urticaria?

Background: This study aimed to determine whether the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) at admission affect the transition of pediatric patients diagnosed with acute spontaneous urticaria to chronic urticaria. Methods: This study included 390 patients who presented to the Department of Pediatrics at Akdeniz University Hospital with acute spontaneous urticaria between January 2020 and December 2022. A statistical comparison was made between the hematological parameters of patients who developed chronic urticaria and those who did not. Neutrophil, lymphocyte, and platelet counts, as well as NLR, PLR, and SII ratios, were used for the comparison. Results: It was observed that acute urticaria progressed to chronic urticaria in 5.8% (n = 23) of the patients. No significant differences in lymphocyte, hemoglobin, and platelet counts were observed between the group progressing to chronic urticaria and the control group (P > 0.05). However, the chronic urticaria group had higher leukocyte and absolute neutrophil counts (P = 0.009 and P < 0.001, respectively). In addition, the NLR was significantly higher in the chronic urticaria group (P = 0.029), whereas no statistically significant difference was observed in the PLR (P = 0.180). The chronic urticaria group had a significantly higher SII than the control group (P = 0.011). Conclusion: Hematological parameters, particularly NLR and SII, may be useful indicators of the transition from acute to chronic urticaria in pediatric patients. The early identification of these markers could help monitor patients and guide treatment decisions. Further comprehensive studies are required to validate these findings.

Escherichia coli brain abscess in a twin pair associated with TLR4 gene mutation.

Brain abscesses are uncommon complications of bacterial meningitis or sepsis in neonates and infants. The causative pathogens of brain abscess in newborns are various. Of those, Escherichia coli is rarely seen as a pathogen in brain abscess at this age. Herein we reported brain abscesses in twin infants caused by E. coli sepsis. Interestingly, genetic analysis identified heterozygous Toll-like receptor 4 (TLR4) gene mutation in the twins. Because TLR plays an important role in the natural response to bacterial products and initiates specific immune response against these pathogens, this may explain the development of brain abscess in the present case.

Factors affecting formula compliance of infants with IgE mediated cow's milk protein allergy during the pandemic.

Introduction: Cow's milk protein allergy (CMPA) is the most commonly encountered food allergy in the world, usually seen in infants under the age of 2 years. This study aims to determine the factors including COVID-19 affecting formula compliance of CMPA patients. Methods: This study is a prospective, observational study based on 10 different Paediatric Allergy-Immunology clinics in Turkey. Patients aged between 6 months and 2 years, who were followed up with IgE-mediated CMPA treatment or newly diagnosed and using breast milk and/or formula were included in the study. The sociodemographic characteristics of the patients, their symptoms, the treatments they received, and the effects of the COVID-19 pandemic on adherence to formula were evaluated with a questionnaire administered to the parents. Results: The compliance rate for formula-based treatment was 30.8% (IQR: 28.3, SD: 21.86). The number of patients with a single and multiple food allergy was 127 (51.6%) and 71 (28.9%), respectively. Breastfeeding duration, daily amount of prescribed formula and addition of sweetener to the formula were found to reduce compliance (p = 0.010, p = 0.003, and p = 0.004, respectively). However, it was determined that the patient's height, weight, age at diagnosis, and age of formula onset did not have a significant effect on compliance. Conclusion: It was found that the duration of breastfeeding, the increase in the daily amount of formula requirement, and the addition of sweeteners had adverse effects on formula compliance. There was no significant correlation between the formula adherence of CMPA patients and the pandemic.

The Asthma Risk Is Increased in Children with Severe Allergic Rhinitis.

OBJECTIVE: The aim of the study was to evaluate the allergic rhinitis severity, to identify risk fac- tors associated with asthma, and to determine the frequency of comorbid conditions in allergic rhinitis patients with positive skin prick test. MATERIALS AND METHODS: Clinical characteristics of pediatric patients with allergic rhinitis were investigated. The frequency of comorbidities and risk factors for asthma development were investigated. RESULTS: A total of 120 patients with a mean age of 13.05 ± 3.20 years were included in the study. Dermatophagoides pteronyssinus was the most common source of allergic sensitization (n = 78, 61.0%), whereas mild-persistent disease was the most common type of allergic rhini- tis severity (n = 44, 36.6%). Sensitization to Dermatophagoides farinea, Dermatophagoides pteronyssinus, and Alternaria was more common in patients with a moderate-severe course of allergic rhinitis than in the mild group (P = .006, P = .008, and P = .005, respectively). The most frequent comorbidity in children with allergic rhinitis was allergic conjunctivitis (71.7%). The inci- dence of asthma in those with moderate-severe allergic rhinitis was found to be significantly higher compared to those with mild disease severity (P = .009). Also, the multivariate analysis disclosed moderate-severe allergic rhinitis severity and persistent allergic rhinitis symptoms (OR: 3.822; 95% CI: 1.587-9.200; P =0.003 and OR: 0.333; 95% CI: 0.150-0.737; P =.007, respec- tively) as risk factors for asthma development. CONCLUSION: Sensitization to Dermatophagoides farinea, Dermatophagoides pteronyssinus, and Alternaria was more frequent in patients with moderate-severe allergic rhinitis course. Also, having moderate-severe allergic rhinitis severity and persistent allergic rhinitis symptoms are associated with the development of asthma. Awareness of the risk factors could prevent the progression and complications of allergic rhinitis in children.

Psychological State of Parents of Children with Primary Immunodeficiencies During the COVID-19 Pandemic.

Background: COVID-19 has affected humanity not only physically but also mentally. It was expected to have impact on high-risk groups such as the immunocompromised patients and parents/caregivers of them. Our study was aimed to investigate the COVID-19 related anxiety, post-traumatic stress levels, and sleep-related parameters of the parents of children with primary immunodeficiency. Methods: Parents of children with primary immunodeficiency and age and gender-matched control group completed questionnaires. Results: Anxiety and post-traumatic stress levels of the study group were found to be significantly higher than the control group. Furthermore, sleep time of the study group was significantly lower than the control group. The subjective sleep quality of the study group was also lower in the study group, but the difference did not reach a significant level. Conclusions: In the ongoing and other possible pandemic processes, professional support for the parents of these children is of great importance.

Specific Granule Deficiency Due To Novel Homozygote SMARCD2 Variant.

Background: Specific granule deficiency (SGD) is a rare immunodeficiency associated with CCAT/enhancer-binding protein epsilon (CEBPE) gene variants. It can cause severe recurrent infections and is lethal without successful stem cell transplantation. Few cases with SGD of both type 1 and type 2 have been described in the literature. In this study, we present the first report of a case with a novel homozygous c.511 C > T (p.Gln171Ter) mutation in the SMARCD2 gene of SGD type 2, which was successfully treated with bone marrow transplantation. Case: A male infant presented to our neonatal intensive care unit on the second day of life with an icteric appearance and mild hypotonia. He was evaluated for immunodeficiency as the cause of delayed cord separation and refractory neutropenia. At 6 weeks of age, SGD type 2 with a new variant was diagnosed and successfully treated by bone marrow transplantation. Conclusion: SGD is an immunodeficiency disease that is quite rare. However, we believe that SGD diagnosis and associated new variants can be detected more frequently with the widespread use of all whole-exome sequencing techniques.

Incidental pulmonary nodules in children: characteristic features and clinical course.

BACKGROUND: There exists insufficient information about the natural course of incidental pulmonary nodules (IPN) determined on tomography in children. The aim was to determine the characteristic features and factors affecting the course of IPN. METHODS: This retrospective study included patients who presented at the Pediatric Pulmonology, Allergy & Immunology Section of Akdeniz University Hospital between January 2014-2020, and were determined with pulmonary nodules on high-resolution computed tomography (HRCT). The patients were separated into two groups as those with a nodule decreased in size or which had disappeared on the follow-up HRCT (Group 1) and those with a nodule which had remained at the same size (Group 2). These two groups were compared in respect to demographic data, nodule size and characteristics, and accompanying findings on HRCT. RESULTS: A total of 177 nodules were determined in the 66 patients included in the study. A follow-up HRCT was taken within mean 16.29±11.38 months in 27 patients. In these patients, 78 nodules were determined on the initial HRCT. On the follow-up, twelve of the nodules were seen to have shrunk or disappeared compared to the initial images, 66 had remained the same size, and none had grown. The mean age of the patients in Group 1 was statistically significantly lower than that of patients in Group 2 (p < 0.001). The rates of an accompanying mosaic attenuation pattern (p < 0.001) on HRCT and subsolid density (p=0.011) of the nodules in Group 1 were statistically significantly higher compared to Group 2 and the rate of calcification content was statistically significantly lower (p=0.002). No suspicious or confirmed malignancy was observed in any case throughout the mean follow-up period of 38.33±16.5 months after the initial HRCT. CONCLUSIONS: The young age of patients, subsolid structure of nodules, calcification content and the presence of an accompanying mosaic attenuation pattern on HRCT, could be useful factors in the estimation of size in the follow-up of nodules.