Expanded Newborn Screening for Inborn Errors of Immunity: The Experience of Tuscany.

BACKGROUND: Inborn errors of immunity (IEIs) include 485 inherited disorders characterized by an increased susceptibility to life-threatening infectious diseases, autoimmunity, and malignant diseases with a high mortality rate in the first years of life. Severe combined immunodeficiency is the most severe of the IEIs, and its detection should be a primary goal in a newborn screening (NBS) program. The term "actionable" has recently been used for all IEIs with outcomes that can be demonstrably improved through early specialized intervention. OBJECTIVE: To evaluate the results of the expanded NBS strategy for IEIs in Tuscany Region (Italy), based on T-cell receptor excision circle, kappa recombining excision circle, and tandem mass-based assays. METHODS: This is a retrospective study collecting data from all infants born in Tuscany from October 10, 2018, to October 10, 2022. Tandem mass assay to identify adenosine deaminase and purine nucleoside phosphorylase deficiency, together with T-cell receptor excision circle and kappa recombining excision circle molecular analysis, was conducted on dried blood spot from the newborns' Guthrie Cards. A new dried blood spot and evaluation by an immunologist were carried out when the results of the first test were outside the diagnostic cutoffs. RESULTS: A total of 94,319 newborns were evaluated. Referral rates for T-cell recombining excision circles (0.031%) and kappa recombining excision circles (0.074%) in this study are in line with the data available in literature. The results from the expanded NBS strategy revealed an incidence rate of 1 per 9431 affected newborns. CONCLUSIONS: This work represents the first description of a sustainable and real-life-based expanded NBS program for IEIs with a high diagnostic incidence facilitating prompt management of identified patients.

Corrigendum: HLH as an additional warning sign of inborn errors of immunity beyond familial-HLH in children: a systematic review.

[This corrects the article DOI: 10.3389/fimmu.2024.1282804.].

HLH as an additional warning sign of inborn errors of immunity beyond familial-HLH in children: a systematic review.

Background: Hemophagocytic Lymphohistiocytosis (HLH) is a rare and life-threatening condition characterized by a severe impairment of the immune homeostasis. While Familial-HLH (FHL) is a known cause, the involvement of other Inborn Errors of Immunity (IEI) in pediatric-HLH remains understudied. Objective: This systematic review aimed to assess the clinical features, triggers, laboratory data, treatment, and outcomes of pediatric HLH patients with IEI other than FHL (IEInotFHL), emphasizing the importance of accurate identification and management. Methods: A systematic search for studies meeting inclusion criteria was conducted in PubMed, EMBASE, MEDLINE, and Cochrane Central. Quality assessment was performed through JBI criteria. Results: A comprehensive search yielded 108 records meeting inclusion criteria, involving 178 patients. We identified 46 different IEI according to IUIS 2022 Classification. Combined immunodeficiencies, immune dysregulation disorders, and phagocyte defects were the IEI most frequently associated with HLH. In 75% of cases, HLH preceded the IEI diagnosis, often with an unrecognized history of severe infections. Triggers reflected the specific infection susceptibilities within IEI groups. Liver and central nervous system involvement were less common than in FHL cases. Treatment approaches and outcomes varied, with limited long-term follow-up data, limiting the assessment of therapeutic efficacy across IEI groups. Conclusion: A comprehensive evaluation encompassing immunological, infectious, and genetic aspects is essential in pediatric-HLH. Relying solely on FHL or EBV susceptibility disorders tests is insufficient, as diverse other IEI can contribute to HLH. Early recognition of HLH as a potential warning sign can guide timely diagnostic investigations and facilitate tailored therapeutic interventions for improved outcomes. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=371425, PROSPERO, CRD42022371425.

Reshaping Our Knowledge: Advancements in Understanding the Immune Response to Human Respiratory Syncytial Virus.

Human respiratory syncytial virus (hRSV) is a significant cause of respiratory tract infections, particularly in young children and older adults. In this review, we aimed to comprehensively summarize what is known about the immune response to hRSV infection. We described the innate and adaptive immune components involved, including the recognition of RSV, the inflammatory response, the role of natural killer (NK) cells, antigen presentation, T cell response, and antibody production. Understanding the complex immune response to hRSV infection is crucial for developing effective interventions against this significant respiratory pathogen. Further investigations into the immune memory generated by hRSV infection and the development of strategies to enhance immune responses may hold promise for the prevention and management of hRSV-associated diseases.

Four-Component Recombinant Protein-Based Vaccine Effectiveness Against Serogroup B Meningococcal Disease in Italy.

Importance: Population-based data on the 4-component recombinant protein-based (4CMenB) vaccine effectiveness and reduction in incidence rate ratios (IRRs) are continuously needed to assess vaccine performance in the prevention of serogroup B invasive meningococcal disease (IMD). Objective: To assess the effectiveness and reduction in IRRs associated with the 4CMenB vaccine in the pediatric population in 6 regions in Italy. Design, Setting, and Participants: This retrospective cohort screening study and case-control study included data from children aged younger than 6 years in 6 highly populated Italian regions from January 1, 2006, to January 1, 2020. Participants included children younger than 6 years diagnosed with serogroup B IMD without predisposing factors. Data were collected from regional surveillance and vaccination registries and were analyzed from September 2021 to January 2022. Exposures: Routine 4CMenB vaccination, per regional vaccination programs. Main Outcomes and Measures: The main outcome was the effectiveness of the 4CMenB vaccine in the prevention of serogroup B IMD in the population of children aged younger than 6 years in 6 Italian regions. The percentages of vaccine effectiveness (VE) were obtained through the concomitant use of a screening method and a case-control study. Secondary outcomes were the comparison of effectiveness results obtained using the 2 different computational methods, the description of serogroup B IMD incidence rates, and reduction in IRRs before and after 4CMenB introduction, as a proxy for vaccine impact. Results: The cohort screening study included a resident population of 587 561 children younger than 6 years in 3 regions with similar surveillance protocols, and the matched-case controls study assessed a resident population of 1 080 620 children younger than 6 years in 6 regions. Analyses found that 4CMenB VE in fully immunized children was 94.9% (95% CI, 83.1%-98.4%) using the screening method and 91.7% (95% CI, 24.4%-98.6%) using the case-control method. Overall reduction in IRR was 50%, reaching 70% in regions with early-start vaccination schedules. The case-control method involving 6 highly-populated Italian regions included 26 cases and 52 controls and found an estimated VE of 92.4% (95% CI, 67.6%-97.9%) in children old enough for the first vaccine dose and 95.6% (95% CI, 71.7%-99.1%) in fully immunized children. VE was more than 90% for partially immunized children. Even in regions where the first dose was administered at age 2 months, almost 20% of unvaccinated cases were among infants too young to receive the first 4CMenB dose. Conclusions and Relevance: This screening cohort study and matched case-controls study found high effectiveness of 4CMenB vaccination and greater reduction in IRR for early-start vaccination schedules in preventing invasive serogroup B meningococcal disease. The high proportion of children too young to be vaccinated among unvaccinated cases suggests that starting the vaccination even earlier may prevent more cases. Screening and case-control methods provided similar estimates of VE: either method may be used in different study settings, but concomitant use can provide more robust estimates.

Risk of thyroid neoplasms in patients with 22q11.2 deletion and DiGeorge-like syndromes: an insight for follow-up.

Introduction: The chromosome 22q11.2 deletion syndrome comprises phenotypically similar diseases characterized by abnormal development of the third and fourth branchial arches, resulting in variable combinations of congenital heart defects, dysmorphisms, hypocalcemia, palatal dysfunction, developmental or neuropsychiatric disorders, and impairment of the immune system due to thymic dysfunction. Other genetic syndromes, often called DiGeorge-like, share clinical and immunological features with 22q11.2 deletion syndrome. This syndrome has been rarely associated with malignancies, mainly hematological but also hepatic, renal, and cerebral. Rarely, malignancies in the head and neck region have been described, although no aggregate of data on the development of thyroid neoplasms in patients with this clinical phenotype has been conducted so far. Materials and methods: To characterize this possible association, a multicenter survey was made. Thus, we present a case series of five pediatric patients with 22q11.2 deletion syndrome or DiGeorge-like syndrome who were occasionally found with confirmed or highly suspected neoplasms of the thyroid gland during their follow-up. In three cases, malignancies were histologically confirmed, but their outcome was good due to an early recognition of suspicious nodules and precocious surgery. Conclusions: This study underlines for clinicians the higher risk of neoplasms in the head and neck district for patients affected by these syndromes. It also emphasizes the importance of a prolonged clinical and ultrasound follow-up for patients with this clinical and immunological phenotype.

IgE-Mediated Shellfish Allergy in Children.

Shellfish, including various species of mollusks (e.g., mussels, clams, and oysters) and crustaceans (e.g., shrimp, prawn, lobster, and crab), have been a keystone of healthy dietary recommendations due to their valuable protein content. In parallel with their consumption, allergic reactions related to shellfish may be increasing. Adverse reactions to shellfish are classified into different groups: (1) Immunological reactions, including IgE and non-IgE allergic reactions; (2) non-immunological reactions, including toxic reactions and food intolerance. The IgE-mediated reactions occur within about two hours after ingestion of the shellfish and range from urticaria, angioedema, nausea, and vomiting to respiratory signs and symptoms such as bronchospasm, laryngeal oedema, and anaphylaxis. The most common allergenic proteins involved in IgE-mediated allergic reactions to shellfish include tropomyosin, arginine kinase, myosin light chain, sarcoplasmic calcium-binding protein, troponin c, and triosephosphate isomerase. Over the past decades, the knowledge gained on the identification of the molecular features of different shellfish allergens improved the diagnosis and the potential design of allergen immunotherapy for shellfish allergy. Unfortunately, immunotherapeutic studies and some diagnostic tools are still restricted in a research context and need to be validated before being implemented into clinical practice. However, they seem promising for improving management strategies for shellfish allergy. In this review, epidemiology, pathogenesis, clinical features, diagnosis, and management of shellfish allergies in children are presented. The cross-reactivity among different forms of shellfish and immunotherapeutic approaches, including unmodified allergens, hypoallergens, peptide-based, and DNA-based vaccines, are also addressed.

CD38high/HLA-DR+ CD8+ T cells as potential biomarker of hemophagocytic lymphohistiocytosis secondary to visceral Leishmania infection.

Leishmaniasis is a cause of infection associated with hemophagocytic lymphohistiocytosis (HLH). The measurement of the CD8+ CD38high/HLA-DR+ T cells in children presenting with acute onset of shock and multisystem organ failure represents an important parameter to distinguish HLH from sepsis or healthy control. CONCLUSION: We report a case series of 4 Italian children suffering from HLH secondary to visceral Leishmaniasis in which the lymphocyte subset assay suggests a potential role of CD38high/HLA-DR+ CD8+ T cells as HLH diagnostic biomarkers. WHAT IS KNOWN: • Visceral Leishmaniasis is a well-known cause of infection associated with hemophagocytic lymphohistiocytosis (HLH). • The measurement of the CD8+ CD38high/HLA-DR+ T cells in children presenting with acute onset of shock and multisystem organ failure represents an important diagnostically useful parameter to readily distinguish HLH from sepsis or healthy controls. WHAT IS NEW: • We report a case series of 4 Italian children suffering from HLH secondary to visceral Leishmaniasis in which the lymphocyte subset assay suggests a potential role of CD38high/HLA-DR+ CD8+ T cells as HLH diagnostic biomarker. • The flow cytometry assay, performed at the disease onset before starting treatment, revealed a mean percentage value of CD38 cells of 36.95% among CD8+ T cells.

DR4/DQ2 haplotype confers susceptibility to T1DM with early clinical disease onset: A retrospective analysis in a tertiary-care hospital in Italy.

INTRODUCTION: T1DM is the most frequent form of diabetes in children. It has a multifactorial pathogenesis in which genetic, environmental and immunological factors are involved. Among genetic explanations a major role is attributed to second class HLA genes, with the greatest risk associated with the simultaneous presence of the haplotypes DR3DQ2 and DR4DQ8. Based on results obtained in other countries, the aim of this research is to verify a possible association between the haplotype DRB1 * 04: 05-DQA1 * 03-DQB1 * 02 and the onset of T1DM among Italian children with possible genotype-phenotype correlations. Greater knowledge of genes which increase or decrease susceptibility is important for genome analysis. MATERIALS AND METHODS: 165 patients with type 1 diabetes treated at the Diabetology Unit of the Meyer Children's University Hospital, were clinically analyzed. Data relating to age at diagnosis, pancreatic anti-beta cell autoimmunity, comorbidities with date of diagnosis and family history were retrospectively collected from medical data. A case-control study was conducted to investigate the HLA types of the patients compared to a control group of 819 Tuscan donors enrolled in the National Bone Marrow Donor Register. Typing was carried out using the Eurospital "DIABEGEN" kit, currently in use at the immunology laboratory of the Meyer Children's University Hospital. RESULTS: Mean age at diagnosis was 9.3 years; most children (97%) had anti-pancreatic beta cell autoimmunity; the anti-insulin antibody (IAA) was more frequent among children with early clinical disease onset (0-5 years of age). From the case control comparison performed on HLA typing, it emerged that the greatest risk for the development of type 1 diabetes is conferred by the haplotypes DR3DQ2 and DR4DQ8, but in addition to these haplotypes, already known in other countries, we identified another haplotype, DR4DQ2 (DRB1 * 04: 05-DQA1 * 03-DQB1 * 02) which appears to predispose children to type 1 diabetes (p value 2.80E-08) and it is associated with early clinical disease onset (p-value = 0.002). CONCLUSIONS: We report a new haplotype which increases susceptibility to type 1 diabetes among Italian children and which is associated with early clinical disease onset. Given the central role attributed to genetic factors in the pathogenesis of T1DM and to the II class HLA genes, this new haplotype ought to be recognized as a risk factor and included in tests routinely carried out to identify patients with a genetic predisposition to type I diabetes in Italy. These findings could have practical implications in research and prevention programs.

Characterization of Autoimmune Thyroid Disease in a Cohort of 73 Paediatric Patients Affected by 22q11.2 Deletion Syndrome: Longitudinal Single-Centre Study.

BACKGROUND: Chromosome 22q11.2 Deletion Syndrome (22q11.2DS) is the most frequent microdeletion syndrome and is mainly characterized by congenital cardiac defects, dysmorphic features, hypocalcemia, palatal dysfunction, developmental delay, and impaired immune function due to thymic hypoplasia or aplasia. Thyroid anomalies are frequently reported in patients with 22q11.2DS, although only a few well-structured longitudinal studies about autoimmune thyroid disease (ATD) have been reported. AIM: To longitudinally evaluate the frequency of thyroid anomalies and ATD in patients with 22q11.2DS. PATIENTS AND METHODS: Pediatric patients with a confirmed genetic diagnosis of 22q11.2DS were recruited and followed up on longitudinally. Clinical, biochemical, and immunological data were collected, as well as thyroid function, autoimmunity, and thyroid sonographic data. RESULTS: The study included 73 children with 22q11.2DS, with a mean follow-up duration of 9.51 ± 5.72 years. In all, 16 of the 73 enrolled patients (21.9%) developed ATD before 18 years of age (mean age 12.92 ± 3.66 years). A total of 20.5% developed Hashimoto's Thyroiditis (HT), of whom 50% required L-thyroxine treatment; 1.4% developed Graves Disease. Thyroid hypoplasia was found in 6/16 patients with ATD and left lobe hypoplasia in 9/16 patients. These features were also found in patients affected by 22q11.2DS without ATD. Among patients who developed ATD, at the first altered ultrasound scan, the most frequent anomalies suggestive of thyroiditis were inhomogeneous echotexture, diffuse or irregular hypo-echogenicity, and vascular overflow. CONCLUSION: We strongly recommend periodic screening of thyroid function and for autoimmunity in patients affected by 22q11.2DS. Along with blood tests, ultrasound scans of the thyroid gland should be performed periodically since some patients who go on to develop an ATD could have specific anomalies on ultrasound prior to any other anomaly.

Subpromille Measurements and Calculations of CO (3-0) Overtone Line Intensities.

Intensities of lines in the near-infrared second overtone band (3-0) of ^{12}C^{16}O are measured and calculated to an unprecedented degree of precision and accuracy. Agreement between theory and experiment to better than 1‰ is demonstrated by results from two laboratories involving two independent absorption- and dispersion-based cavity-enhanced techniques. Similarly, independent Fourier transform spectroscopy measurements of stronger lines in this band yield mutual agreement and consistency with theory at the 1‰ level. This set of highly accurate intensities can provide an intrinsic reference for reducing biases in future measurements of spectroscopic peak areas.

Unbalanced serum immunoglobulins in clinical subtypes of pediatric tuberculosis disease.

Immune response to tuberculosis (TB) has been extensively studied in the past decades and classically involves cellular immunity. However, evidence suggests that humoral immunity may play a relevant role. Past studies regarding serum immunoglobulin (Ig) levels in TB are dated and only involve adult subjects. In this study, we retrospectively studied a cohort of 256 children with TB disease and analyzed 111 patients screened for total serum Ig at diagnosis. According to the severity and extent of organ involvement, subjects were divided into four groups, namely, uncomplicated pulmonary TB (UCPTB, 56.3% of patients), complicated pulmonary TB (CPTB, 22.5%), lymph node extrapulmonary TB (LN-EPTB, 7.2%), and extra-nodal extrapulmonary TB (EN-EPTB, 13.5%). Serum IgG and IgA levels were significantly higher in more severe and extended TB disease. Median IgG levels progressively increased from uncomplicated to complicated pulmonary and nodal forms, reaching their highest values in diffuse extra-pulmonary TB. In parallel, UCPTB showed significantly lower frequencies of patients presenting a substantial increase in IgG levels when compared with the other three groups. No relevant differences in IgM levels were detected. Ig screening at follow-up showed a significant reduction in IgG and IgA levels. Finally, we unveiled three cases of selective IgA and one case of selective IgM deficiencies (SIgMD), the latter with a severe clinical course. Serum IgG and IgA may be a useful clinical tool to assess the severity and monitor the treatment response in pediatric TB disease. Moreover, immunological workup in children with TB disease may unmask primary defects of humoral immunity.

A Report of 2 Cases of Kidney Involvement in ADA2 Deficiency: Different Disease Phenotypes and the Tissue Response to Type I Interferon.

Adenosine deaminase 2 (ADA2) deficiency is a rare autosomal recessive disease that is caused by loss-of-function mutations in the ADA2 gene. It is considered a monogenic form of polyarteritis nodosa and frequently is positive for a type I interferon (IFN) signature. Renal manifestations in ADA2 deficiency are poorly characterized. We herein report 2 cases of ADA2 deficiency with different kidney patterns due, respectively, to a predominantly macroscopic and microscopic vasculopathy, and review the literature on kidney disease in ADA2 deficiency. Patient 1 presented with a spontaneous perirenal hematoma; angiography demonstrated multiple microaneurysms but no further defects of the renal parenchyma; his kidney function remained normal. Patient 2 experienced slowly deteriorating kidney function and proteinuria. No major angiographic abnormalities were detected, while kidney biopsy revealed massive vasculopathy resembling chronic thrombotic microangiopathy (TMA) of the small and medium-sized vessels. Both patients had a positive peripheral type I IFN signature. In immunofluorescence staining of a kidney biopsy sample from patient 2, we observed marked expression of the type I IFN-induced protein MXA within endothelial cells, especially in vessels with TMA, and in infiltrating T cells. Our findings confirm that the kidney phenotype of ADA2 deficiency results from small and medium-sized vessel vasculopathy and suggest that type I IFN may be involved in the pathogenesis of kidney lesions.

Mycophenolate mofetil-induced hypogammaglobulinemia and infectious disease susceptibility in pediatric patients with chronic rheumatic disorders: a monocentric retrospective study.

Mycophenolate mofetil (MMF) is an immunosuppressive drug used for the treatment of autoimmune rheumatological diseases. To test the risk of hypothetical drug-induced hypogammaglobulinemia, the aim of this study was to report the trend of the immunoglobulin (Ig) values and of the infectious diseases in children treated with MMF. This study retrospectively evaluated demographic, clinical, and laboratory data of a cohort of patients affected by a chronic rheumatic disease receiving MMF, followed at the Rheumatology Unit of Meyer Children Hospital, Florence. A total of 29 pediatric patients were enrolled. In patients with normal values of immunoglobulins at the baseline, treatment with MMF resulted in a statistically significant reduction of the IgG levels (p = 0.0058) and in a decrease of IgM levels not reaching statistical significance. The levels of IgA were not affected. During the follow-up, seven patients developed an humoral immune defect. The univariate analysis did not identify any risk factors related to the iatrogenic hypogammaglobulinemia. The infection rate during MMF therapy was significantly higher than the 12-month period before therapy (p = 0.006), while the severe infections did not significantly increase (p = 0.1818), even considering only the patients with hypogammaglobulinemia. CONCLUSION: In pediatric patients with chronic rheumatic diseases, immunological first level tests and serological analyses to screen the protection against the common childhood pathogens are suggested before starting an immunosuppressive drug. These patients should also complete the vaccination schedule. In patients treated with MMF a strict monitoring of Ig is required during treatment and after discontinuation of the drug. WHAT IS KNOWN: • MMF is an immunosuppressive drug initially used for the treatment of the graft-versus-host disease. • Mycophenolic acid is an inhibitor of inosine-5'-monophosphate dehydrogenase, expressed in lymphocytes; therefore, MMF could impair the immune system function. WHAT IS NEW: • MMF resulted in a reduction of IgG and an increase of not severe infection rate. • Immunological first level tests, including Ig, lymphocyte subpopulations, and antibody response to vaccines, are suggested in pediatric patients before starting MMF; a strict monitoring of Ig is important before, during, and after MMF treatment.

STAT3-confusion-of-function: Beyond the loss and gain dualism.

BACKGROUND: Germline mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for 2 distinct human diseases: autosomal-dominant hyper-IgE syndrome (AD-HIES) caused by STAT3 loss-of-function mutations and STAT3 gain-of-function disease. So far, these entities have been regarded as antithetic, with AD-HIES mainly associated with characteristic infections and a connective tissue phenotype and STAT3 gain-of-function characterized by lymphoproliferation and poly-autoimmunity. The R335W substitution in the DNA-binding domain of STAT3 was initially described in 2 patients with typical AD-HIES, but paradoxically, recent functional analysis demonstrated a gain-of-function effect of this variant. OBJECTIVES: A patient with Sjögren syndrome and features of AD-HIES with this mutation is described and the molecular consequences are further characterized. METHODS: This study provides a clinical and immunological description of the patient. STAT phosphorylation in primary patient cells was studied and A4 cells transfected with the patient allele were used to study phosphorylation kinetics, transcriptional activity, and target-gene induction. RESULTS: The hybrid clinical features of the patient were associated with normal TH17 cells. Enhanced and prolonged STAT3 phosphorylation, an increased STAT3 driven luciferase reporter activity upon IL-6 stimulation, but reduced IL-6-induced SOCS3 production were all observed. CONCLUSIONS: The germline R335W-STAT3 variant displays a mixed behavior in vitro that mainly shows gain-of-function, but also loss-of-function features. This is matched by an ambiguous clinical and immunological phenotype that dismantles the classical antithetic dualism of gain- versus loss-of-function. Germline STAT3 mutation-related disease represents a pathological spectrum with the p.R335W associated phenotype locating between the 2 recognized clinical disease patterns.

Severe pertussis disease in a paediatric population: The role of age, vaccination status and prematurity.

AIM: To estimate hospitalisation rate and investigate the role of age, prematurity and vaccination status in severe pertussis cases. METHODS: We retrospectively evaluated 200 children aged 0-14 years, admitted to the emergency rooms of Meyer Hospital of Florence and Pisa Hospital with a diagnosis of pertussis from 1 October 2010 to 31 January 2020. RESULTS: Children younger than 12 months were 63.0%. Preterm infants were 6.5%. The rate of hospitalisation was 49.0%. Among hospitalised cases, 80.6% were younger than 5 months. Overall, 62.0% were unvaccinated; this percentage increased among hospitalised (73.5%) and preterm subsamples (76.9%). Delays in pertussis vaccination were found in 57.7% of term infants and in 80.0% of preterms. Multivariable analysis confirmed the age under 2 months as the variable at higher risk for hospitalisation (OR 4.49, 95% CI 1.85-10.96, p < 0.001). Being fully vaccinated represented a significant protective factor (OR 0.12, 95% CI 0.04-0.35, p < 0.001). CONCLUSION: Older classes of age and a complete vaccination, in time with the recommended schedule, are both protective factors for hospitalisation in severe pertussis disease. The widespread vaccination delay frequently observed in preterm children may be the cause for their higher rate of hospitalisation.

Inborn errors of immunity underlying a susceptibility to pyogenic infections: from innate immune system deficiency to complex phenotypes.

BACKGROUND: Pyogenic bacteria are associated with a wide range of clinical manifestations, ranging from common and relatively mild respiratory and cutaneous infections to life-threatening localized or systemic infections, such as sepsis and profound abscesses. Despite vaccination and the widespread use of effective antibiotic treatment, severe infection is still observed in a subset of affected patients. OBJECTIVES: We aim to summarize the available data regarding inborn errors of immunity that result in a high risk of severe pyogenic infections. SOURCES: Case series, as well as review and original articles on human genetic susceptibility to pyogenic infections were examined. CONTENT: We review host-associated factors resulting in inborn errors of immunity and leading to a susceptibility to pyogenic infections, including deficiency in major components of the immune system (e.g., neutrophils, complement, immunoglobulin, and spleen function) and novel monogenic disorders resulting in specific susceptibility to pyogenic infection. Specifically, innate immune system deficiency involving toll-like receptors and associated signaling typically predispose to a narrow spectrum of bacterial diseases in otherwise healthy people, making a diagnosis more difficult to suspect and confirm. More complex syndromes, such as hyper IgE syndrome, are associated with a high risk of pyogenic infections due to an impairment of the interleukin-6 or -17 signaling, demonstrating the pivotal role of these pathways in controlling bacterial infections. IMPLICATIONS: In clinical practice, awareness of such conditions is essential, especially in the pediatric setting, to avoid a potentially fatal diagnostic delay, set the most proper and prompt treatment, and ensure prevention of severe complications.