Mucocutaneous Candidiasis: Insights Into the Diagnosis and Treatment.

Recent progress in the methods of genetic diagnosis of inborn errors of immunity has contributed to a better understanding of the pathogenesis of chronic mucocutaneous candidiasis (CMC) and potential therapeutic options. This review describes the latest advances in the understanding of the pathophysiology, diagnostic strategies, and management of chronic mucocutaneous candidiasis.

Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency.

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 .

Reply to Özdemir, Ö. Allergic Disease with Selective IgA Deficiency. Comment on "Cinicola et al. The Allergic Phenotype of Children and Adolescents with Selective IgA Deficiency: A Longitudinal Monocentric Study. J. Clin. Med. 2022, 11, 5705".

We carefully read the correspondence [...].

Hemophagocytic inflammatory syndrome in ADA-SCID: report of two cases and literature review.

Hemophagocytic inflammatory syndrome (HIS) is a rare form of secondary hemophagocytic lymphohistiocytosis caused by an impaired equilibrium between natural killer and cytotoxic T-cell activity, evolving in hypercytokinemia and multiorgan failure. In the context of inborn errors of immunity, HIS occurrence has been reported in severe combined immunodeficiency (SCID) patients, including two cases of adenosine deaminase deficient-SCID (ADA-SCID). Here we describe two additional pediatric cases of ADA-SCID patients who developed HIS. In the first case, HIS was triggered by infectious complications while the patient was on enzyme replacement therapy; the patient was treated with high-dose corticosteroids and intravenous immunoglobulins with HIS remission. However, the patient required HLA-identical sibling donor hematopoietic stem cell transplantation (HSCT) for a definitive cure of ADA-SCID, without HIS relapse up to 13 years after HSCT. The second patient presented HIS 2 years after hematopoietic stem cell gene therapy (GT), secondarily to Varicella-Zoster vaccination and despite CD4+ and CD8+ lymphocytes' reconstitution in line with other ADA SCID patients treated with GT. The child responded to trilinear immunosuppressive therapy (corticosteroids, Cyclosporine A, Anakinra). We observed the persistence of gene-corrected cells up to 5 years post-GT, without HIS relapse. These new cases of children with HIS, together with those reported in the literature, support the hypothesis that a major dysregulation in the immune system can occur in ADA-SCID patients. Our cases show that early identification of the disease is imperative and that a variable degree of immunosuppression could be an effective treatment while allogeneic HSCT is required only in cases of refractoriness. A deeper knowledge of immunologic patterns contributing to HIS pathogenesis in ADA-SCID patients is desirable, to identify new targeted treatments and ensure patients' long-term recovery.

Immunological characterization of an Italian PANDAS cohort.

This cross-sectional study aimed to contribute to the definition of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) pathophysiology. An extensive immunological assessment has been conducted to investigate both immune defects, potentially leading to recurrent Group A ß-hemolytic Streptococcus (GABHS) infections, and immune dysregulation responsible for a systemic inflammatory state. Twenty-six PANDAS patients with relapsing-remitting course of disease and 11 controls with recurrent pharyngotonsillitis were enrolled. Each subject underwent a detailed phenotypic and immunological assessment including cytokine profile. A possible correlation of immunological parameters with clinical-anamnestic data was analyzed. No inborn errors of immunity were detected in either group, using first level immunological assessments. However, a trend toward higher TNF-alpha and IL-17 levels, and lower C3 levels, was detected in the PANDAS patients compared to the control group. Maternal autoimmune diseases were described in 53.3% of PANDAS patients and neuropsychiatric symptoms other than OCD and tics were detected in 76.9% patients. ASO titer did not differ significantly between the two groups. A possible correlation between enduring inflammation (elevated serum TNF-α and IL-17) and the persistence of neuropsychiatric symptoms in PANDAS patients beyond infectious episodes needs to be addressed. Further studies with larger cohorts would be pivotal to better define the role of TNF-α and IL-17 in PANDAS pathophysiology.

The Allergic Phenotype of Children and Adolescents with Selective IgA Deficiency: A Longitudinal Monocentric Study.

BACKGROUND: Selective IgA deficiency (SIgAD) is the most common inborn error of immunity. The exact prevalence and pathogenesis of allergy in SIgAD have not yet been defined. We aimed to describe the prevalence and the characteristics of allergy in pediatric SIgAD subjects, evaluate the association between allergy and other comorbidities, and define the immune phenotype of allergic and non-allergic patients. METHODS: Clinical and immunological data from 67 SIgAD patients were collected over a 13-year period at a single center. Patients' characteristics were analyzed according to the presence of allergy. RESULTS: Allergy was diagnosed in 34% of SIgAD patients, with a median age at allergy diagnosis of 8 years. Allergy was the second-most-common clinical manifestation, following recurrent respiratory infections. Among the allergic group, 74% had rhinitis, 30% asthma, 30% atopic dermatitis, and 22% food allergy; one out of three had more than one allergic manifestation. SIgAD patients showed more frequent transitory lymphopenia and a lower count of CD19+ at diagnosis than at last FU. However, compared to non-allergic subjects, allergic patients did not differ in their immune phenotype, number and severity of infections, or increased autoimmunity. CONCLUSIONS: In our longitudinal study, compared to non-allergic SIgAD patients, those with allergies did not present a more severe immune defect or complex clinical phenotype. However, evaluation and early identification of allergy in the context of SIgAD assessment, both at diagnosis and during FU, and definition of a proper management are important to prevent complications and improve the patient's quality of life.

Short-Term Side Effects and SARS-CoV-2 Infection after COVID-19 Pfizer-BioNTech Vaccine in Children Aged 5-11 Years: An Italian Real-World Study.

Vaccination against COVID-19 is the most effective tool to protect both the individual and the community from this potentially life-threatening infectious disease. Data from phase-3 trials showed that two doses of the BNT162b2 vaccine were safe, immunogenic, and effective against COVID-19 in children aged 5-11 years. However, no surveys in real-life settings have been carried out in this age range. Here, we conducted a cross-sectional study to evaluate the short-term adverse reactions (ARs) and the rate of protection against infection of the BNT162b2 vaccine in children aged 5-11 years by the compilation of two surveillance questionnaires conceived using Google Forms. Five-hundred and ninety one children were included in the analysis. ARs were reported by 68.9% of the children, being mainly local. The incidence of systemic ARs, especially fever, was higher after the second dose. The incidence of infection after completing the immunization accounted for 13.6% of the children. COVID-19 symptoms reported were mild, with the exception of one case of pneumonia. Only 40% of infected participants needed to take medication to relieve symptoms, mostly paracetamol and NSAIDs, and none reported persistent symptoms. The Pfizer-BioNTech vaccine in children aged 5-11 years is safe and well tolerated. The mild clinical course of COVID-19 in immunized children confirmed the favorable risk-benefit ratio, encouraging parents to immunize their children.

Narrative review on the management of moderate-severe atopic dermatitis in pediatric age of the Italian Society of Pediatric Allergology and Immunology (SIAIP), of the Italian Society of Pediatric Dermatology (SIDerP) and of the Italian Society of Pediatrics (SIP).

Currently, there are a few detailed guidelines on the overall management of children and adolescents with moderate-severe atopic dermatitis. AD ​​is a complex disease presenting with different clinical phenotypes, which require an individualized and multidisciplinary approach. Therefore, appropriate interaction between primary care pediatricians, pediatric allergists, and pediatric dermatologists is crucial to finding the best management strategy. In this manuscript, members of the Italian Society of Pediatric Allergology and Immunology (SIAIP), the Italian Society of Pediatric Dermatology (SIDerP), and the Italian Society of Pediatrics (SIP) with expertise in the management of moderate-severe atopic dermatitis have reviewed the latest scientific evidence in the field. This narrative review aims to define a pathway to appropriately managing children and adolescents with moderate-severe atopic dermatitis.

Management of BNT162b2 mRNA COVID-19 vaccine in children aged 5-11 years with allergies, asthma, and immunodeficiency: consensus of the Italian Society of Pediatric Allergy and Immunology (SIAIP).

BNT162b2 vaccine, developed by BioNTech and Pfizer ha recently approved for use in children aged 5 to 11 years. Recent data show evidence of safety on the administration and serious adverse events have been rarely reported. However, allergic systemic reactions could occur. In some cases, a correct allergic evaluation allows identifying patients at risk of developing an anaphylactic reaction. Risk assessment of allergic reactions to COVID-19 vaccines is useful to limit contraindications to vaccination and help to safely vaccinate people supposed to be at risk of allergic reactions.

Progressive Depletion of B and T Lymphocytes in Patients with Ataxia Telangiectasia: Results of the Italian Primary Immunodeficiency Network.

Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated (ATM) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype-phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects.

Selective IgA Deficiency and Allergy: A Fresh Look to an Old Story.

Selective IgA deficiency (SIgAD) is the most common human primary immune deficiency (PID). It is classified as a humoral PID characterized by isolated deficiency of IgA (less than 7 mg/dL but normal serum IgG and IgM) in subjects greater than 4 years of age. Intrinsic defects in the maturation of B cells and a perturbation of Th cells and/or cytokine signals have been hypothesized to contribute to SIgAD pathogenesis. The genetic basis of IgA deficiency remains to be clarified. Patients with SIgAD can be either asymptomatic or symptomatic with clinical manifestations including allergy, autoimmunity and recurrent infections mainly of the respiratory and gastrointestinal tract. Studies analyzing allergy on SIgAD patients showed prevalence up to 84%, supporting in most cases the relationship between sIgAD and allergic disease. However, the prevalence of allergic disorders may be influenced by various factors. Thus, the question of whether allergy is more common in SIgAD patients compared to healthy subjects remains to be defined. Different hypotheses support an increased susceptibility to allergy in subjects with SIgAD. Recurrent infections due to loss of secretory IgA might have a role in the pathogenesis of allergy, and vice versa. Perturbation of microbiota also plays a role. The aim of this review is to examine the association between SIgAD and atopic disease and to update readers on advances over time at this important interface between allergy and SIgAD.

Intermittent and mild persistent asthma: how therapy has changed.

In the last few years much attention has been focused on research on severe asthma and the role of biologicals in its treatment, also in children. However, mild asthma is way more common in childhood and still causes as many as 30-40% of asthma exacerbations requiring emergency consultation. The management of "intermittent" and "mild persistent" asthma phenotypes is still a matter of debate, even if the role of inhaled corticosteroids, both continuous and intermittent, is a cornerstone in this field. Nevertheless, updates on the strategies to manage these patients are coming, since evidence emerged on the role of inflammation also in these asthma phenotypes as well as on the potential side effect and risks of short-acting beta 2 agonists overuse, which is common in patients for which they have been prescribed as the only as-needed treatment. Unsurprisingly, international guidelines, including GINA, are starting to recommend associating a corticosteroid when using a reliver. In this paper we overview the (r)evolution regarding the management of intermittent and mild persistent asthma. We also focus on the importance of knowing the chemical and physical characteristics of drugs and inhaler devices in order to optimize the treatment and reach the distal airways, as well as of trying to achieve a good compliance to treatments, especially in adolescents, for which it is currently possible to rely also on new digital health technologies.

Vernal keratoconjunctivitis: state of art and update on treatment.

Vernal keratocongiuntivitis (VKC) is a chronic inflammatory disease affecting the ocular conjunctiva and cornea. It is a rare and underestimated pathology, whose missed or delayed diagnosis can lead to the development of serious ocular complications. Moreover, despite VKC symptoms are well known, they can overlap and be mistaken with allergic conjunctivitis. In fact, diagnostic criteria and severity grading are not standardized yet. The pathogenesis of VKC is still controversial and it is difficult to identify a single mechanism underlying the chronic ocular inflammation. Different studies hypothesized both allergies and autoimmune diseases and also oxidative stress contribute significantly to the origin of the disease. However, the unclear pathogenesis and the lack of specific disease biomarkers make treatment a challenge. The standard therapy includes antihistamines, anti-inflammatory and immunosuppressant drugs and novel therapies are currently under investigation. However, considering treatment guidelines and recommendations are not well defined yet, therapy should be personalized on the clinical features of the patient. This paper provides an overview of the VKC and updates on the challenges that need to be addressed in the future to improve the management of the patient with this disease and improve his quality of life.

Digital health in the management of allergic diseases.

In recent years there has been an important implementation in the medical field of both Mobile Health, such as the use of mobile communication devices, and of other telemedicine tools in general, with the aim of supporting the supervision of diseases from the moment of the first diagnosis to the therapeutic follow-up. In fact, Digital Health can also have a very positive impact on the management of allergic patients, who are known to have the greatest need for regular monitoring, simplifying contact between doctor and patient, but there is still a need to improve implementation regulations, define certification programs and adequate reimbursement systems, as well as to guarantee a high level of attention to the protection of sensitive data. The hope is that one positive outcome of the Covid-19 pandemic will be an acceleration, by all stakeholders involved, of the process of the modernization of health care.

Tailored therapies for primary immunodeficiencies.

Primary immunodeficiency disorders (PIDs) are rare inherited monogenic disorders of the immune system, characterized by an increased risk of infection, immune dysregulation and malignancies. To date, more than 420 PIDs have been identified. The recent introduction of high throughput sequencing technologies has led to identifying the molecular basis of the underlying aberrant immune pathway, and candidate targets to develop precision treatment, aimed at modifying the clinical course of the disease. In PID, targeted therapies are especially effective to manage immune dysregulation and autoimmunity, also reducing the incidence of side effects compared to conventional treatments, sparing the use of steroids and immunosuppressive drugs. Moreover, in the last years, the approach of conventional treatments such as immunoglobulin replacement therapies has evolved and the indication has expanded to new diseases, leading to individualized strategies to both improve infection control and quality of life.  Similarly, the new advent of gene therapy in selected PIDs has introduced the benefit to correct the immunological defect, reducing at the same time the complications related to the hematopoietic stem cell transplantation. Here, we illustrate the most recent findings on tailored treatments for PIDs.

Agreements and controversies of national guidelines for bronchiolitis: Results from an Italian survey.

INTRODUCTION: Significant variations in the management of bronchiolitis are often recorded, and, in parallel, to recommend a univocal clinical approach is challenging and still questioned. This study is aimed to evaluate the diagnostic and therapeutic management of bronchiolitis in children adopted by Italian pediatricians following the national guidelines. MATERIAL AND METHODS: A survey study was designed and carried out by sending an email an open-ended questionnaire developed by an expert panel of the Scientific Board of the Italian Society of Pediatric Allergology and Immunology (SIAIP). Questions were designed according to the national intersociety consensus document on treatment and prevention of bronchiolitis in newborns and infants. RESULTS: Overall, 234 pediatricians were taking part in the study. When diagnosing bronchiolitis, only 44.01% (103/234) of participants correctly followed the national guidelines. All participants (100%) would perform laboratory tests and/or radiological exams. 44.01% administered oxygen (O2 ) when O2 saturation was minor than 92%. About the therapeutic regimen, marked discrepancies between national guidelines and recorded answers were reported. Indications for hospital admission and discharge criteria were in line with the national guidelines. CONCLUSIONS: There is a significant practice variation in the management of acute bronchiolitis among Italian physicians. Some wrong attitudes need to be further discouraged, such use of diagnostic procedures and therapeutic approaches. Further research is urgently required to define the best management of patients with bronchiolitis and implement strategies to standardize care and improve the quality of care.

The Protective Role of Maternal Immunization in Early Life.

With birth, the newborn is transferred from a quasi-sterile environment to the outside world. At this time, the neonatal immune system is inexperienced and continuously subject to a process of development as it encounters different antigenic stimuli after birth. It is initially characterized by a bias toward T helper 2 phenotype, reduced T helper 1, and cytotoxic responses to microbial stimuli, low levels of memory, and effector T and B cells and a high production of suppressive T regulatory cells. The aim of this setting, during fetal life, is to maintain an anti-inflammatory state and immune-tolerance. Maternal antibodies are transferred during pregnancy through the placenta and, in the first weeks of life of the newborn, they represent a powerful tool for protection. Thus, optimization of vaccination in pregnancy represents an important strategy to reduce the burden of neonatal infections and sepsis. Beneficial effects of maternal immunization are universally recognized, although the optimal timing of vaccination in pregnancy remains to be defined. Interestingly, the dynamic exchange that takes place at the fetal-maternal interface allows the transfer not only of antibodies, but also of maternal antigen presenting cells, probably in order to stimulate the developing fetal immune system in a harmless way. There are still controversial effects related to maternal immunization including the so called "immunology blunting," i.e., a dampened antibody production following infant's vaccination in those infants who received placentally transferred maternal immunity. However, clinical relevance of this phenomenon is still not clear. This review will provide an overview of the evolution of the immune system in early life and discuss the benefits of maternal vaccination. Current maternal vaccination policies and their rationale will be summarized on the road to promising approaches to enhance immunity in the neonate.