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Inborn errors of immunity associated with atopy (IEIs-A) are a group of inherited monogenic disorders that occur with immune dysregulation and frequent skin involvement. Several pathways are involved in the pathogenesis of these conditions, including immune system defects, alterations of skin barrier and metabolism perturbations. Current technological improvements and the higher accessibility to genetic testing, recently allowed the identification of novel molecular pathways involved in IEIs-A, also informing on potential tailored therapeutic strategies. Compared to other systemic therapy for skin diseases, biologics have the less toxic and the best tolerated profile in the setting of immune dysregulation. Here, we review IEIs-A with skin involvement focusing on the tailored therapeutic approach according to their pathogenetic mechanism.

Introduction: The mutation of the beta-globin gene that causes sickle cell disease (SCD) results in pleiotropic effects, such as hemolysis and vaso-occlusive crisis that can induce inflammatory mechanisms with deleterious consequences on the organism. Moreover, SCD patients display an increased susceptibility to infections. Few studies are currently available that evaluate a wide immunological profile in a pediatric population. This study proposes an evaluation of the immune profile in subjects with SCD in a pediatric population through a detailed analysis by flow cytometry.Methods and Materials: Peripheral blood samples from 53 pediatric patients with SCD (mean age 9.8 years, interquartile range 9 years) were obtained and then analyzed by flow cytometry, in order to evaluate changes in the immune populations compared to 40 healthy donors (mean age 7.3 years, interquartile range 9.5 years).Results: Our data showed an increase in neutrophils (with a reduction in the CD62L + subpopulation) and monocytes (with a decrease in HLA-DRlow monocytes) with normal values of lymphocytes in SCD patients. In the lymphocyte subpopulations analysis we observed lower values of CD4+ T cells (with higher number of memory and central memory T lymphocytes) with increased frequency of CD8+ T cells (with a predominant naive pattern). Moreover, we observed higher values of CD39+ Tregs and lower HLA-DR+ and CD39− T cells with an increased Th17, Th1-17 and Th2 response.Conclusion: We observed immunological alterations typical of an inflammatory status (increase in activated neutrophils and monocytes) associated with a peculiar Treg pattern (probably linked to a body attempt to minimize inflammation intrinsic to SCD). Furthermore, we highlighted a T helper pathway associated with inflammation in line with other studies. Our data showed that immunological markers may have an important role in the understanding the pathophysiology of SCD and in optimizing targeted therapeutic strategies for each patient.

Spherocytosis is a hereditary disease caused by the deficiencies of different membrane proteins of red blood cells. Currently, splenectomy is the main therapeutic strategy available, although it is accompanied by an increased risk of sepsis. Several evidences have supported the hypothesis of spleen dysfunction in patients with spherocytosis that haven't yet undergone splenectomy. The aim of this study is to furtherly characterize this aspect, by describing the immune subpopulations in peripheral blood samples obtained from 41 pediatric patients with hereditary spherocytosis by flow cytometry, in order to evaluate changes in the composition of the immune populations compared to 16 healthy donors. Patients were divided in two groups: splenectomized and non-splenectomized. In the splenectomized population, data showed neutrophilic leukocytosis, thrombocytosis, increase in NK and reduction in CD4+ lymphocytes. However, we observed that most of the results obtained in the splenectomized group were found in the non-splenectomized patients as well (increase in neutrophils, in NK, reduction of CD19+, CD4+ lymphocytes and CD4+ and CD8+ naïve cells). The alterations of the immune system may be mainly due to the disease itself, regardless of splenectomy. Therefore, immunological criteria could be included in clinical phenotype assessment in order to better optimize the timing for splenectomy.

Resistant pathogens have become a major healthcare problem in children with cancer, causing different kinds of infections such as the bloodstream ones, most common, and most frequently described and the urinary tract ones, of which less data are available. We analyzed and compared the proportions, and the trends of resistance in pathogens isolated from blood and urines in children with cancer followed in IRCCS Istituto Giannina Gaslini, Genova, Italy, from January 2007 to December 2018. Overall, 345 strains detected in urines and 282 in bloodstream infections were analyzed. Enterobacteriales were the most frequently isolated pathogens. During the study period in urines, there was a significant increase of resistance to ceftazidime, ciprofloxacin, piperacillin/tazobactam, and trimethoprim-sulfamethoxazole, but pathogens from blood were significantly more frequently resistant to amikacin, piperacillin/tazobactam, and combination therapy piperacillin/tazobactam+amikacin, even if with a decreasing trend during the study period. These data confirm the importance of surveillance of isolated microorganism and antibiotic resistance in cancer children.

Patients affected by Inflammatory Bowel Disease (IBD) present higher risk for infection and suboptimal response upon vaccination. The immunogenicity of SARS-CoV2 vaccination is still largely unknown in adolescents or young adults affected by IBD (pIBD). We investigated the safety and immunogenicity of the BNT162B2 mRNA COVID-19 vaccine in 27 pIBD, as compared to 30 healthy controls (HC). Immunogenicity was measured by anti-SARS-CoV2 IgG (anti-S and anti-trim Ab) before vaccination, after 21 days (T21) and 7 days after the second dose (T28). The safety profile was investigated by close monitoring and self-reported adverse events. Vaccination was well tolerated, and short-term adverse events reported were only mild to moderate. Three out of twenty-seven patients showed IBD flare after vaccination, but no causal relationship could be established. Overall, pIBD showed a good humoral response upon vaccination compared to HC; however, pIBD on anti-TNFα treatment showed lower anti-S Ab titers compared to patients receiving other immune-suppressive regimens (p = 0.0413 at first dose and p = 0.0301 at second dose). These data show that pIBD present a good safety and immunogenicity profile following SARS-CoV-2 mRNA vaccination. Additional studies on the impact of specific immune-suppressive regimens, such as anti TNFα, on immunogenicity should be further investigated on larger cohorts.

Very young age could be a potential risk factor for community‐acquired severe acute respiratory syndrome coronavirus 2, due to immature immune systems. We retrospectively enrolled 39 infants up to 6 months of age who had presented to our tertiary Italian children's hospital emergency room between 9 March 2020 and 8 March 2021 and tested positive for the virus. Of those, 38 had a non‐specific mild or asymptomatic clinical course and only one patient was admitted to intensive care with severe symptoms. We concluded that very young infants with COVID‐19 had a generally favourable disease course.

International audience; Among 143 patients with elastase, neutrophil-expressed (ELANE)-related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte-colony stimulating factor (G-CSF), on G-CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem-cell transplantation. During the disease’s natural history period (without G-CSF; 1913 person-years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37·4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (3000/mm(3) ) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G-CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism.

INTRODUCTION: The aim of this study was to describe the rate and types of community-acquired respiratory infections observed in a pediatric ED during the SARS-CoV-2 related lockdown in Italy and to compare data with the same period of previous year. METHODS: A retrospective analysis of medical charts of patients arrived at the ED of Gaslini Children's Hospital from 10th March 2020 to 30th April 2019 and the same frame of 2020 were performed. We compared two groups by demographics, duration of fever before ED admission, triage code, number of patients hospitalized after ED evaluation. We calculated proportion and incidence rate for airborne infections, fever, and urinary tract infections (UTI), appendicitis, and gastroenteritis for control. RESULTS: 1362 children arrived at the ED during the lockdown compared to 5628 in the same period of 2019 (-75,8%). No difference was noticed (27.7% vs 28.4%) in the total amount of infectious episodes. A significant reduction in rate of incidence and proportion were observed for upper respiratory tract infections (21,4% vs 28%), otitis (2,6% vs 16,2%), streptococcal infections (0,5% vs 5,2%) and bronchiolitis (2,1% vs 5,7%). Conversely, FUO (27,8 vs 11,1%), infectious mononucleosis (2,6% vs 0,4%), UTI (7,4% vs 2,9%) and appendicitis (6,8% vs 1,1%) significantly increased. Median time from the onset of fever and arrival in ED was significantly lower in 2020 group. CONCLUSION: Our results demonstrated a reduction in community-acquired respiratory infections during the lockdown for COVID-19. The increase in rate of FUO and febrile conditions, together with the short time from fever onset and ED visit could be related to the fear for a SARS-CoV-2 infection.

The SARS-CoV-2 vaccine roll-out has been successful around the world. However, there are increasing concerns about adverse events. We report two pediatric cases of Multisystem-Inflammatory-Syndrome (MIS-C) with neurological involvement that occurred after SARS-CoV-2 vaccination and unknown recent SARS-CoV-2 infection. Brain magnetic resonance revealed mild-encephalopathy with reversible-splenial-lesion in both cases and complete resolution within 4 weeks. In conclusion, this report aims to describe rare emerging clinical entities that can help pediatricians to make an early diagnosis and to provide appropriate treatment. Multisystem-Inflammatory-Syndromes following COVID-19 vaccination remain rare events. When a history of a recent contact with SARS-CoV-2 is present, a careful evaluation by the clinicians in charge of immunization activities is suggested prior to proceeding with the vaccination.

Respiratory syncytial virus (RSV) infection is the leading cause of bronchiolitis among infants

Children appear to have milder COVID-19 than adults and a more favourable clinical course (1-2). Adult comorbidities, including advanced age, diabetes and cardiovascular disease, have been associated with severe COVID-19 and the highest mortality rates (3). We presume that children with pre-existing conditions face a higher risk from COVID-19 than healthy peers, but studies are scarce and detailed clinical information has often been lacking. Bixler et al studied 121 people under 21 years, whose deaths were associated with COVID-19 and had been reported to the American Centers for Disease Control by 31 July 2020. They found that 75% had at least one underlying medical condition (4) and the most frequent were chronic lung disease, including asthma, and neurological, developmental and cardiovascular conditions. A systematic review by Williams et al reported that paediatric comorbidities increased the risk of critical COVID-19 and cardiac disease was the most common comorbidity (5).

International audience; ELANE neutropenia is associated with myelodysplasia and acute leukemia (MDS–AL), and severe infections. Because the MDS–AL risk has also been shown to be associated with exposure to GCSF, since 2005, in France, patients receiving high daily GCSF doses (>15 μg/kg/day) are eligible for HSCT, in addition to classic indications (MDS–AL or GCSF refractoriness). We analyzed the effect of this policy. Among 144 prospectively followed ELANE-neutropenia patients enrolled in the French Severe Congenital Neutropenia Registry, we defined two groups according to period: “before 2005” for those born before 2005 and followed until 31/12/2004 (1588 person-years); and “after 2005” comprised of those born after 2005 or born before 2005 but followed after 2005 until 31/03/2019 (1327 person-years). Sixteen of our cohort patients underwent HSCT (14 long-term survivors) and six developed MDS–ALs. Six leukemic transformations occurred in the before-2005 group and none after 2005 (respective frequencies 3.8 × 10–3 vs. 0; P

Magnusiomyces clavatus is an ascomycetous fungus causing invasive disease in immuno-compromised patients. Neutropenia, contaminated venous catheters, previous antifungal treatment are risk factors for this infection. We report a case of Magnusiomyces clavatus fungemia with pulmonary, renal and skin localizations in a 6-year-old boy with prolonged neutropenia because of three allogeneic hematopoietic stem cell transplantations. The infection was controlled by aggressive and strictly monitored combination therapy with voriconazole and liposomial-ampthotericine-B along with durable recover from neutropenia. Keywords: Magnusiomyces clavatus, Dimorphic fungi, Neutropenia, HSCT

Although children seem to be less affected than adults by COVID-19, Italianpaediatric hospitals have had to significantly reorganise services to deal with the pandemic. These include thetertiary-level Gaslini Children's Hospital in Genoa, which handles around 35,000 emergency room (ER) visits per year. The Government lockdown has dramatically reduced ER admissions and delayed programmed admissions (1).

Primary autoimmune neutropenia (pAN) is typified by onset in early infancy and a mild/moderate phenotype that resolves within 3 years of diagnosis. In contrast, secondary AN is classically an adult disease associated with malignancy, autoimmunity, immunodeficiency, viral infection, or drugs. This study describes a cohort of 79 children from the Italian Registry who, although resembling pAN, did not fully match the criteria for pAN because neutropenia either appeared after age 5 years (LO-Np) or lasted longer than 3 years (LL-Np). These 2 categories compared with classical pAN showed a far inferior rate of resolution (P < .001), lower severity of neutropenia (P = .03), leukopenia (P < .001), lymphopenia (P < .001) with low B+ (P = .001), increased need of granulocyte colony-stimulating factor (P = .04), and increased frequency of autoimmunity over the disease course (P < .001). A paired comparison between LO-Np and LL-Np suggested that LO-Np had a lower rate of resolution (P < .001) and lower white blood cell (P < .001) and lymphocyte (P < .001) values, higher occurrence of apthae (P = .008), and a stronger association with autoimmune diseases/markers (P = .001) than LL-Np, thus suggesting a more pronounced autoimmune signature for LO-Np. A next-generation sequencing panel applied in a small subgroup of LO-Np and LL-Np patients identified variants related to immune dysregulations. Overall, these findings indicate that there are important differences among pAN LL-Np and LO-Np. Forms rising after 3 years of age, with low tendency to resolution, require tight monitoring and extensive immune investigations aimed to early identify underlying immunologic disease.

Opportunistic Infections (OIs) still remain a major cause of morbidity and death in children with either malignant or nonmalignant disease. : OIs are defined as those infections occurring due to bacteria, fungi, viruses or commensal organisms that normally inhabit the human body and do not cause a disease in healthy people, but become pathogenic when the body's defense system is impaired. OIs can also be represented by unusually severe infections caused by common pathogens. An OI could present itself at the onset of a primary immunodeficiency syndrome as a life-threatening event. More often, OI is a therapyassociated complication in patients needing immunosuppressive treatment, among long-term hospitalised patients or in children who undergo bone marrow or solid organ transplantation. : The aim of the present review is to provide a comprehensive and ‘easy to read’ text that briefly summarises the currently available knowledge about OIs in order to define when an infection should be considered as opportunistic in pediatrics as a result of an underlying congenital or acquired immune-deficit.