Preliminary data revealing efficacy of Streptococcus salivarius K12 (SSK12) in Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome: A multicenter study from the AIDA Network PFAPA syndrome registry.

Objective: To evaluate the potential role of Streptococcus salivarius K12 (SSK12) in controlling febrile flares in patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome. Further aims were to assess the impact of SSK12 on (i) flare duration, (ii) variation in the degree of the highest body temperature during flares, (iii) steroid-sparing effect, and (iv) change of PFAPA accompanying symptoms before and after SSK12 introduction. Patients and methods: The medical charts from 85 pediatric patients with PFAPA syndrome (49 males and 36 females) enrolled in the AIDA registry and treated with SSK12 for a median period of 6.00 ± 7.00 months in the period between September 2017 and May 2022 were examined. Children recruited had a median time of disease duration of 19.00 ± 28.00 months. Results: The number of febrile flares significantly decreased comparing the 12 months before [median (IQR), 13.00 (6.00)] and after SSK12 initiation [median (IQR), 5.50 (8.00), p < 0.001]. The duration of fever was significantly reduced from 4.00 (2.00) days to 2.00 (2.00) days [p < 0.001]. Similarly, the highest temperature in°C was found significantly lower in the last follow-up assessment [median (IQR), 39.00 (1.00)] compared to the period prior to SSK12 start [median (IQR), 40.00 (1.00), p < 0.001]. Steroid load (mg/year) of betamethasone (or any equivalent steroid) significantly decreased between 12 months before treatment with SSK12 [median (IQR), 5.00 (8.00) mg/year] and the last follow-up visit [median (IQR), 2.00 (4.00) mg/year, p < 0.001]. The number of patients experiencing symptoms including pharyngitis/tonsillitis (p < 0.001), oral aphthae (p < 0.001) and cervical lymphadenopathy (p < 0.001) significantly decreased following SSK12. Conclusion: SSK12 prophylaxis given for at least 6.00 months was found to reduce febrile flares of PFAPA syndrome: in particular, it halved the total number per year of fever flares, shortened the duration of the single febrile episode, lowered body temperature by 1°C in the febrile flare, provided a steroid-sparing effect, and significantly reduced the accompanying symptoms related to the syndrome.

Pediatric Recurrent Pericarditis: Appropriateness of the Standard of Care and Response to IL-1 Blockade.

OBJECTIVE: To analyze, in a cohort of pediatric patients with recurrent pericarditis undergoing anti-interleukin (IL)-1 treatment: the agent and dosing used as first-line treatment, the long-term efficacy of IL-1 blockers, the percentage of patients achieving a drug-free remission, and the presence of variables associated with drug-free remission. STUDY DESIGN: Data were collected from patients' charts. The annualized relapse rate (ARR) was used for evaluation of treatment efficacy, and bivariate logistic regression analysis was used for variables associated with drug-free remission. RESULTS: Fifty-eight patients, treated between 2008 and 2018, were included in the study (mean follow-up. 2.6 years). Of the 56 patients treated with first-line drugs, 14 not responsive patients were underdosed. Fifty-seven patients were treated with anakinra: the ARR before and during daily treatment was 3.05 and 0.28, respectively (P < .0001); an increase to 0.83 was observed after the reduction/withdrawal of treatment (P < .0001). The switch from anakinra to canakinumab (5 patients) was associated to an increase of the ARR (0.49 vs 1.46), but without statistical significance (P = .215). At last follow-up, only 9 of the 58 patients had withdrawn all treatments. With the limits of a retrospective study and the heterogeneity between the patients enrolled in the study, a shorter duration of treatment with anakinra was the only variable associated with drug-free remission. CONCLUSIONS: This study shows that most pediatric patients with recurrent pericarditis needing IL-1 blockade received an inadequate treatment with first-line agents. The effectiveness of anakinra is supported by this study, but few patients achieved drug-free remission. The different rate of response to anakinra and canakinumab may suggest a possible role of IL-1α in the pathogenesis of recurrent pericarditis.

Incidence and predictors of pericardial effusion following surgical closure of atrial septal defect in children: A single center experience.

Objectives: To evaluate the incidence of pericardial effusion (PE) after surgical atrial septal defect (ASD) closure and to investigate the presence of predictive risk factors for its development. Methods: We collected data from 203 patients followed at Bambino Gesù Children's Hospital of Rome who underwent cardiac surgery for ASD repair between January 2015 and September 2019. Results: A total of 200/203 patients with different types of ASD were included. Patients were divided into two groups: Group 1) 38 (19%) who developed PE and Group 2) 162 (81%) without PE. No differences were noted between the two groups with regard to gender or age at the surgery. Fever in the 48 h after surgery was significantly more frequent in group 1 than in group 2 (23.7 vs. 2.5%; p < 0.0001). ECG at discharge showed significant ST-segment elevation in children who developed PE, 24.3 vs. 2.0% in those who did not (p < 0.0001). Group 1 patients were divided into two subgroups on the basis of the severity of PE, namely, 31 (81.6%) with mild and 7 (18.4%) with moderate/severe PE. Patients with moderate/severe PE had a significantly higher BMI value (median 19.1 Kg/m2) (range 15.9-23.4, p = 0.004). Conclusion: The presence of fever and ST-segment elevation after surgery predicts subsequent development of PE suggesting a closer follow-up for these categories of patients. A higher BMI appears to be associated with a higher risk of moderate/severe PE.

Identification of a Novel Mutation in TNFAIP3 in a Family With Poly-Autoimmunity.

Haploinsufficiency of A20 (HA20) is an inflammatory disease caused by mutations in the TNFAIP3 gene classically presenting with Behcet's-like disease. A20 acts as an inhibitor of inflammation through its effect on NF-kB pathway. Here we describe four consanguineous patients (three sisters and their mother) with a predominantly autoimmune phenotype, including thyroiditis, type I diabetes, hemolytic anemia and chronic polyarthritis. All patients had recurrent oral ulcers, with only 1 patient presenting also recurrent fever episodes, as a classical autoinflammatory feature. Next generation sequencing identified a novel heterozygous frameshift mutation (p.His577Alafs*95) that causes a premature stop codon in the zinc finger domain of A20, leading to a putative haploinsufficiency of the protein. Functional analyses confirmed the pathogenicity of the mutation. The variant was associated with decreased levels of A20 in blood cells. Accordingly, ex-vivo lipopolysaccharide (LPS)-stimulated patients' peripheral blood mononuclear cells (PBMCs) showed higher levels of p65 NF-kB phosphorylation, as well as increased production of the proinflammatory cytokines IL-1ß, IL-6 and TNF-α. Moreover, in agreement with recent observations, demonstrating a role for A20 in inhibiting STAT1 and IFNγ pathways, markedly higher circulating levels of the two IFNγ-inducible chemokines CXCL9 and CXCL10 were detected in all patients. Supporting the findings of a hyperactivation of IFNγ signaling pathway in HA20 patients, patients' monocytes showed higher levels of STAT1 without stimulation, as well as higher phosphorylated (active) STAT1 levels following IFNγ stimulation. In conclusion, our study show that in the clinical spectrum of HA20 autoimmune features may predominate over autoinflammatory features and demonstrate, from a molecular point of view, the involvement of A20 in modulating not only the NF-kB, but also the IFNγ pathway.

Tocilizumab for massive refractory pleural effusion in an adolescent with systemic lupus erythematosus.

BACKGROUND: Pleural effusion in systemic lupus erythematous (SLE) is a common symptom, and recent studies demonstrated that IL-6 has a pivotal role in its pathogenesis. CASE PRESENTATION: We report a case of a 15 years old Caucasian boy with a history of persistent pleural effusion without lung involvement or fever. Microbiological and neoplastic aetiologies were previously excluded. Based on the presence of pleuritis, malar rash, reduction of C3 and C4 levels and positivity of antinuclear antibody (ANA) and anti-double stranded DNA (dsDNA), the diagnosis of juvenile SLE (JSLE) was performed. Treatment with high dose of intravenous glucocorticoids and mycophenolate mofetil was started with partial improvement of pleural effusion. Based on this and on adults SLE cases with serositis previously reported, therapy with intravenous tocilizumab (800 mg every two weeks) was started with prompt recovery of pleural effusion. CONCLUSION: To the best of our knowledge, this is the first case of JSLE pleuritis successfully treated with tocilizumab.

Renal involvement and metabolic alterations in adults patients affected by cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is one of the most frequent genetic diseases and the median survival of these patients has improved in the last few decades, therefore it becomes necessary to evaluate the long-term complications as renal and cardiovascular risk factors. AIM OF THE STUDY: To evaluate the incidence, the manifestations of renal disease and the possible association with metabolic and endothelial dysfunction markers in the CF population. MATERIALS AND METHODS: We performed a cross-sectional, observational study on 226 CF patients. Clinical and laboratory instrumental parameters (metabolic, inflammatory and endothelial dysfunction markers) were evaluated. RESULTS: We showed 65 patients with chronic kidney disease (CKD) and 158 patients with a reduced value of forced expiratory volume in 1 s (FEV1), of which 58 patients with a severe reduction of FEV1. Moreover 28 patients had undergone lung transplantation and them had a significant lower estimated Glomerular Filtration Rate (eGFR) with respect to the non-transplanted patients (p < 0.001). We reported also a significant association between lower eGFR value and serum triglycerides, total cholesterol and low-density lipoproteins (LDL) (p = 0.005, p < 0.001, p = 0.040; respectively), with a significant negative correlation between eGFR and serum triglycerides (r = - 0.28; p < 0.01). Moreover we found a significant association between lower eGFR value and serum uric acid (SUA) (p = 0.005), while we did not found an association with 25-hydroxy-vitamin-D value, serum glucose and hemoglobin A1c levels. CONCLUSIONS: Our study showed a high prevalence of CKD in CF patients. Moreover we showed an increase of endothelial dysfunction and metabolic indexes in patients with reduced renal function, as SUA, serum triglycerides and LDL, suggesting the need for an early and complete screening of the main metabolic indexes to reduce cardiovascular risk and progression of renal damage, in particular in patients with lung transplant.

Long-term renal function and hypertension in adult survivors of childhood sarcoma: Single center experience.

AIM: Little data is available on long-term renal impairment in survivors from childhood sarcoma. We investigated the prevalence of renal impairment and hypertension after very long-term follow-up in survivors who reached adulthood after treatment for childhood sarcoma. METHODS: A cross-sectional single center study was performed. Outcomes included estimating glomerular filtration rate (eGFR), albuminuria, glycosuria, serum phosphate and magnesium, tubular reabsorption phosphate (TRP), chronic kidney disease (CKD) according to the "Kidney Disease: Improving Global Outcomes" (KDIGO) guidelines and blood pressure (BP). RESULTS: Out of 87 > 5-year sarcoma survivors, 30 adults (10F/20M, median age at diagnosis 9 years, median age at investigation 26 years, median follow-up 16 years, mean 19 years) were identified. Renal impairment was detected in four cases (13.3%); three of these fulfilled the criteria for CKD. Among the adult survivors, a subgroup of 15 cases (50%) had received ifosfamide without confounding factors such as a diagnosis of genito-urinary rhabdomyosarcoma or administration of other potentially nephrotoxic chemotherapy (platinum-based drugs or methotrexate); no renal dysfunction was detected in this subgroup. In the whole cohort of sarcoma survivors, hypertension was diagnosed in four cases (13.3%); BP was significantly correlated with body mass index [p .014]. CONCLUSION: In our series of adult survivors treated for a diagnosis of sarcoma in their childhood, the prevalence of CKD was 10%. We found survivors treated with ifosfamide as the only nephrotoxic agent did not present glomerular or tubular toxicity at long term follow-up, but further studies including a larger number of cases are required to confirm it.

Pathogenesis of Vernal Keratoconjunctivitis and Associated Factors.

AIM: To investigate the role of some variables, including allergy and autoimmunity, in the pathogenesis of vernal keratoconjunctivitis (VKC). The VKC is a chronic and often severe form of bilateral keratoconjunctivitis. Usually, it begins during the first decade and disappears during the end of the second decade of life. MATERIALS AND METHODS: 26 patients with VKC were selected. The diagnosis was performed by the ophthalmologist through a score based on ocular signs and subjective symptoms before and after administration of 1% cyclosporine A (Cy) eyedrops. Each variable was graded: 0 = absent; 1 = mild; 2 = moderate; 3 = severe. Patients with a total score ≥7 were included in the study. Blood samples were collected at the initial time for the determination of autoimmunity by total IgE and antinuclear antibodies (ANA). A Skin Prick Test (SPT) was performed on each patient to common inhalants and food allergens. RESULTS: 53.8% of the children resulted atopic. The most important allergens were house dust mites and grasses. 46.1% of the patients showed total IgE >100 UI/ml and 30.8% had ANA positivity at the first determination. The photophobia occurred in 42.3% of children, most frequently with respect to other symptoms like secretion or tearing (30.8%), foreign body sensation (15.4%), itching and conjunctival hyperemia (11.5%). CONCLUSIONS: Fortunately all children improved their symptoms after Cy eyedrop therapy. Moreover, there was an elevated percentage (30.8%) of children with ANA positivity compared with the values in the general pediatric population. Despite the fact that it is a non-specific autoantibody, its high presence in a population of children with VKC may have an important role in clarifying etiopathogenesis and chronic inflammation.

High-mobility group box-1 (HMGB-1) and serum soluble receptor for advanced glycation end products (sRAGE) in children affected by vernal keratoconjunctivitis.

BACKGROUND: Vernal keratoconjunctivitis (VKC) is a chronic disease affecting conjunctiva even though the immunopathogenetic mechanisms underlying this inflammation are unclear. The aim of our study is to investigate serum levels of HMGB1 and circulating sRAGE in children affected by VKC before and after treatment with cyclosporine A (CsA) eye drops and in a group of healthy children. METHODS: Twenty-four children affected by VKC aged between 5 and 12 yrs of life were enrolled at the Department of Pediatrics, Division of Allergy and Immunology, 'Sapienza' University of Rome. Twenty-four healthy children without atopy, ocular, and systemic disease, cross-matched for sex and age to patients affected by VKC, represented the controls. All children affected by VKC were treated with CsA 1% eye drops for 4 wks, and blood samples were collected before and 2 wks after the end of treatment while the controls underwent to a single blood sample at the time of enrollment. RESULTS: Serum basal levels of HMGB1 and sRAGE were higher in children with VKC when compared with controls while, in patients affected by VKC, no difference was detected between atopic and non-atopic, and between ANA-positive and ANA-negative children. A significant reduction in serum HMGB1 and sRAGE levels was detected after the therapy while CsA serum levels were negative. CONCLUSIONS: Our study gives a support to the definition of VKC as a systemic inflammation in which HMGB1 and its soluble receptors could play a role.

Habitual snoring and atopic state: correlations with respiratory function and teeth occlusion.

BACKGROUND: Allergy represents a risk factor at the base of sleep-disordered breathing in pediatric age. Among allergic diseases, the atopy is characterized by a tendency to be "hyperallergic." Sleep-disordered breathing is also known in orthodontics as correlated with the morphology of craniofacial complex. The aim of this study was to investigate the relation between atopy and sleep-disordered breathing (oral breathers with habitual snoring), comparing atopic children with sleep-disordered breathing (test group) with nonatopic ones with sleep-disordered breathing (control group), in the prevalence of dento-skeletal alterations and other risk factors that trigger sleep-disordered breathing, such as adenotonsillar hypertrophy, turbinate hypertrophy, obesity, and alteration of oxygen arterial saturation. METHODS: In a group of 110 subjects with sleep-disordered breathing (6 to 12 years old), we grouped the subjects into atopic (test group, 60 subjects) and nonatopic (control group, 50 subjects) children and compared the data on the following: skin allergic tests, rhinoscopy, rhinomanometry, night home pulsoxymetry, body mass index, and dento-facial alterations. RESULTS: Even if our results suggest that atopy is not a direct risk factor for sleep-disordered breathing, the importance of a physiologic nasal respiration in the pathogenesis of sleep-disordered breathing seems to be demonstrated in our study by the higher prevalence of hypertrophy in the adenotonsillar lymphatic tissue, odontostomatological alterations, alterations of the oxygen saturation to pulsoxymetry, and higher prevalence of obesity observed in our children with sleep-disordered breathing, in percentages higher than that of the general pediatric population previously observed in the literature. CONCLUSIONS: The importance of a physiologic nasal respiration in the pathogenesis of sleep-disordered breathing is demonstrated in our study.

Treating allergic rhinitis by sublingual immunotherapy: a review.

OBJECTIVE: Allergic rhinitis (AR) is a disease with high and increasing prevalence. The management of AR includes allergen avoidance, anti-allergic drugs, and allergen specific immunotherapy (AIT), but only the latter works on the causes of allergy and, due to its mechanisms of action, modifies the natural history of the disease. Sublingual immunotherapy (SLIT) was proposed in the 1990s as an option to traditional, subcutaneous immunotherapy. MATERIAL AND METHODS: We reviewed all the available controlled trials on the efficacy and safety of SLIT. RESULTS AND CONCLUSION: Thus far, more than 60 trials, globally evaluated in 6 meta-analyses, showed that SLIT is an effective and safe treatment for AR. However, it must be noted that to expect clinical efficacy in the current practice SLIT has to be performed following the indications from controlled trials, that is, sufficiently high doses to be regularly administered for at least 3 consecutive years.

Pathophysiology, favoring factors, and associated disorders in otorhinosinusology.

The pathogenesis of rhinosinusitis (RS) is related to inflammation, caused by infections in the acute form of the disease but also by other agents in the chronic forms. Cytology allows to evaluate the defensive components, such as hair cells and muciparous cells, while the presence in the nasal mucosa of eosinophils, mast cells, bacteria and/or fungal hyphae, or spores indicates the nasal pathology. The anatomic and physiologic characteristics of the otorhinosinusal system account for the frequent concomitant involvement of the different components. The pivotal pathophysiologic sites are the ostiomeatal complex, the spheno-ethmoidal recess, and the Eustachian tube. The latter is the link with acute otitis media (AOM), which is the most common disease in infants and children and has major medical, social, and economic effects. Moreover, because of the strict relationship between upper and lower airways, nasal sinus disease may contribute to asthma and sinusitis may be considered as an independent factor associated with frequent severe asthma exacerbations. Concerning the role of allergy, the available data do not permit to attribute a central role to atopy in sinusitis and thus allergy testing should not be a routine procedure, while an allergologic evaluation may be indicated in children with OM, especially when they have concomitant rhinitis.