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Objective: The objective of this study was to describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers., Study Design: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period., Results: Among 608 patients on ETI, 109 (17.9%) reported at least 1 AE. The majority (n = 85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA P value .026)., Conclusions: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Bronchiolitis is a common lower respiratory tract infection (LRTI) affecting infants and young children. Respiratory syncytial virus (RSV) has historically been the primary causative agent, but other viruses also contribute to the LRTI epidemiology. Recent changes in epidemiology and clinical patterns due to the coronavirus disease 2019 (COVID-19) pandemic have raised concerns. This study aims to analyze the impact of the pandemic on bronchiolitis epidemiology and severity., Methods: Two consecutive bronchiolitis seasons (October 2021 to March 2022 and October 2022 to March 2023) were compared. Data on viral agents, hospitalization duration, clinical severity, and respiratory support requirements were collected from pediatric patients at San Marco Hospital, University of Catania., Results: In the 2021-2022 season, RSV was the predominant virus (40%), followed by other viruses, with mild clinical outcomes. In the 2022-2023 season, RSV remained prevalent (58.7%), but other viruses, including rhinovirus (RV) and influenza, showed a significant increase (p < .05) in bronchiolitis cases and severity. Notably, RSV-related bronchiolitis did not exhibit greater severity compared to non-RSV cases in the 2022-2023 season, contrary to the previous year., Conclusion: The COVID-19 pandemic appears to have shifted the epidemiological landscape of bronchiolitis, with a peak incidence in November instead of January/February. Non-RSV viruses (RV, influenza A and B, as well as metapneumovirus) have gained prominence, possibly due to viral competition and reduced pandemic-related restrictions. Traditionally, RSV has been the primary pathogen responsible for most bronchiolitis cases. Nonetheless, the findings of this study indicate a shifting landscape in bronchiolitis etiology, with RSV gradually diminishing in its role. Contrary to the previous year, RSV-related bronchiolitis did not exhibit greater severity compared to non-RSV cases in the 2022-2023 season., (© 2024 Wiley Periodicals LLC.)

Objectives: Aim of this study was to identify risk factors for a progression to cystic fibrosis (CF) in individuals detected as CF Screening Positive, Inconclusive Diagnosis (CFSPID)., Methods: This is a systematic review through literature databases (2015-2023). Blood immunoreactive trypsinogen (b-IRT) values, CFTR genotype, sweat chloride (SC) values, isolation of Pseudomonas aeruginosa (Pa) from respiratory samples, Lung Clearance Index (LCI) values in CFSPIDs who converted to CF (CFSPID > CF) and age at CF transition were assessed., Results: Percentage of CFSPID > CF varies from 5.3 % to 44 %. Presence of one CF-causing CFTR variant in trans with a variant with variable clinical consequences (VVCC), an initial SC ≥ 40 mmol/L, an increase of SC > 2.5 mmol/L/year and recurrent isolation of pseudomonas aeruginosa (Pa) from airway samples could allow identification of subjects at risk of progression to CF., Conclusions: CFSPIDs with CF causing variant/VVCC genotype and first SC in the higher borderline range may require more frequent and prolonged clinical follow-up., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are genetic respiratory diseases featured by chronic upper and lower airway inflammation and infection, mainly due to impaired mucociliary clearance due to genetic mutations. Sleep is crucial to healthy children's normal physical and psychological development and has an important value in chronic respiratory diseases. Impaired sleep quality, such as sleep deprivation or insufficient sleep during the night, and sleep respiratory disorders (SRDs) are common in 5% to 30% of the general population. Sleep disruption leads to attention deficits, daytime sleepiness, fatigue and mood disorders and correlates to a worsened quality of life. Furthermore, sleep respiratory disorders (SRSs) are under-recognized comorbidities in CF and PCD patients. SRSs include a spectrum of symptoms ranging from primary snoring through upper airway resistance to obstructive sleep apnea (OSA), nocturnal hypoventilation and hypoxemia occurring in people with moderate to severe lung disease and damaging the disease-related outcomes and quality of life. Effective screening during sleep with polysomnography is very important for the timely initiation of efficacious treatments and to prevent worsened respiratory, metabolic and cardiovascular outcomes. However, the impact of SRDs on health and quality of life is still underinvestigated.

Background: The COVID-19 pandemic has had a significant impact on the epidemiology of respiratory viruses. Non-pharmaceutical interventions (NPIs) led to a dramatic reduction in respiratory infections. However, the long-term effects on respiratory virus epidemiology remain unclear., Materials and Methods: We conducted a comparative study on hospitalized pediatric patients with respiratory illness during two seasons: 1 October 2021 to 15 March 2022 and 1 October 2022 to 15 March 2023. We compared the type of virus, mean duration of hospitalization, and disease severity., Results: In the first season, 47.1% of patients (65/138) tested positive for at least one respiratory virus, with respiratory syncytial virus (RSV) being the most frequent (23.2%). In the second season, 82.9% of patients (102/123) tested positive, with RSV and Rhinovirus being the most prevalent (28.38% and 27.03%, respectively). Other viruses, such as Influenza A/B, Metapneumovirus , and Adenovirus , also showed increased prevalence. Disease severity and mean duration of hospitalization were similar between the two seasons., Conclusions: Our study highlights increased prevalence in respiratory viruses, including RSV and Rhinovirus , following the easing of NPIs. The prevalence in respiratory viruses, including RSV and Rhinovirus , increased in the second season compared to the first one. Interestingly, RSV's peak incidence shifted from February to November. The emergence of rhinovirus as the most prevalent respiratory virus during certain months suggests viral competition and dynamic changes in viral circulation. The overall severity of respiratory infections remained relatively stable between the seasons.

Cystic fibrosis (CF) is a genetic disorder affecting multiple organs, primarily the lungs and digestive system. Over the years, advancements in medical care and treatments have significantly increased the life expectancy of individuals with CF. However, with this improved longevity, concerns about the potential risk of developing certain types of cancers have arisen. This narrative review aims to explore the relationship between CF, increased life expectancy, and the associated risk for cancers. We discuss the potential mechanisms underlying this risk, including chronic inflammation, immune system dysregulation, and genetic factors. Additionally, we review studies that have examined the incidence and types of cancers seen in CF patients, with a focus on gastrointestinal, breast, and respiratory malignancies. We also explore the impact of CFTR modulator therapies on cancer risk. In the gastrointestinal tract, CF patients have an elevated risk of developing colorectal cancer, pancreatic cancer, and possibly esophageal cancer. The underlying mechanisms contributing to these increased risks are not fully understood, but chronic inflammation, altered gut microbiota, and genetic factors are believed to play a role. Regular surveillance and colonoscopies are recommended for early detection and management of colorectal cancer in CF patients. Understanding the factors contributing to cancer development in CF patients is crucial for implementing appropriate surveillance strategies and improving long-term outcomes. Further research is needed to elucidate the molecular mechanisms involved and develop targeted interventions to mitigate cancer risk in individuals with CF.

Background: Lung ultrasound (LUS) is a widely available technique allowing rapid bedside detection of different respiratory disorders. Its reliability in the diagnosis of community-acquired lung infection has been confirmed. However, its usefulness in identifying infections caused by specific and less common pathogens (e.g., in immunocompromised patients) is still uncertain., Methods: This systematic review aimed to explore the most common LUS patterns in infections caused by intracellular, fungal pathogens or mycobacteria., Results: We included 17 studies, reporting a total of 274 patients with M. pneumoniae , 30 with fungal infection and 213 with pulmonary tuberculosis (TB). Most of the studies on M. pneumoniae in children found a specific LUS pattern, mainly consolidated areas associated with diffuse B lines. The typical LUS pattern in TB consisted of consolidation and small subpleural nodes. Only one study on fungal disease reported LUS specific patterns (e.g., indicating "halo sign" or "reverse halo sign")., Conclusions: Considering the preliminary data, LUS appears to be a promising point-of-care tool, showing patterns of atypical pneumonia and TB which seem different from patterns characterizing common bacterial infection. The role of LUS in the diagnosis of fungal disease is still at an early stage of exploration. Large trials to investigate sonography in these lung infections are granted.

Introduction: There are no recent data on primary ciliary dyskinesia (PCD) distribution, diagnosis and treatment in Italy., Methods: A descriptive study based on a survey questionnaire. It consisted of three sections (patients, diagnosis, and treatment), and sent to all the Italian PCD Centers., Results: Questionnaires obtained from 20/22 centers in 12/20 regions showed that the total number of PCD patients treated at the participating centers was of 416. Out of all centers, 55% follow <20 patients, two centers have >40 patients, and 75% follow both pediatric and adults. Age at diagnosis was between 4 and 8 years in 45% of the centers, <3 years in three centers. Nasal nitric oxide, transmission electron microscopy and ciliary high-speed video microscopy are performed in 75%, 90%, and 40% of centers, respectively. Immunofluorescence is available in five centers. Genetic analysis is offered in 55% of the centers, and in seven centers >50% of the patients have a known genetic profile. Patients treated at all centers receive inhaled saline solutions, corticosteroids and chest physiotherapy. Prophylactic antibiotics and mucolytics are prescribed in 95% and 50% of the centers, respectively. Pseudomonas infection is treated with oral or inhaled antibiotics., Conclusions: Many Italian centers care for a small number of pediatric and adult patients, and diagnosis is often delayed. We found a great variability in the available diagnostic procedures, as well in the prescribed therapies. Our study will help to uniform diagnostic algorithm and share treatments protocols for PCD in Italy and allowed to set specific national goals., (© 2023 Wiley Periodicals LLC.)

Background: Asthma guidelines have recommended continuing treatment with biologics during coronavirus disease 2019 (COVID-19) pandemic. However, a continuation of treatment with biologics in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been little investigated., Objective: To assess the safety of biologics in patients with SARS-CoV-2 infection., Methods: A pilot, monocentric, prospective study. Patients aged 6 years old and older with severe asthma on treatment with biologics and confirmed SARS-CoV-2 infection were enrolled. Patients were followed-up with periodic calls at different time points up to 3 months to detect any adverse effect and its relationship with biologic treatment according to the Naranjo Adverse Probability Scale (NAPS). The severity of SARS-CoV-2 infection and clinical outcome were also assessed., Results: Overall, we included 21 patients (10 on therapy with omalizumab, 9 with dupilumab, and 2 with mepolizumab). Only a patient-reported two local adverse events. No other adverse event was reported. Twenty out of 21 patients had a mild COVID-19 course, and no adverse outcome was observed., Conclusion: We showed that the scheduled dose of the biologic therapy can be administered safely on time in patients with SARS-CoV-2 infection, as the treatment did not result in adverse events or outcomes., (© 2023 Wiley Periodicals LLC.)

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators represent targeted therapies directly acting on the CFTR channel. The triple therapy Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) has been demonstrated to improve lung function and quality of life in cystic fibrosis (CF) patients. However, the effects of ELX/TEZ/IVA on sleep-disordered breathing (SDB) and respiratory muscle strength are poorly studied. The aim of this study was to assess the effects of ELX/TEZ/IVA in patients with CF and severe lung disease on cardiorespiratory polygraphy parameters, maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) measures., Methods: patients with CF aged ≥ 12 who started treatment in a compassionate use program were retrospectively studied through the evaluation of nocturnal cardiorespiratory polygraphy parameters, MIP and MEP; and six-minute walk test (6MWT) at baseline and at months 3, 6, and 12 of treatment., Results: Nine patients (mean age 30.3 ± 6.5 years) with severe CF (mean baseline ppFEV1 34.6 ± 5.1%) were evaluated. A significant improvement in nocturnal oxygenation measured by mean SpO 2 (92.4 vs. 96.4%, p < 0.05), time spent with SpO 2 ≤ 90% (-12.6, -14.6, -15.2 min from baseline at months 3, 6, and 12, respectively, p < 0.05), and respiratory rate (RR) was shown, at month 12 and across the time points compared with baseline, as well as in respiratory muscle strength, although only the change in MEP was significant., Conclusions: We provide further evidence on the efficacy of the CFTR modulators ELX/TEZ/IVA, adding information about their effect on the respiratory muscles' performance and cardiorespiratory polygraphy parameters in CF patients with severe lung disease.

Respiratory tract exacerbations play a crucial role in progressive lung damage of people with cystic fibrosis, representing a major determinant in the loss of functional lung tissue, quality of life and patient survival. Detection and monitoring of respiratory tract exacerbations are challenging for clinicians, since under- and over-treatment convey several risks for the patient. Although various diagnostic and monitoring tools are available, their implementation is hampered by the current definition of respiratory tract exacerbation, which lacks objective "cut-offs" for clinical and lung function parameters. In particular, the latter shows a large variability, making the current 10% change in spirometry outcomes an unreliable threshold to detect exacerbation. Moreover, spirometry cannot be reliably performed in preschool children and new emerging tools, such as the forced oscillation technique, are still complementary and need more validation. Therefore, lung imaging is a key in providing respiratory tract exacerbation-related structural and functional information. However, imaging encompasses several diagnostic options, each with different advantages and limitations; for instance, conventional chest radiography, the most used radiological technique, may lack sensitivity and specificity in respiratory tract exacerbations diagnosis. Other methods, including computed tomography, positron emission tomography and magnetic resonance imaging, are limited by either radiation safety issues or the need for anesthesia in uncooperative patients. Finally, lung ultrasound has been proposed as a safe bedside option but it is highly operator-dependent and there is no strong evidence of its possible use during respiratory tract exacerbation. This review summarizes the clinical challenges of respiratory tract exacerbations in patients with cystic fibrosis with a special focus on imaging. Firstly, the definition of respiratory tract exacerbation is examined, while diagnostic and monitoring tools are briefly described to set the scene. This is followed by advantages and disadvantages of each imaging technique, concluding with a diagnostic imaging algorithm for disease monitoring during respiratory tract exacerbation in the cystic fibrosis patient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Landini, Ciet, Janssen, Bertolo, Ros, Mattone, Catalano, Majo, Costa, Gramegna, Lucca, Parisi, Saba, Tiddens and Morana.)

Background: Children's interstitial lung disease (chILD) is a rare group of pediatric lung diseases affecting the lung interstitium diffusely. In this work, we focused our attention on a specific infant group of chILD, also known as "specific conditions of undefined aetiology", including pulmonary interstitial glycogenosis (PIG) and neuroendocrine cell hyperplasia of infancy (NEHI)., Methods: PubMed was searched to conduct this narrative review. We searched for articles in English using the following keywords: (1) neuroendocrine cell hyperplasia of infancy; (2) NEHI; (3) pulmonary interstitial glycogenosis; (4) PIG; (5) chILD., Results: An increasing interest and insight into these two conditions have been reported. The updated literature suggests that it is possible to look at these disorders as a continuum of diseases, rather than two different entities, since they share a pulmonary dysmaturity., Conclusions: NEHI and PIG are featured by dysmaturity of airway development and consequent respiratory distress. Understanding the underlying pathogenic mechanisms would lead to identifying new targeted therapies to ameliorate the mortality and morbidity of these rare conditions.

Background: The COVID-19 pandemic has dramatically affected the global epidemiology of other infectious respiratory diseases, leading to a significant decrease in their incidence. Hence, we aimed to characterize the epidemiology of RSV-bronchiolitis in children. Methods: children aged ≤2 years diagnosed with RSV-mediated bronchiolitis admitted to our Unit from October 2018 to December 2021, were retrospectively enrolled. Results: We included 95 patients (M/F = 46/49; mean age 7.56 ± 6.6 months). Specifically, 17 infants in 2018, 34 in 2019, 0 during 2020 lockdown, 1 during 2020 post-lockdown, and 43 in 2021. Incidence was significantly lower in 2020 compared with 2018, 2019 and 2021 (p < 0.05). No differences were found concerning need for respiratory support. Discussion: Several factors related to SARS-CoV-2 pandemic, especially restrictive measures, may have contributed to a significant reduction in hospitalizations due to RSV. The new outbreak in RSV infection-related hospitalizations reported between October and December 2021 has been suggested it may be due to an increased number of susceptible individuals to RSV infection. Conclusion: The experience of the SARS-CoV-2 outbreak has led to a marked decrease in other viral respiratory infections, such as RSV. This may pave the way for new approaches in preventing respiratory infections, highlighting the role of preventive measures., Competing Interests: The authors declare no conflicts of interest.

Background Cystic fibrosis related diabetes is a complication of cystic fibrosis (CF). Aim of our study was to evaluate the effects of insulin therapy in overt diabetics or pre-diabetics CF patients on BMI and respiratory function.  Methods  We selected a sample of 17 insulin treated patients (Group T) and a sample of 17 CF control patients  with normal glucose metabolism (Group C). Group T was also subdivided into overt diabetic patients and pre-diabetic patients (IGT, INDET). For  treated patients an observation period was established from the first insulin administration to 12 months. For control patients, a comparable year of observation was chosen. Data regarding BMI, FVC, FEV1 and PEF were collected at time 0, and at time 12. The number of hospital admissions for infectious episodes during the year of observation and during the preceding year were recorded for  Group T patients. Results The results showed a significant increase in BMI in treated patients compared to control, specially for overt diabetics. The study of spirometric parameters showed a significant improvement of PEF, the main effort-dependent respiratory index, specially for over diabetics, suggesting a hypothetical positive impact of the insulin anabolic action on the magnitude of expiratory effort. In contrast, the study of infectious episodes revealed a significant reduction of hospital admissions in pre diabetic treated patients.  Conclusion Overall, our study focuses on the importance of glycemic monitoring during the early stages of CF disease and on the advantage of insulin treatment in the early stages of glucose alteration .

Background: Dornase alfa (DNase) is the only mucus-degrading agent that has proven efficacy in cystic fibrosis (CF). Few studies have evaluated the effects of DNase on the lung clearance index (LCI). We report the experience of two CF centers in which LCI monitoring was used to evaluate the efficacy of DNase therapy., Methods: This is a prospective and observational study, evaluating the effects of DNase therapy on LCI values in three CF children followed at CF centers in Florence and Catania, Italy. In both centers, LCI was performed routinely, every 3-6 months, based on the clinical picture and severity of the lung disease. In this study, we evaluated the LCI before and after long-term DNase therapy., Results: DNase improved LCI values in the absence of respiratory exacerbations: in case n. 1 LCI decreased by 39% in 16 months (from 11.1 to 6.8); in case n. 2 by 20% in 12 months (from 9.3 to 7.4); in case n. 3 by 24% in 16 months (from 9.3 to 7.0)., Conclusions: This case series confirms the efficacy of DNase therapy in CF children, as demonstrated by the LCI reduction in treated patients. Furthermore, our results suggest that LCI is a sensitive marker of disease and can be used for the evaluation of response to treatment.

Chronic rhinosinusitis (CRS) is defined as an inflammatory disorder of the paranasal sinuses and of the nasal mucosa that lasts 12 weeks or longer. In CRS microbes contribute to the disease pathogenesis. Clinical microbiology is focused on finding single pathogens that causes the disease and the main goal is the use of antibiotics to kill bacteria. Efforts to achieve a better understanding of CRS include the study of the sinus microbiome, and to evaluate the ability of probiotics to augment homeostasis and modulate the immune response of the host mucosa. This review provides an update on the role of the microbiome in CRS. The study was conducted using two databases: PubMed and Science Direct. We searched for articles in English that matched the review topic. We first used the abstracts of articles to assess whether they met the inclusion criteria. We also reviewed the references of the selected articles and read those with titles that might be of interest. Several studies have shown that endogenous microbiome dysbiosis can impact mucosa health and disease severity. Some bacterial species presenting protective or pathogenic effect. Antimicrobial agents can create a similar disruption and impact the nasal microbiome balance. On the other hand, probiotics offers a promising avenue for developing systemic and topical therapies geared towards strategic manipulation of the biological host load, thereby augmenting immune homeostasis. A better comprehension of sinus-nasal microbiome in healthy and in CRS patients and the link with different CRS phenotype can help in developing new prognostics, diagnostics, and therapeutics strategies. Going forward, the use of probiotics can restore the native sinus ecology with significant therapeutic and preventive implications.

Nutrition has a central role in child growth with long-term effects, and nutrition management in gastrointestinal disorders has great importance for child health and disease outcomes. Breast milk is the first choice for infant nutrition. When it is not available, special milk formulas are adopted in specific conditions, as a medical treatment. Moving from the strong guidelines, recommendations and the new possibilities of special diet treatment, this review will analyse the current diet treatment in different gastrointestinal disorders, including food allergy, cystic fibrosis, inflammatory bowel diseases, short-bowel syndrome, gastroesophageal reflux, and eosinophilic esophagitis. The review also aimed at understanding the role of diet and its effects on these diseases. The growth monitoring can prevent malnutrition and improve disease outcomes, particularly in children, and an appropriate dietary management targeted to specific disorders is the best therapeutic choice alone or in combination with pharmacological therapy., (© 2022. The Author(s).)

There is substantial evidence in the literature that patients with cystic fibrosis (CF) have higher oxidative stress than patients with other diseases or healthy subjects. This results in an increase in reactive oxygen species (ROS) and in a deficit of antioxidant molecules and plays a fundamental role in the progression of chronic lung damage. Although it is known that recurrent infection-inflammation cycles in CF patients generate a highly oxidative environment, numerous clinical and preclinical studies suggest that the airways of a patient with CF present an inherently abnormal proinflammatory milieu due to elevated oxidative stress and abnormal lipid metabolism even before they become infected. This could be directly related to cystic fibrosis transmembrane conductance regulator (CFTR) deficiency, which appears to produce a redox imbalance in epithelial cells and extracellular fluids. This review aims to summarize the main mechanism by which CFTR deficiency is intrinsically responsible for the proinflammatory environment that characterizes the lung of a patient with CF.

Background: H1-antihistamines (H1AH) represent the current mainstay of treatment for chronic spontaneous urticaria (CSU). However, the response to H1AH is often unsatisfactory, even with increased doses. Therefore, guidelines recommend the use of omalizumab as an add-on treatment in refractory CSU. This paved the way for the investigation of targeted therapies, such as monoclonal antibodies (mAbs), in CSU. Methods: A literature review was conducted including papers published between 2009 and 2022 and ongoing trials about the efficacy and safety of mAbs as treatment for CSU. Results: Twenty-nine articles, a trial with preliminary results, and seventeen ongoing or completed clinical trials on the use of mAbs in CSU were included. Randomized controlled trials (RCTs), meta-analysis, and real-life studies have proven the effectiveness and safety of omalizumab as a third-line treatment in refractory CSU. However, a percentage of patients remain unresponsive to omalizumab. Therefore, other mAbs, targeting different pathways, have been used off-label in case series and others are under investigation in RCTs. Most of them have showed promising results. Conclusions: Omalizumab remains the best choice to treat refractory CSU. Although results from other mAbs seem to be encouraging to achieve symptom control in refractory CSU, thus improving patients' QoL, RCTs are needed to confirm their effectiveness and safety.

Background: Aspergillus fumigatus is a common saprophytic fungus causing allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis (CF). The recommended first-line treatment for ABPA is oral steroids, followed by antifungal therapy. However, both treatments are not free from adverse effects; thus, efforts are being made to identify new drugs showing the same effectiveness but with fewer or no side-effects. Therein, biologic drugs have been significantly implemented in clinical practice in treating ABPA in patients with CF., Objective: To systematically review the available literature, providing evidence for the administration of biologic drugs as a new potential treatment of ABPA in both the paediatric and adult populations with CF., Methods: A systematic review of the literature published between January 2007 and July 2021 was performed, using a protocol registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42021270932)., Results: A total of 21 studies focusing on the use of biologics in treating ABPA in CF patients was included. We highlighted a paucity of data providing evidence for biologic drug use in ABPA., Conclusion: Scientific evidence is insufficient to support firm conclusions and randomised clinical trials are urgently required to investigate the efficacy and safety of biologics for ABPA in CF patients., Competing Interests: Conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright ©The authors 2022.)

Background and aim Recurrent wheezing is often triggered by viral respiratory infections. The aims of our study were: i) to evaluate whether the addition of a nutraceutical (Leucodif®), could improve the efficacy of montelukast or inhaled steroids (ICS) compared to the single treatment; ii) to verify whether a treatment is more effective than another. Our study was biased by the COVID-19 pandemic, which resulted in a lockdown of almost two months in Italy. Methods The multicenter, open-label study enrolled 84 children aged 2-6 years diagnosed with recurrent wheezing and randomized them into four treatment arms for three months: ICS treatment; ii) montelukast; iii) montelukast + Leucodif; iv) ICS + Leucodif. Children were assessed at baseline and after one, two, and three months of treatment using the TRACK score for both the caregiver and the physician. Results Out of the 84 patients, 18 patients received ICS therapy, 22 patients ICS + Leucodif, 24 patients montelukast, and 20 patients montelukast + Leucodif. All four treatments resulted in a significant reduction in symptoms with no differences among the various groups. Conclusions Our study demonstrates that montelukast therapy appears to be equally effective as ICS therapy and that the addition of the nutraceutical Leucodif does not appear to improve the treatment outcome. However, in our opinion our study was strongly influenced and biased by the lockdown due to the COVID-19 pandemic, which inherently resulted in reduced exposure to the viruses that commonly cause respiratory infections in children.

Background: Few studies have been conducted on the short-term response to sublingual immunotherapy (SLIT)., Objective: The purpose of our experimental trial was to evaluate if two markers such as nasal nitric oxide (nNO) and nasal cytology could be useful to identify a precocious clinical efficacy of SLIT treatment., Methods: We enrolled 34 children aged 6 to 14 years old with diagnosis of allergic rhinitis (AR) and documented sensitization towards house dust mites. We started allergoid-monomeric tablets immunotherapy along with any conventional therapy for AR and we evaluated at baseline (T0), after one (T1), two (T2), three (T3), and six months (T6) the effects of the treatment through the study of: i) a visual analogue scale (VAS 1-10); ii) measurement of nNO; iii) measurement of FeNO; iv) nasal cytology; v) spirometry; and vi) evaluation of any conventional therapy., Results: We observed an improvement in symptoms evaluated by global VAS (T0 vs. T6: 47.13 vs. 17.57; p < .05) and a statistically significant reduction of nNO (1035.2 ± 956.08 vs. 139.2 ± 59.01; p < .05). In this case, significance was reached when the patients completed the 6 months of treatment. Cytological evaluation revealed significant reduction in nasal eosinophils (T0 vs. T6: 87% vs. 16%; p < .01). Moreover, at T0, 56% of patients had also neutrophils that were reduced up to the 8% at T6 (p < .05)., Conclusions: Our data confirm the effectiveness of SLIT treatment from a clinical perspective and identifies two biomarkers, such as nNO and nasal cytology, as predictive of treatment efficacy in the short term.

Objective: Imaging represents an important noninvasive means to assess cystic fibrosis (CF) lung disease, which remains the main cause of morbidity and mortality in CF patients. While the development of new imaging techniques has revolutionised clinical practice, advances have posed diagnostic and monitoring challenges. The authors aim to summarise these challenges and make evidence-based recommendations regarding imaging assessment for both clinicians and radiologists., Study Design: A committee of 21 experts in CF from the 10 largest specialist centres in Italy was convened, including a radiologist and a pulmonologist from each centre, with the overall aim of developing clear and actionable recommendations for lung imaging in CF. An a priori threshold of at least 80% of the votes was required for acceptance of each statement of recommendation., Results: After a systematic review of the relevant literature, the committee convened to evaluate 167 articles. Following five RAND conferences, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 28 main statements., Conclusions: There is a need for international guidelines regarding the appropriate timing and selection of imaging modality for patients with CF lung disease; timing and selection depends upon the clinical scenario, the patient's age, lung function and type of treatment. Despite its ubiquity, the use of the chest radiograph remains controversial. Both computed tomography and magnetic resonance imaging should be routinely used to monitor CF lung disease. Future studies should focus on imaging protocol harmonisation both for computed tomography and for magnetic resonance imaging. The introduction of artificial intelligence imaging analysis may further revolutionise clinical practice by providing fast and reliable quantitative outcomes to assess disease status. To date, there is no evidence supporting the use of lung ultrasound to monitor CF lung disease., Competing Interests: Conflict of interest: P. Ciet reports personal fees from Editamed, during the conduct of the study. S. Bertolo reports personal fees from Vertex pharmaceuticals, outside the submitted work. M. Ros reports personal fees from Vertex Pharmaceuticals, personal fees from Chiesi Farmaceutici, outside the submitted work. R. Casciaro has nothing to disclose. M. Cipolli has nothing to disclose. S. Colagrande reports that during the last 5 years, he has had and has various projects in place that have involved remuneration, which has always been devolved to the SBSC department for which Prof. Colagrande works. This refers to experimental/conventional activities for which it has received compensation. Nothing has ever been personally perceived by Prof. Colagrande and all the part destined to the university was conferred to the department. The companies involved were Novartis, Sanofi, Lilly, Celther, Pfizer, Janssen, etc. All the fees have been paid following the signing of a contract among the company, the university and the Hospital. S. Costa has nothing to disclose. V. Galici has nothing to disclose. A. Gramegna has nothing to disclose. C. Lanza has nothing to disclose. F. Lucca has nothing to disclose. L. Macconi has nothing to disclose. F. Majo has nothing to disclose. A. Paciaroni has nothing to disclose. G.F. Parisi has nothing to disclose. F. Rizzo has nothing to disclose. I. Salamone has nothing to disclose. T. Santangelo has nothing to disclose. L. Scudeller has nothing to disclose. L. Saba has nothing to disclose. P. Tomà has nothing to disclose. G. Morana has nothing to disclose., (Copyright ©The authors 2022.)

Background: The role of allergic sensitization seems to be protective against SARS CoV2 infection. The aim of this study was to evaluate, using online surveys, the impact of COVID-19 on Italian allergic children, comparing the prevalence of AR and asthma symptoms between the first and second pandemic wave., Methods: Both surveys were emailed to Italian pediatricians in April 2020 (first survey) and in March 2021 (second survey). The first one was related to the impact of COVID-19 and the most frequently reported symptoms. The second one was superimposed on the previous one, taking into account some additional aspects in the management of disease., Results: A total of 99 pediatricians participated in the first survey and 267 in the second one. The first survey showed that, asthma and allergic rhinoconjunctivitis prevalence was mostly between 0 and 20% throughout the country. The second survey showed a lower prevalence of both diseases nationwide in comparison to the first one. Comparing the two surveys, statistically significant differences were reported only in the distribution of asthma prevalence in Southern Italy while no differences were highlighted in the North and in the Center. Finally regarding allergic rhinoconjunctivitis prevalence, no differences were noticed nationwide., Conclusions: Allergic rhinoconjunctivitis and asthma, if under control, did not represent risk factors for the susceptibility to SARS CoV2. Therefore, it is strongly recommended to continue therapies during COVID-19 outbreak, according to the international guidelines. However, being COVID-19 a new disease, actual knowledge will undergo continuous improvements over time., (© 2022. The Author(s).)

Recently, type 2 inflammation has been recognized as one of the most critical factors participating in the pathogenesis of cystic fibrosis (CF). On the one hand, type 2 inflammation restores tissue homeostasis and contributes to the resolution of inflammation following an injury. On the other hand, type 2 response-activated immune cells may become dysregulated or chronically activated, causing tissue fibrosis. Among the type 2 cytokine-driven inflammatory pathways, the transforming growth factor β (TGFβ), interleukin (IL)-17, IL-33, and IL-13 have been identified as essential mediators in patients suffering from CF. Given their critical role, we firmly believe that an adequate comprehension of the type 2-mediated pathways can identify attractive targets to decrease pharmacologically the inflammation and fibrosis occurring in the pulmonary tissue of patients suffering from CF., (© 2022 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

More than a year and a half after the beginning of the coronavirus disease 2019 (COVID-19) pandemic, symptoms, such as loss of smell and taste (anosmia and ageusia, respectively), remain difficult to characterize and quantify, especially in children, since no validated tests to assess these disorders are available. However, these symptoms can also be seen in children, although less frequently than observed in the adult population. In this article, we present the results of a national survey that collected the responses of 267 Italian pediatricians on the presence of anosmia and ageusia in children affected by COVID-19. These data were then compared with existing literature., (© 2022 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Multiple properties of lactoferrin have been reported in the literature so far. Decades of in vitro and in vivo studies have demonstrated the important antimicrobial, anti-inflammatory, anti-oxidant, and immunomodulating properties. It suggests the use of lactoferrin as an effective and safe option for the treatment of several common disorders. Herein, we show the applications of lactoferrin in clinical practice, highlighting its evidence-based capacities for the treatment of heterogeneous disorders, such as allergic, gastrointestinal, and respiratory diseases, and hematologic, oncologic, gynecologic, dermatologic, and dental disorders. Moreover, the widespread use of lactoferrin in neonatology is summarized here. As a result of its antiviral properties, lactoferrin has also been proposed as a valid option for the treatment for COVID-19 patients. Here, the uses of lactoferrin in clinical practice as a new, safe, and evidence-based treatment for many types of disorders are summarized.

Vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) are potentially severe and complex disease in its management among the various allergic eye diseases. In this regard, studies clarified the etiopathogenetic mechanisms. The workup should be multidisciplinary. The treatment includes topical and systemic medications with anti-inflammatory and immunosuppressant activity. However, a definition of nationally- and internationally-shared diagnostic protocols would also be needed and validated access to therapeutic options of proven safety and efficacy to avoid the use of galenic preparations, up to now still essential in the management of moderate-severe VKC. Finally, recognizing VKC and AKC, among rare diseases, at a national and international level would be an essential step to allow the management of VKC with adequate timings and settings within the National Health System.

Introduction: Although the long term negative effects of bronchopulmonary dysplasia (BPD) are well known, follow-up studies of preterm infants with BPD into childhood are lacking., Methods: Forty-two preschool children (age range 3-6 years) who were born before 32 weeks of gestational age and affected by BPD were enrolled. Pre-, peri-, and post-natal data were collected. During the follow up appointment complete physical examination and lung function (impulse oscillometry (IOS)) were recorded. The European Community Respiratory Health Survey (ECRHS) questionnaire was administered to all enrolled subjects., Results: Thirty patients were included in the final analysis. The BPD group did not differ in comparison to the non-BPD group in terms of lung function ( p  > 0.05). By comparing all subjects enrolled, We detected extremely low-birth-weight (ELBW) infants with height-, weight-, and gender-related reference values and a significant trend of increasing resistance values (R5Hz, R5-20 Hz) and respiratory impedance (Z5Hz) ( p  < 0.05). No significant difference in bronchial reversibility test was observed among BPD non-BPD groups ( p  < 0.05). The frequency of gastroesophageal reflux disease was significantly higher in patients with BPD when compared to non-BPD group ( p  < 0.05). Significant differences in gestational age, oxygen supplementation (days), mechanical ventilation therapy (days), and sepsis between BPD and non-BPD groups were also observed ( p  < 0.05). There were no significant differences in the prevalence of family and personal history of atopy and/or allergic diseases, tobacco exposure, respiratory symptoms, respiratory syncytial virus bronchiolitis, exercise induced dyspnea, treatment with ß-2 bronchodilators and inhaled corticosteroids among the groups ( p  > 0.05)., Conclusions: The respiratory function in preschool children born with ELBW is characterized by an increase in impedance and resistance of small airways. No statistically significant differences were found between ELBW children with BPD and without BPD. With regards to the smallest gestational age, the longer duration of O 2 therapy during hospitalization, and sepsis significantly resulted in a worse respiratory function.

The persistence of symptoms after recovery from Coronavirus 2019 (COVID-19) is defined as long COVID, an entity that had occurred among adults but which is not yet well characterized in pediatric ages. The purpose of this work was to present some of the data from a survey addressed to Italian pediatricians concerning the impact of long-COVID among children who recovered from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The questionnaire was designed and pre-tested in February 2021 by a working group of experts from the Italian Pediatric Society for Allergy and Immunology (SIAIP). The survey was emailed once in March 2021 to a sample of Italian pediatricians. A total 267 Italian pediatricians participated in our survey. According to most pediatricians (97.3%), the persistence of symptoms is found in less than 20% of children. Specifically, with regard to the symptoms that persist even after swab negativization, fatigue was the most mentioned one (75.6%). Long-COVID would seem to be a phenomenon of limited occurrence in pediatric ages, affecting less than 20% of children. Among all of the symptoms, the one that was most prevalent was fatigue, a pathological entity that is associated with many viral diseases.

Food allergy (FA) is a pathological immune response, potentially deadly, induced by exposure to an innocuous and specific food allergen. To date, there is no specific treatment for FAs; thus, dietary avoidance and symptomatic medications represent the standard treatment for managing them. Recently, several therapeutic strategies for FAs, such as sublingual and epicutaneous immunotherapy and monoclonal antibodies, have shown long-term safety and benefits in clinical practice. This review summarizes the current evidence on changes in treating FA, focusing on monoclonal antibodies, which have recently provided encouraging data as therapeutic weapons modifying the disease course.

In recent years, there has been a growth in scientific interest in nutraceuticals, which are those nutrients in foods that have beneficial effects on health. Nutraceuticals can be extracted, used for food supplements, or added to foods. There has long been interest in the antiviral properties of nutraceuticals, which are especially topical in the context of the ongoing COVID-19 pandemic. Therefore, the purpose of this review is to evaluate the main nutraceuticals to which antiviral roles have been attributed (either by direct action on viruses or by modulating the immune system), with a focus on the pediatric population. Furthermore, the possible applications of these substances against SARS-CoV-2 will be considered.

COVID-19 is less serious in children than in adults. However, respiratory management dominates the clinical picture of hospitalized COVID-19 even in children. In some case series, deterioration of the clinical picture wherein dyspnea, cyanosis, and the onset of acute respiratory distress syndrome (ARDS) emerged ~8-10 days after the onset of SARS-CoV-2 infection, which could rapidly progress to multiple organ failure and death. This review aimed to evaluate the characteristics of COVID-19 pneumonia in pediatric populations, beginning from its etiology and pathological mechanisms and closing with its clinical management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Parisi, Indolfi, Decimo, Leonardi and Miraglia del Giudice.)

Introduction: Childhood cancer survivors (CSs) might face an increased lifelong risk of lung function impairment. The lung clearance index (LCI) has been described as being more sensitive than spirometry in the early stages of some lung diseases. The aim of this study was to evaluate this index in a cohort of patients with a history of childhood cancer for the first time., Materials and Methods: We evaluated 57 off-treatment CSs aged 0-18 years old and 50 healthy controls (HCs). We used the multiple-breath washout method to study LCI and spirometry., Results: CSs did not show any differences from the controls in ventilation homogeneity (LCI 6.78 ± 1.35 vs. 6.32 ± 0.44; p: not significant [ns]) or lung function (FEV1 99.9 ± 11.3% vs. 103.0 ± 5.9% of predicted; p: ns; FVC 98.2 ± 10.3% vs. 101.1 ± 3.3% of predicted). LCI significantly correlated with the number of years since the last chemotherapy (r = .35, p < .05)., Conclusions: Our study describes the trend of LCI in a cohort of CSs and compares it with the results obtained from HCs. The results show that patients maintain both good values of respiratory function and good homogeneity of ventilation during childhood. Moreover, as LCI increases and worsens as the years pass after the end of the treatment could identify the tendency toward pulmonary fibrosis, which is typical of adult CSs, at an earlier time than spirometry., (© 2020 Wiley Periodicals LLC.)

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder in cystic fibrosis (CF), and based on various studies, its prevalence is elevated since childhood. There are several pathogenetic mechanisms on the basis of association between CF and GERD. However, there are no specific guidelines for GERD in CF patients, so diagnosis is based on guidelines performed on patients not affected by CF. The aim of this review is to provide the pathophysiology, diagnostic and therapeutic options, complications, and future directions in the management of GERD patients with CF., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to disclose that could be perceived as prejudicing the impartiality of the research reported., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disease caused by Aspergillus induced hypersensitivity that occurs in immunocompetent but susceptible patients with asthma and/or cystic fibrosis (CF). In children, ABPA remains mostly undiagnosed resulting in one of the most common causes of poorly controlled asthma and highly significant morbidity in children with CF. Currently, no specific diagnostic criteria of ABPA for children are available. Corticosteroids and itraconazole are the mainstays of therapy although there is a lack of randomized clinical trials regarding their usefulness for ABPA in children. Several monoclonal antibodies, such as omalizumab and mepolizumab, may be potential therapies for refractory ABPA in pediatric patients; however, further data are required to clarify the optimal dose and duration of therapy as a routine treatment approach., (© 2020 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Histamine is a chemical mediator, released predominantly by tissue mast cells, circulating basophils, and neurons, which are activated in response to various immunological and non-immunological stimuli. Histamine has to bind to specific receptors to exert its physiological and pathophysiological functions. Endogenous histamine is the main mediator of the immediate allergic response, which moreover, performs other multiple functions, including regulation of gastric secretion, neurotransmission in the central nervous system, and immunomodulatory activity. The involvement of histamine in various disorders and the importance of receptors in the clinical features have relevant implications in clinical practice. Anti-H1 antihistamines contrast the histamine-dependent effects, mainly concerning nasal symptoms and cutaneous itching and wheal. Antihistamines are among the most prescribed drugs in pediatric care. This review updates the practical use of antihistamines in children and adolescents., (Copyright © 2020 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

The clinical spectrum of SARS-CoV-2 infection is mixed. It ranges from asymptomatic cases, medium-intensity forms with mild to moderate symptoms, to severe ones with bilateral lung involvement and respiratory distress, which can require transfer to ICUs and intubation. In most cases, the clinical picture is characterized by a persistent fever, cough, dyspnoea, expectoration, myalgias, arthralgias, headache, gastrointestinal symptoms, nasal congestion, and pharyngodynia. The spread of COVID-19 in Europe has highlighted an atypical presentation of disease involving upper airways and, above all, dysfunction of olfactory and gustatory senses. There is ample evidence that COVID-19 is significantly less severe in children than in adults. However, due to difficulties in assessing the disorder in children, especially among very young patients, the olfaction and gustatory dysfunctions remain open issues. This article sheds light on the upper airway involvement in pediatric COVID-19 subjects., (© 2020 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: There is ample evidence that COVID-19 is significantly less severe in children than in adults and asthma and allergy, the most common chronic disorders in children, are not included in the top 10 comorbidities related to COVID-19 fatalities. Nevertheless, concerns about asthma and allergy are still high.. In order to evaluate the impact of paediatric COVID-19 among Italian paediatricians, we sent a 20-questions anonymous internet-based survey to 250 Italian paediatricians with particular address to allergic symptoms and those affecting the upper airways., Methods: The questionnaire was conceived and pretested in April 2020, by a working group of experts of the Italian Paediatric Society for Allergy and Immunology (SIAIP), and structured into different sections of 20 categorized and multiple choice questions. The first part included questions about epidemiological data follows by a second part assessing the way to manage a suspected COVID-19 infection and personal experiences about that. The third part concerned questions about patients' clinical characteristics and clinical manifestations. The survey was emailed once between April and mid-May 2020., Results: A total 99 participants had participated in our survey and provided responses to our electronic questionnaire. The distribution of patients reported per month varies significantly according to the geographical area (P = 0.02). Data confirmed that in the North part of Italy the rate of patients referred is higher than in the rest of Italy. Almost all respondents (98%) reported caring for up to a maximum of 10 infected children and the last 2% more than twenty. Among these patients, according to the 75% of responders, a maximum rate of 20% were affected by allergic rhino-conjunctivitis and in particular in the North of Italy while in the Centre and in the South there was a higher incidence (P = 0.09). Almost the same applies for asthma, 83% of responders declared that up to a maximum of 20% of affected children were asthmatic, from 20 to 40% for the 13,5% of responders and from 40 to 60% for the last 3,5%. As for the allergic conjunctivitis also for asthma, we found a higher incidence in the Centre and in South than in the North (P = 0.03)., Conclusions: This study is the first to provide a comprehensive review of COVID-19 knowledge and impact among paediatricians in Italy about allergic asthma and upper airway involvement. From our point of view, it provides important information clearly useful for improving a good practice.

The rising incidence of allergic disease requires more specific, effective and safe therapeutic strategies. In this regard, several kinds of biologically active substances, commonly known as immunostimulants, have been introduced for the prevention and treatment of allergic diseases in pediatric population. Among the heterogeneous group of biologically active molecules to date available, pidotimod (Axil, Valeas S.p.A, Milan) is proved to be able to ameliorate both innate and adaptive immunity and enhances the immune system properties often impaired in patients with allergic disorders.

Background: Despite to PFAPA syndrome is considered a benign and self-limited condition in childhood its impact on patients and families can be remarkable in many cases. Currently, the therapeutic options for managing are non-specific and no consensus exists about the best treatment to use. Pidotimod has been suggested as a new potential treatment in PFAPA syndrome for its immunodulatory effects. We conducted a preliminary, prospective, controlled, open, cross-over trial to assess the efficacy and the safety of Pidotimod in the treatment of children with PFAPA syndrome., Methods: 22 children with PFAPA syndrome were randomly allocated to treatment with pidotimod (with 2 vials of 400 mg daily) in combination with betamethasone 0.5-1 mg on need, based on parents/caregivers' decision (group A) or betamethasone 0.5-1 mg on need, based on parents/caregivers' decision (group B). Each treatment period was for 3 months (Phase 1), after that patients were switched to the other arm for other 3 months (Phase 2). Efficacy was expressed in terms of number of episodes of fever, pharyngitis, or aphthous stomatitis, as well as the additional use of betamethasone on need. Safety and tolerability of the Pidotimod were evaluated on the basis of the number and type of adverse events (AEs) recorded during the treatment., Results: Patients receiving Pidotimod and use betametasone showed a significant decrease in frequency of fevers (p = 0.002); number of episodes of pharyngitis (p = 0.049); aphthous stomatitis (p = 0.036) as well as the betamethasone use on need (p = 0.007). Overall, 19/22 (86.4%) showed benefits from Pidotimod administration. The safety profile of Pidotimod was excellent as no serious adverse events have been reported in the treated groups., Conclusions: We firstly showed that high dosage of Pidotimod could be an effective and safe to reduce the PFAPA attacks in children.

Background: Recurrent respiratory infections (RRIs) are defined by the presence of at least one of the following criteria: (i) > 6 annual respiratory infections (RIs); (ii) > 1 monthly RIs involving the upper airways from September to April; (iii) > 3 annual RIs involving the lower airways represent a very common health problem in the first years of life. We conducted a multi-centre, prospective, single-open study to assess the efficacy and the safety of Streptococcus salivarius 24SMBc and Streptococcus oralis 89a in the prevention of upper respiratory tract infections (URTIs) in children., Methods: Ninety-one children (M:F = 47:44, mean age 7.4 ± 2.3 years) with RRIs were enrolled in the study between September and November 2018. At baseline, children received Streptococcus salivarius 24SMBc and Streptococcus oralis 89a as 2 puffs for nostril twice/day for 7 days/months. The treatment lasted for 3 consecutive months. Efficacy was expressed in terms of absence or presence of fever, cough, bronchospasm, rhinorrhea and otalgia, at 1 month (T1), and 3 (T3) months. Safety and tolerability of the probiotic were evaluated on the basis of the number and type of adverse events (AEs) recorded during the treatment., Results: Children treated with Streptococcus salivarius 24SMBc and Streptococcus oralis 89a showed a significant decrease of symptoms including episodes of fever, cough, bronchospasm, rhinorrhea, and otalgia (p < 0.001) compared to baseline. The treatment significantly reduced the number of episodes of fever, cough, bronchospasm, rhinorrhea, otalgia, and cough also in patients with positive familial history for atopy and in atopic children (p < 0.05). No significant differences in symptoms among children with negative familial history for atopy and children with positive familial history for atopy subgroups, not atopic and atopic children subgroups, and smoke-exposed and not smoke-exposed subgroups were observed (p > 0.05). Conducting a subgroup analysis according to the age, it has been reported that children aged 1-3 years old showed an improvement in all symptoms, however, they become statistically significant only at the end of the 3 months of treatment (p < 0.05). Conversely, in children aged 3-6 and 6-12 years old, the therapeutic efficacy was progressive and significant already from the first month of therapy (p < 0.05). None of the children were withdrawn from the study because of AEs, although 9 children experienced burning nose leading to interruption of therapy., Conclusions: Our findings suggest that Streptococcus salivarius 24SMBc and Streptococcus oralis 89a treatment is safe and seems to be effective on short-term in the treatment of RRIs. Studies involving a longer observation period are necessary to establish the real efficacy of the product for the treatment of pediatric patients affected by RRIs.