An updated reappraisal of dupilumab in children and adolescents with moderate-severe atopic dermatitis.

Atopic dermatitis (AD) is still a demanding challenge in clinical practice. Type 2 inflammation is the most common inflammatory pathway in children and adolescents with AD. Anti-inflammatory drugs, mainly corticosteroids (CS) and immunomodulant agents are the primary therapeutic approach to dampening type 2 inflammation. However, AD patients may require long-term high CS doses or drug combinations with possibly significant adverse effects to achieve and maintain disease control. In this regard, the advent of biologics constituted a breakthrough in managing this condition. Dupilumab is a monoclonal antibody directed against the IL-4 receptor α-subunit (IL-4Rα), antagonizing both IL-4 and IL-13 and is approved for pediatric severe AD. This review presents and discusses the most recent published studies on dupilumab in children and adolescents with AD. There is convincing evidence that dupilumab is safe and effective in managing AD. It can reduce skin lesions and associated itching, reduce the need for additional medications, and improve disease control and quality of life. However, a thorough diagnostic pathway is mandatory, especially considering the different AD phenotypes. The ideal eligible candidate is a child or adolescent with AD requiring systemic treatment because of severe clinical manifestations and impaired quality of life.

Tablet allergen immunotherapy: the anaphylaxis issue.

For the first time 15 years ago, tablet allergen immunotherapy (T-AIT) formulations were approved by regulatory agencies for treating allergic rhinitis caused by grass pollen in adults and children aged >5 years. Extensive evidences existed about effectiveness and safety of AIT. However, the safety profile is particularly compelling in children. Generally, T-AIT causes local reactions, mostly in the oral cavity, that are usually mild-to-moderate and often self-resolving. However, systemic allergic reactions are also observed with T-AIT, anaphylaxis representing the most fearsome adverse event, considering that it occurs in subjects treated for allergic rhinitis. Therefore, we conducted a literature search of patients reporting anaphylaxis because of T-AIT. Nine cases of anaphylactic reactions were reported in literature. Notably, no death was reported using T-AIT. This outcome was very important as it underscored the substantial safety of T-AIT. However, T-AIT deserves careful attention, mainly in the pediatric population. In this regard, after the first report of anaphylactic reaction at the first administration of T-AIT, manufacturers recommended that the first dose should be administered in a medical facility in the presence of staff with experience in managing anaphylaxis and the patient should be observed for at least 30 min. Interestingly, reported anaphylactic reactions were due to grass pollen extracts, with no report concerning other allergen extracts. However, it is relevant to note that anaphylactic reactions because of T-AIT are not reported in recent years.

Managing children with frequent respiratory infections and associated wheezing: a preliminary randomized study with a new multicomponent nasal spray.

BACKGROUND: Preschoolers frequently have respiratory infections (RIs), which may cause wheezing in some subjects. Type 2 polarization may favor increased susceptibility to RIs and associated wheezing. Non-pharmacological remedies are garnering increasing interest as possible add-on therapies. The present preliminary study investigated the efficacy and safety of a new multi-component nasal spray in preschoolers with frequent RIs and associated wheezing. METHODS: Some preschoolers with these characteristics randomly took this product, containing lactoferrin, dipotassium glycyrrhizinate, carboxymethyl-beta-glucan, and vitamins C and D3 (Saflovir), two sprays per nostril twice daily for 3 months. Other children were randomly treated only with standard therapy. Outcomes included the number of RIs and wheezing episodes, use of medications, and severity of clinical manifestations. RESULTS: Preschoolers treated add-on with this multicomponent product experienced fewer RIs and used fewer beta-2 agonists than untreated children (P = 0.01 and 0.029, respectively). CONCLUSIONS: This preliminary study demonstrated that a multicomponent product, administered add-on as a nasal spray, could reduce the incidence of RIs and use of symptomatic drugs for relieving wheezing in children.

Clinical use of ketoprofen lysine salt: a reappraisal in adolescents with acute respiratory infections.

Upper respiratory infections are widespread, and they are mainly of viral etiology. It has to be remarked that every infection is always associated with an inflammatory response. Inflammation implicates a cascade of bothersome symptoms, including fever, pain (headache, myalgia, and arthralgia), malaise, and respiratory complaints. As a result, anti-inflammatory medications could be beneficial as they act on different pathogenetic pathways. The ketoprofen lysine salt (KLS) has a potent anti-inflammatory activity associated with effective analgesic and antipyretic effects and has a valuable safety profile. However, adolescents present peculiar psychological characteristics that determine their difficulty to be managed. In this regard, an adolescent with a respiratory infection requires a prompt and adequate cure. KLS, thanks to its pharmacologic profile, could be favorably used in this regard. A recent primary-care experience outlined its effectiveness in this issue.

Hyperthyroidism in a 15-year-old adolescent treated with Dupilumab for severe allergic asthma and atopic dermatitis.

Dupilumab is a biologic, acting on IL-4 and IL-13 pathways. Dupilumab has a pediatric indication for treating severe asthma and atopic dermatitis. We report a pediatric case concerning paucisymptomatic, transient, and self-resolving hyperthyroidism. The updated literature includes the case of an adult patient who reported with hyperthyroidism, which was transient and self-resolving. Despite that these cases were transient and self-resolving, we would suggest that thyroid function assessment could be included in the follow-up of patients treated with Dupilumab. Dupilumab discontinuation is not required pending endocrinological assessment, mainly if there is an optimal clinical response to the biologic.

Time effect of dupilumab to treat severe uncontrolled asthma in adolescents: A pilot study.

BACKGROUND: Dupilumab is a new biological drug approved for the treatment of type 2 inflammatory diseases, such as asthma. Dupilumab is a fully humanized monoclonal antibody that acts against both interleukin-4 and interleukin-13 receptors. This study evaluated the time--dependent effect of dupilumab on asthma exacerbations and quality of life in adolescents with uncontrolled severe asthma. MATERIALS AND METHODS: Five adolescents suffering from uncontrolled severe asthma and treated with dupilumab were recruited. All subjects were evaluated for 4, 12, and 24 weeks after the first dose of dupilumab. Outcome measures included lung function, fractional exhaled nitric oxide, asthma control and quality of life assessed by validated questionnaires (Asthma Control Test and Asthma Control Questionnaire). RESULTS: The quality of life improved quickly after 4 weeks of treatment and 80% of adolescents halved the dose of inhaled corticosteroids necessary to control asthma symptoms. These results were still maintained for 24 weeks after start of the therapy. None of the patients had any asthma exacerbation during the study period. CONCLUSION: Results of this study demonstrated that dupilumab was quickly effective to reduce asthma exacerbation and ameliorate quality of life in severe asthmatic adolescents.

Safety of allergen-specific immunotherapy in children.

Allergic respiratory diseases, such as asthma and allergic rhinitis, are global health issues and have had an increasing prevalence in the last decades. Allergen-specific immunotherapy (AIT) is the only curative treatment for allergic rhinitis and asthma, as it has a disease-modifying effect. AIT is generally administered by two routes: subcutaneous (SCIT) and sublingual immunotherapy (SLIT). Local side effects are common, but usually well-tolerated and self-limited. However, systemic side effects are rare, and associated with uncontrolled asthma and bronchial obstruction, or related to errors in administration. Physicians should constantly assess potential risk factors for not only reporting systemic reactions and fatalities but also implementing other therapies to improve AIT safety. This paper highlights recent evidence on local and systemic reactions related to SCIT and SLIT in children.

Oral mannitol for bowel preparation: a dose-finding phase II study.

BACKGROUND: Successful bowel preparation (BP) for colonoscopy depends on the instructions, diet, the laxative product, and patient adherence, which all affect colonoscopy quality. Nevertheless, there are no laxatives which combine effectiveness, safety, easy self-administration, good patient acceptance, and low cost. However, mannitol, a sugar alcohol, could be an attractive candidate for use in clinical practice if it is shown to demonstrate adequate efficacy and safety. AIMS: The present phase II dose-finding study compared three doses of mannitol (50, 100, and 150 g) to identify the best dose to be used in a subsequent phase III study. METHODS: The Boston Bowel Preparation Scale, caecal intubation rate, adherence, acceptability, and safety profile, including measurement of potentially dangerous colonic gas concentrations (CH4, H2, O2), were considered in all patients. A weighted algorithm was used to identify the best mannitol dose for use in the subsequent study. RESULTS: The per-protocol population included 60 patients in the 50 g group, 54 in the 100 g group, and 49 in the 150 g group. The 100 g dose was the best as it afforded optimal colon cleansing efficacy (94.4% of patients had adequate BP), adherence, acceptability, and safety, including negligible gas concentrations. CONCLUSIONS: The present study demonstrated that the colon cleansing efficacy and safety of mannitol were dose dependent. Conversely, gas concentrations were not dose dependent and negligible in all patients. Combined evaluation of efficacy, tolerability, and safety, using a weighted algorithm, determined that mannitol 100 g was the best dose for the phase III study.

The role of bronchodilation testing in children and adolescents with asthma in clinical practice.

The change in forced expiratory volume in 1 s (FEV1) in response to a bronchodilator (ΔFEV1) is a diagnostic tool. Moreover, bronchodilation testing may give clinically relevant outcomes beyond diagnostic purposes. The present study aimed, therefore, to investigate the nationwide role of bronchodilation testing in daily practice. The study included 280 subjects, 202 (72.1%) males and 78 (27.9%) females; the mean age was 11.6 years. Notably, 67 (24%) children had bronchial reversibility (BDR). Age, initial FEV1, FEV1/FVC, and FVC were significantly associated with BDR (OR 1.16, 1.66, 0.71, and 0.67, respectively). Interestingly, 39 (58.2%) children with BDR had no bronchial obstruction. In conclusion, the BDR is usually associated with low values of the lung function parameters, even if within the normal ranges.

The comparison between children and adolescents with asthma provided by the real-world "ControL'Asma" study.

OBJECTIVE: Because asthma is a disease that changes over time, the Italian Society of Pediatric Allergy and Immunology launched a nationwide study on asthma control (the ControL'Asma study). The intent was to test the hypothesis that children with asthma could present a different pattern compared to adolescents. In the study, we compared children with adolescents in a real-world setting by analyzing the asthma control grade and other asthma-related parameters. METHODS: This cross-sectional real-world study included 471 asthmatic children (

Primary care experience on Stimunex® gocce in children with recurrent respiratory infections: a real-world study during the COVID-19 pandemic era.

BACKGROUND: Respiratory infections (RI) significantly burden society, mainly when there are recurrent respiratory infections (RRI). Thus, there is a need to prevent RI in clinical practice. In this regard, the modulation of the immune system and resolution of the inflammatory cascade could represent an ideal way to prevent RI. Stimunex® gocce, a multicomponent food supplement, contains Sambucus nigra extract, ß-glucan, Zinc, and Vitamin D3. This study investigated its ability to prevent RRI in children using a real-world setting: the pediatric primary care. MATERIALS AND METHODS: Two hundred and ninety-eight children with RRI were enrolled in the current study. The food supplement was randomly prescribed to 160 children with RRI daily for 4 months (Active group); the remaining 138 children with RRI were treated only with standard therapy for RI (Control group). The number and duration of RI, parental perception of symptom severity and treatment efficacy, use of medications, and school and working absence were evaluated. RESULTS: Children treated with Stimunex® gocce had significantly less RI than the Control group, both concerning upper and lower RI (p˂0.001 and 0.003, respectively) during the follow-up period. Moreover, children in the Active group experienced shorter RI duration during the treatment and follow-up phases (p˂0.001 for both). In addition, parents of treated children perceived less severe symptoms and better treatment efficacy during the first and follow-up phases (p˂0.001 for all). The food supplement was well tolerated and there was no adverse event. CONCLUSIONS: The current real-world study demonstrated that Stimunex® gocce supplementation in children with RRI might safely prevent RI episodes and reduce RI duration. These outcomes should be highlighted as obtained during the COVID-19 pandemic era, characterized by a dramatic reduction of RI.

Mometasone furoate nasal spray in Italian children with seasonal allergic rhinitis: a comprehensive assessment.

OBJECTIVE: Seasonal allergic rhinitis (SAR) is a common disease of childhood and is characterized by type 2 inflammation, bothersome symptoms, and impaired quality of life (QoL). Intranasal corticosteroids are effective medications in managing SAR. In addition, mometasone furoate nasal spray (MFNS) is a well-known therapeutic option. However, the literature provided no data about the effects of MFNS in European children with SAR. Thus, this study addressed this unmet requirement. METHODS: MFNS was compared to isotonic saline. Both treatments were prescribed: one drop of spray per nostril, twice a day, for 3 weeks. Nasal cytology, total symptom score (TSS), visual analogic scale concerning the parental perception of severity of symptoms, and the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) were assessed at baseline, after 7 and 21 days, and 1 month after discontinuation. RESULTS: MFNS significantly reduced eosinophil and mast cell counts, improved QoL, and relieved symptoms, as assessed by doctors and perceived by parents. These effects persisted over time, even after discontinuation. Both treatments were safe and well-tolerated. CONCLUSIONS: The present study documented that a 3-week MFNS treatment was able to significantly dampen type 2 inflammation, improve QoL, and reduce severity of symptoms in Italian children with SAR, and was safe.

Omalizumab and allergen immunotherapy for respiratory allergies: A mini-review from the Allergen-Immunotherapy Committee of the Italian Society of Pediatric Allergy and Immunology (SIAIP).

Although currently approved to treat severe asthma and chronic spontaneous urticaria, omalizumab has also been an effective and safe add-on treatment for other allergic diseases. Namely, omalizumab has been proposed to be used as add-on therapy in patients with allergic rhinitis and asthma and undergoing specific allergen immunotherapy (AIT). AIT is the only treatment that modifies the natural history of IgE-mediated diseases. This brief review summarizes the available evidence and controversies on the efficacy and safety of omalizumab combined with specific AIT.

Smell impairment in patients with chronic rhinosinusitis: a real-life study.

OBJECTIVE: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a frequently occurring condition involving type 2 inflammation. It has a global prevalence of approximately 4% and has a major effect on the quality of life of those affected by it. CRSwNP is a complex condition for otorhinolaryngologists to manage, since its precise pathogenic basis has not been established, treatment is challenging and the condition often recurs. It is common to find abnormalities in smelling in those with CRSwNP. MATERIALS AND METHODS: This cross-sectional study enrolled patients suffering from CRS. Three groups were compared: 1812 patients with CRS, 571 with CRSwNP, and 120 with CRSwNP treated by FESS. The Sniffin' Sticks® olfactory test was used to measure olfactory function in all patients. RESULTS: Olfactory dysfunction was a common symptom in patients with CRS, ranging in frequency from 56 to 74%. In patients with CRSwNP, impairment of sense of smell affected 64% of subjects (42% with anosmia, 10% with hyposmia, and 12% with cacosmia). After surgery, there was a significant improvement in the ability to smell normally. CONCLUSION: The present study confirms that impairment of smell is a common symptom in patients with chronic rhinosinusitis, mainly in subjects with nasal polyps. FESS reduces the prevalence of olfactory dysfunction.

Obesity and Asthma: An Intriguing Link in Childhood and Adolescence.

BACKGROUND: Asthma is a chronic disease characterized by airway inflammation. Obesity is common and may be associated with asthma. OBJECTIVE: The objective of this study is to investigate the possible relationship between asthma control and obesity in children. METHODS: A nationwide study included 462 children and adolescents, 319 (69%) males, mean age 11.3 years. Asthma control grade, asthma control test, body mass index calculated as percentiles, and lung function were evaluated. RESULTS: Obesity affected 64 (13.9%) children with asthma. This outcome underlined the high prevalence of obesity in children and adolescents with asthma. On the other hand, obesity did not affect the asthma control as well as lung function. CONCLUSION: This study showed that body weight did not affect asthma control and lung function in a large population of children and adolescents with asthma followed in Italian tertiary allergy/asthma centers and adequately managed.

Eosinophilic gastrointestinal disorders and allergen immunotherapy: Lights and shadows.

Allergic diseases, such as IgE-mediated food allergy, asthma, and allergic rhinitis, are relevant health problems worldwide and show an increasing prevalence. Therapies for food allergies are food avoidance and the prompt administration of intramuscular epinephrine in anaphylaxis occurring after accidental exposure. However, allergen immunotherapy (AIT) is being investigated as a new potential tool for treating severe food allergies. Effective oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) induce desensitization and restore immune tolerance to the causal allergen. While immediate side effects are well known, the long-term effects of food AIT are still underestimated. In this regard, eosinophilic gastrointestinal disorders (EGIDs), mainly eosinophilic esophagitis, have been reported as putative complications of OIT for food allergy and sublingual immunotherapy (SLIT) for allergic asthma and rhinitis. Fortunately, these complications are usually reversible and the patient recovers after AIT discontinuation. This review summarizes current knowledge on the possible causative link between eosinophilic gastrointestinal disorders and AIT, highlighting recent evidence and controversies.

Turbinate Hypertrophy, Allergic Rhinitis, and Otitis Media.

PURPOSE OF REVIEW: Otitis media (OM) is a disease with high prevalence in infancy; it has a substantial burden on healthcare resources, and a relevant impact on the quality of life of families. The link between OM and allergic rhinitis (AR) is still debated. However, there is agreement about the relevance of type 2 inflammation on turbinate hypertrophy (TH) generation. There is also evidence that TH is associated with middle ear dysventilation: a pathogenic factor promoting OM. Therefore, a vicious circle among AR, TH, and OM may occur. RECENT FINDINGS: There are some recent studies exploring this issue through different approaches, such as epidemiological, mechanistic, and therapeutic. Identifying allergy as a pathogenic factor for OM could improve the management of OM patients. Vice versa, suspecting AR in OM patients, could be reasonable in selected patients. The current narrative review provides an overview of the evidence concerning the potential role of AR, and associated TH, in OM patients.

Turbinate Hypertrophy, Allergic Rhinitis, and Otitis Media.

PURPOSE OF REVIEW: Otitis media (OM) is a disease with high prevalence in infancy; it has a substantial burden on healthcare resources and a relevant impact on the quality of life of families. The link between OM and allergic rhinitis (AR) is still debated. However, there is agreement about the relevance of type 2 inflammation on turbinate hypertrophy (TH) generation. There is also evidence that TH is associated with middle ear dysventilation: a pathogenic factor promoting OM. Therefore, a vicious circle among AR, TH, and OM may occur. RECENT FINDINGS: There are some recent studies exploring this issue through different approaches, such as epidemiological, mechanistic, and therapeutic. Identifying allergy as a pathogenic factor for OM could improve the management of OM patients. Vice versa, suspecting AR in OM patients could be reasonable in selected patients. The current narrative review provides an overview of the evidence concerning the potential role of AR, and associated TH, in OM patients.

Impact that the COVID-19 pandemic on routine childhood vaccinations and challenges ahead: A narrative review.

AIM: To document the decline in vaccination coverage in the first months of 2020 as an indirect effect of the COVID-19 pandemic. METHODS: We performed a literature review in medical databases. Overall, 143 articles were initially retrieved, out of which 48 were selected and included in the review. RESULTS: Our review retrieved similar data in many countries worldwide, and, globally, preliminary data from the first 4 months of 2020 indicate a decline in diphtheria-tetanus-pertussis coverage, generally considered the marker of vaccination coverage across countries. World Health Organization recommends maintaining vaccination services, prioritising primary series vaccinations especially for measles-rubella or poliomyelitis, but it also lets each country decide whether to maintain the immunisation services evaluating the current epidemiology of vaccine-preventable diseases and the COVID-19 local transmission scenario. Successively, recovering of vaccinations should be planned. Moreover, during the pandemic, influenza vaccination should be promoted as a central public health measure. CONCLUSION: Future challenges will be to maintain the vaccination programmes, especially in children younger than 2 years old and adolescents, to plan the recovery of vaccinations for subjects who postponed them during the lockdown, and to early identify any vaccine-preventable disease outbreak.

The real-world "ControL'Asma" study: a nationwide taskforce on asthma control in children and adolescents.

BACKGROUND: Asthma control is the goal of asthma management. A nationwide study on this aspect was launched by the Italian Society of Paediatric Allergy and Immunology (ControL'Asma study). OBJECTIVE: To define variables associated with different asthma control grades in a nationwide population of asthmatic children and adolescents. METHODS: This cross-sectional real-world study included 480 asthmatic children and adolescents (333 males, median age 11.2 years) consecutively enrolled in 10 third level pediatric allergy clinics. According to the Global Initiative for Asthma (GINA) document, history, medication use, perception of asthma symptoms assessed by visual analog scale (VAS), clinical examination, lung function, childhood asthma control test (cACT)/asthma control test (ACT), and asthma control level were evaluated. RESULTS: Considering GINA criteria, asthma was well controlled in 55% of patients, partly controlled in 32.4%, and uncontrolled in 12.6%. Regarding cACT/ACT, asthma was uncontrolled in 23.2%. Patients with uncontrolled asthma had the lowest lung function parameters and VAS scores, more frequent bronchial obstruction and reversibility, and used more oral and inhaled corticosteroids (CS). CONCLUSIONS: The ControL'Asma study, performed in a real-world setting, showed that asthma in Italian children and adolescents was usually more frequent in males. Asthmatic patients had an early onset and allergic phenotype with very frequent rhinitis comorbidity. Uncontrolled and partly controlled asthma affected about half of the subjects, and the assessment of asthma symptom perception by VAS could be a reliable tool in asthma management.