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BackgroundSolar urticaria represents an uncomfortable form of chronic inducible urticaria. First and second-line treatments are ineffective in some patients, leading to an impairment in their quality of life. Omalizumab represents a safe therapeutic option in case of refractory solar urticaria.Case presentationWe update a case of a 21-year-old Caucasian girl affected by solar urticaria from the age of 14. Poor disease control was achieved with standard or high-dose of H1-antihistamines. Several omalizumab courses, including a 1-year-long course, were practiced resulting in clinical remission and significant improvement in patient’s quality of life.ConclusionOur experience confirms the effectiveness and safety of omalizumab for the management of refractory solar urticaria. Future studies are awaited in order to monitor long term effects and chronic doses of this treatment, particularly in patients who need concomitant therapy with antihistamines.

Background: Italy was one of the first affected countries by coronavirus disease 2019 (COVID-19) pandemic. Public health measures like quarantine or national lockdown were adopted, with negative psychological and clinical effects on patients with chronic diseases. To investigate the impact of lockdown on patients with multiple sclerosis (MS), we developed a 36 items self-report questionnaire. Methods: Questionnaires were emailed to 120 patients with MS and 100 with chronic migraine (CM) as a control group, matched for age, sex, and education. The questionnaire was divided into five domains, evaluating concerns about 1) MS and therapy during COVID-19 pandemic, 2) personal and family caregiving, 3) working activities, 4) general and disease-related emotions during the lockdown, 5) future expectations concerning health status, social life, and working activity. Results: patients with MS had higher scores than those with CM in domains 4 and 5, investigating respectively general and disease-related emotions and future expectations (p= 0.05 and 0.02 respectively). About half of the patients with MS expressed some concern about the need to continue their therapy during the pandemic compared to people with CM (p= 0.0002). Conclusions: Covid-19 pandemic had a more negative impact on psychological status of patients with MS compared with those with CM

In recent years, the prevalence of large spectrum of gluten-related disorders (GRDs) has increased. Gluten is one of the most widely distributed components of food in both industrialized and developing countries. The main structural protein complex of wheat and its proteins are classified into albumins, salt-soluble globulins, and insoluble prolamins (gliadins and glutenins). Gluten is also included in other cereals, including rye and barley. GRDs can be classified, based on their pathogenic mechanism, into (i) Autoimmune disorders, (ii) Allergic disorders, (iii) No autoimmune, not allergic disorders. Coeliac disease (CD) is an autoimmune disorder that occurs in genetically predisposed individuals who develop an immune reaction to gluten. It affects about 1% of people in most populations. The disease primarily interests the small intestine, but it is characterized by a wide range of clinical presentations, with both intestinal and extra-intestinal symptoms. Wheat allergy (WA) is an adverse immunologic reaction to wheat proteins. In the large field of WA a further classification can be made, distinguishing IgE-dependent WA, triggered by ingestion, inhalation or cutaneous and/or mucosal contact of wheat, and IgE-non-dependent WA. Its prevalence varies depending on the age and region, from 0.4% to 4%. Urticaria and/or angioedema, and anaphylaxis with or without exercise as a trigger, appear typically during childhood, asthma and/or rhinitis (Baker’s asthma) are more common during adulthood. Non-coeliac gluten sensitivity (NCGS) is a condition in which gluten ingestion leads to one or more of a variety of immunological, morphological or symptomatic (both gastrointestinal or extra gastrointestinal) manifestations in people in whom CD has been excluded. It is supposed it’s due to an activated innate immune response.

Objective Motor surround inhibition (mSI) is a physiological mechanism that contributes to hand movement control by focusing voluntary movement. Growing evidence suggests that hand movement control is impaired in multiple sclerosis. The aim of the study was to evaluate mSI in MS and to investigate the brain structures involved in mSI in multiple sclerosis. Methods We recruited 33 patients and 23 controls. To investigate mSI, we delivered transcranial magnetic single pulses during index finger flexion. Motor evoked potentials were recorded and first dorsal interosseous (“active muscle”) and from the abductor digiti minimi (“surround muscle”). mSI was expressed as the ratio between Motor evoked potentials recorded from the surround muscle during movement and at rest. Participants underwent a magnetic resonance study. Results Patients had impaired mSI as compared with controls. Magnetic resonance showed that basal ganglia had smaller volumes and higher mean diffusivity than controls. Impaired mSI correlated with primary motor cortex and basal ganglia involvement in multiple sclerosis. Conclusion Altered mSI in multiple sclerosis is related to cortical and subcortical grey matter involvement. Significance Our study provides the first demonstration of a pathophysiological mechanism underlying hand movement control dysfunction in multiple sclerosis. mSI represents a new therapeutic target of multiple sclerosis rehabilitative approaches.

Introduction: In recent years, the advent of immunotherapy has remarkably improved the management of IgE-mediated food allergy. However, some barriers still exist. Therefore, the effort of researchers aims to investigate new perspectives in the field of non-allergen specific therapy, also based on the current knowledge of the pathogenesis of this disease.Areas covered: This review aims to focus on the role of biologics as a treatment option in patients with IgE-mediated food allergy. These agents are characterized by their ability to inactivate the Th2 pro-inflammatory pathways. Biologics can be used both alone and in association with immunotherapy. Monoclonal antibodies targeting IgE, the IL-4/IL-13 axis, IL-5, and alarmins have been proposed and investigated for treating food allergy.Expert opinion: The clinical efficacy and safety of biologics have been demonstrated in several preclinical studies and randomized controlled trials. Future studies are still required to address current unmet needs, including the identification of the optimal dose to be used by ensuring the effectiveness of therapy.

Food allergy is a potentially life-threatening medical condition and a significant public health concern worldwide. The current management consists of strict avoidance of the culprit food and treating any adverse reactions from unintended food ingestion. The increasing prevalence of food allergy encouraged research and clinical trials in the field of specific allergen immunotherapy (AIT) which represents an appealing approach, especially in pediatric age. AIT consists of the gradual administration of growing amounts of the offending allergen in order to induce food desensitization, which is an increase in the threshold for reactivity while continuing on regular exposure to the allergen. AIT can be administered through oral, sublingual, epicutaneous, and subcutaneous routes. Reports on oral immunotherapy (OIT) thus far have been more extensive. The desirable goal is to achieve "post desensitization effectiveness", that is the ability to introduce food without reaction even after a period of discontinuation of the offending food. Other therapeutic approaches are being studied alongside immunotherapy such as modified proteins, probiotics, Chinese herbal supplements, biologic therapies, and DNA vaccines.

The COVID-19 pandemic has surprised the entire population. The world has had to face an unprecedented pandemic. Only, Spanish flu had similar disastrous consequences. As a result, drastic measures (lockdown) have been adopted worldwide. Healthcare service has been overwhelmed by the extraordinary influx of patients, often requiring high intensity of care. Mortality has been associated with severe comorbidities, including chronic diseases. Patients with frailty were, therefore, the victim of the SARS-COV-2 infection. Allergy and asthma are the most prevalent chronic disorders in children and adolescents, so they need careful attention and, if necessary, an adaptation of their regular treatment plans. Fortunately, at present, young people are less suffering from COVID-19, both as incidence and severity. However, any age, including infancy, could be affected by the pandemic.Based on this background, the Italian Society of Pediatric Allergy and Immunology has felt it necessary to provide a Consensus Statement. This expert panel consensus document offers a rationale to help guide decision-making in the management of children and adolescents with allergic or immunologic diseases.

Thyroid cancer (TC) in childhood is a rare disease characterized by an excellent prognosis. Thyroid nodules in children, although less common than in adults, have a greater risk of malignancies, particularly in those cases associated with anamnestic, clinical and ultrasonographic risk factors. Among the factors, which have been found to be linked with an increased relative risk of TC in children, an important role seems to be possibly played by an underlying nodular Hashimoto’s thyroiditis (HT) and by the serum levels of TSH. Aim of this Commentary was to specifically address this last point. According to the available pediatric literature on the relationships between these risk factors and phenotypical expression of TC in children, it is possible to conclude that: 1) It is not completely clarified if HT per se predisposes to malignancy or if it represents an incidental histologic finding in cases with TC or if it may be the result of an immune response against tumoral cells. 2) It is unclear whether phenotypic expression of TC is more severe in the cases with associated HT but normal TSH serum levels. 3) Persistently elevated TSH levels play an independent role as predictors of the likelihood of TC, especially in children but also in adults. 4) Patients with nodular HT and subclinical hypothyroidism need to be treated with Levothyroxine in order to prevent the development of both TC and severe thyroid dysfunctions.

Drug hypersensitivity reactions (DHRs) in childhood are mainly caused by betalactam or non-betalactam antibiotics, and non-steroidal anti-inflammatory drugs (NSAIDs). Laboratory tests for identifying children who are allergic to drugs have low diagnostic accuracy and predictive value. The gold standard to diagnose DHR is represented by the drug provocation test (DPT), that aims of ascertaining the causative role of an allergen and evaluating the tolerance to the suspected drug. Different protocols through the administration of divided increasing doses have been postulated according to the type of drug and the onset of the reaction (immediate or non immediate reactions). DPT protocols differ in doses and time interval between doses. In this position paper, the Italian Pediatric Society for Allergy and Immunology provides a practical guide for provocation test to antibiotics and NSAIDs in children and adolescents.

Background: Immunoglobulin E (IgE) mediated food allergy is a potentially life-threatening condition and represents a heavy burden for patients and their families. Identification of the most suitable way for management of each patient has currently become the primary goal for physicians. Methods: This study reviewed the current literature related to IgE-mediated food allergy. Results: The use of innovative diagnostic tools, such as allergen-specific IgG4 determination, basophil activation test, and component-resolved diagnostics, is currently available to facilitate a proper diagnosis of food allergy. After several decades of “passive clinical management” of the disease, which was based only on avoidance of the allergenic food and the use of epinephrine in the event of anaphylaxis, there has been a switch to active treatment. The most recent evidence-practice guidelines strongly recommend the use of immunotherapy as an effective therapeutic option, particularly in cases of allergy to cow's milk, egg, or peanut. The use of omalizumab, in association with immunotherapy or alone, has been tested in several studies, and results on its effectiveness seemed to be encouraging. Other biologics, such as dupilumab, reslizumab, mepolizumab, and other anticytokines therapies, are being investigated. Another interesting future treatment strategy could be the use of DNA vaccines. Conclusion: In recent years, the management of IgE-mediated food allergy has greatly improved. Knowledge of pathogenetic mechanisms, understanding of the disease course, and the introduction of novel biomarkers led to more accurate diagnoses along with the active treatment of patients.

Background: Frailty is an age-related status of increased vulnerability to stressors caused by the accumulation of multiple health deficits. This construct may allow to capture the clinical complexity of patients with multiple sclerosis (MS). Objective: To investigate the relationship between frailty and the clinical manifestations of MS. Methods: Patients with MS were consecutively enrolled at five tertiary dedicated services. Disability and fatigue were assessed. The phenotypes of MS were also identified. Frailty was measured using a frailty index (FI), computed by cumulatively considering 42 age-related multidimensional health deficits. Results: Overall, 745 MS patients (mean age = 48.2 years, standard deviation = 11.7 years; women 68%) were considered. The median FI value was 0.12 (interquartile range = 0.05–0.19) and the 99th percentile was 0.40. FI scores were associated with MS disease duration, disability, fatigue, as well as with the number of previous disease-modifying treatments and current symptomatic therapies. A logistic regression analysis model showed that FI score was independently associated with the secondary progressive phenotype. Conclusion: Frailty is significantly associated with major characteristics of MS. The findings of the present cross-sectional investigation should be explored in future longitudinal studies.

Introduction Bowel dysfunction (BD) is reported as a common and disabling symptom in multiple sclerosis (MS) patients. To date, no studies have explored the prevalence of these symptoms in a large multicenter outpatient setting. The aims of the present study are to assess: (i) the prevalence of BD in a large multicenter Italian MS population, and (ii) the correlation between clinico-demographic variables and the severity of BD. Methods Each of the nine participating center screened MS patients prospectively: 1100 subjects were enrolled. All patients underwent the Expanded Disability Status Scale (EDSS) and completed the Neurogenic Bowel Dysfunction score (NBDs). Multivariable linear and logistic regression models were used to assess the association between NBDs and several clinico-demographic variables. Results Fourteen percent of MS patients showed a moderate/severe BD (NBDs > 10); this percentage increased in patients with high disability, ranging from 26 to 32%. Moderate/severe BD was more frequent in MS patients with: progressive phenotypes, higher disability, older age, and longer disease duration. NBDs severity was predicted by female sex, ambulation impairment and bladder symptoms. Conclusion This study confirms the relatively high prevalence of moderate/severe BD in a large, multicenter, unselected, outpatient MS population. BD appears to be mainly associated to female sex and MS-related disability.

Most patients with multiple sclerosis presenting with a relapsing–remitting disease course at diagnosis transition to secondary progressive multiple sclerosis (SPMS) 1–2 decades after onset. SPMS is characterized by predominant neurodegeneration and atrophy. These pathogenic hallmarks result in unsatisfactory treatment response in SPMS patients. Therefore, early diagnosis of SPMS is necessary for prompt treatment decisions. The aim of this review was to assess neurophysiological and fluid biomarkers that have the potential to monitor disease progression and support early SPMS diagnosis. We performed a systematic review of studies that analyzed the role of neurophysiological techniques and fluid biomarkers in supporting SPMS diagnosis using the preferred reporting items for systematic reviews and meta-analyses statement. From our initial search, we selected 24 relevant articles on neurophysiological biomarkers and 55 articles on fluid biomarkers. To date, no neurophysiological or fluid biomarker is sufficiently validated to support the early diagnosis of SPMS. Neurophysiological measurements, including short interval intracortical inhibition and somatosensory temporal discrimination threshold, and the neurofilament light chain fluid biomarker seem to be the most promising. Cross-sectional studies on an adequate number of patients followed by longitudinal studies are needed to confirm the diagnostic and prognostic value of these biomarkers. A combination of neurophysiological and fluid biomarkers may be more sensitive in detecting SPMS conversion.

Background Patients with neuroimmunological conditions such as multiple sclerosis (MS) often receive disease-modifying therapies (DMTs) or immunosuppressants which may reduce the response to vaccines. BNT162b2 (Pfizer-BioNTech) is the first COVID-19 vaccine authorized in Italy. Its clinical efficacy and serological response were not evaluated in MS patients receiving DMTs or immunosuppressants. This early multicenter study evaluated serological response to BNT162b2 and safety in these patients. Methods From February 2021 we enrolled consecutive MS patients, treated with at least one DMT and all healthcare workers (HCWs), having received or being scheduled to receive the first dose of BNT162b2. Blood samples were collected after the second vaccine dose and analyzed to quantitatively detect the presence of anti-Spike antibodies. Serological response was compared to the one from a control population of HCWs, with neither neuroimmunological conditions nor receiving immunosuppressants. Patients receiving treatments associated with a possible reduced response (Under-scrutiny treatment group) were also compared to those undergoing other treatments. Anti-Spike levels were described as median and interquartile range (IQR). Comparisons were performed with Wilcoxon-Mann-Whitney test. Solicited and unsolicited adverse events (AEs) were collected. Results 39 MS patients and a control population of 273 HCWs were included. One patient, under treatment with ocrelizumab, did not respond to BNT162b2, while all the remaining patients and all controls developed a serological response to the vaccine. Median anti-Spike levels were similar between patients (1471.0 BAU/ml; IQR 779.7 to 2357.0) and controls (1479.0 BAU/ml; IQR 813.1 to 2528.0) (p = 0.53). Patients included in the Under-scrutiny treatments group showed reduced anti-Spike levels (156.4 BAU/ml; IQR 33.4 to 559.1) compared to those receiving other treatments (1582.4 BAU/ml; IQR 1296.5 to 2219.0) (p = 0.001). Solicited AEs were all mild to moderate in severity, generally reported in the first days after vaccination, and resolved in the following days. Two MS patients reported a clinical relapse after the second vaccine dose. Conclusion BNT162b2 induced a serological response in MS patients treated with DMTs similar to controls not receiving DMTs or immunosuppressants. Some treatments were associated with reduced levels of anti-Spike antibodies in patients. These observations have relevant implications for treated patients receiving BNT162b2 and the community.

Biologic drugs are widely used in pediatric medicine. Monoclonal antibodies (mAbs) in particular are a therapeutic option for rheumatic, autoinflammatory and oncologic diseases. Adverse drug reactions and hypersensitivity reactions (HSR) to mAbs may occur in children. Clinical presentation of HSRs to mAbs can be classified according to phenotypes in infusion-related reactions, cytokine release syndrome, both alpha type reactions and type I (IgE/non-IgE), type III, and type IV reactions, all beta-type reactions. The aim of this review is to focus on HSRs associated with the most frequent mAbs in childhood, with particular attention to beta-type reactions. When a reaction to mAbs is suspected a diagnostic work-up including in-vivo and in-vitro testing should be performed. A drug provocation test is recommended only when no alternative drugs are available. In selected patients with immediate IgE-mediated drug allergy a desensitization protocol is indicated. Despite the heavy use of mAbs in childhood, studies evaluating the reliability of diagnostic test are lacking. Although desensitization may be effective in reducing the risk of reactions in children, standardized pediatric protocols are still not available.

The recent EAACI/GA2 LEN/EDF/WAO guidelines recommend omalizumab (anti-IgE) for the management of patients aged ≥12 years with chronic urticaria unresponsive to high-doses second-generation H1 -antihistamines (antiH1 ). However, there is little published information on the success of omalizumab for such a treatment in children. We reported our experience of six patients with chronic spontaneous urticaria (CSU) treated with omalizumab. Mean age of our case series was 14.7 years (range 11-16 years) with a prevalence of male gender (66.7%). All six patients were treated with at least one 6-months course of omalizumab. The average follow-up period was 13 ± 6 months. Only one patient was no responder to omalizumab therapy. Thus far, two patients have experienced a complete CSU regression over 12 months after the final omalizumab administration. The remaining three patients needed a second course of treatment. Our experience demonstrates that omalizumab is effective and safe as treatment option for CSU unresponsive to antiH1 , even in adolescent age.

Background Approximately 10% of the parents report suspected drug hypersensitivity reactions to at least one drug in their children, but most of these reactions are not confirmed after an adequate diagnostic work-up. The diagnosis of drugs hypersensitivity is frequently laborious and based on anamnesis, skin tests, serum specific IgE research and drug provocation test. Nevertheless, drug provocation test is necessary to confirm or definitively exclude the diagnosis of allergy. Aims of our study were to evaluate the real incidence of drug hypersensitivity in a large pediatric population and the validity of a short diagnostic algorithm. Methods One hundred nine patients with a history of self-reported, immediate and mild drug hypersensitivity reactions to β-lactam antibiotics, macrolides and non-steroidal anti-inflammatory drugs underwent drug provocation test without prior skin or blood tests. After one-year, a telephone questionnaire was conducted in order to evaluate patient's use of the tested drug and any reactions. Results Only 7 of the 109 patients (6.4%) resulted positive to drug provocation test. No severe reactions were reported. After the challenge, 64 patients took the culprit drug again within one year and only two reported a drug reaction. Conclusions Drug hypersensitivity is highly overestimated. Our results prompt the opportunity to directly perform the challenge for those children with self-reported, mild and immediate drug hypersensitivity reaction.

Aims Aim of our observational study was to assess the prevalence of allergic contact dermatitis among children and adolescents with type 1 diabetes who use technological devices for diabetes treatment and its management. Secondary outcome was to identify possible clinical and/or demographic variables that could be associated to contact dermatitis. Methods Among a total of 215 patients using insulin pumps and/or glucose sensors followed-up at our Pediatric Diabetes Centre between January and September 2018, 64 patients were enrolled and 42 (19 male and 23 female) completed the study. Demographic and clinical features of the study population were statistically analysed. All the patients underwent patch testing with specific allergens belonged to resin and acrylate classes. Results Eighteen patients experienced skin reactions suggestive of allergic contact dermatitis, demonstrating a prevalence of 8.4%. None of the demographic or clinical variables were associated to skin reactions. Colophonium was the most identified sensitizing allergen (87.5% of the cases). Conclusions The rate of sensitization to allergens included into diabetes devices among pediatric patients is higher than commonly assumed. Well-designed studies are needed to better investigate the association between type 1 diabetes and allergic contact dermatitis. Moreover, we suggest that manufactures should supply detailed information about adhesives in order to avoid dermatological complications and consequently a worsening of disease management and patients’ quality of life.

Omalizumab is a monoclonal antibody, targeting Fc receptor of IgE, approved for the treatment of allergic asthma and chronic spontaneous urticaria. Its utility in atopic dermatitis appears controversial from data in literature since the molecule is well tolerated but it seems less effective than other medications used in adult patients (eg, Dupilumab). At present, the use of Dupilumab is not approved in pediatric patients therefore there are no second level treatments available in this age group. Here we report two clinical cases of patients (15 and 16 years old) suffering from both atopic dermatitis and asthma, treated with Omalizumab. Our experience suggests that atopic eczema of young patients with allergic comorbidities can benefit from asthma treatment with Omalizumab observing improvement on both conditions.

ᅟ Aim of this commentary is to summarize the salient literature views on the relationships between presentation and evolution patterns of thyroid function in children with Hashimoto’s thyroiditis (HT). According to the most recent reports, children with HT and subclinical hypothyroidism (SH) are more prone to the risk of developing severe thyroid dysfunctions over time, if compared to those presenting with euthyroidism. In contrast, children presenting with HT and either overt or subclinical hyperthyroidism are incline to exhibit a definitive resolution of the hyperthyroid phase within some months, although there is a wide variability between the different individuals. The natural history of frank hypothyroidism in the children with HT has never been investigated so far, since in these cases an immediate onset of replacement treatment is mandatory. Conclusions 1) a deterioration of thyroid status over time may be observed especially in the children presenting with SH, but also in those presenting with euthyroidism; 2) a definitive resolution of the hyperthyroid phase is generally observed in those presenting with either overt or subclinical hyperthyroidism.

The COVID-19 pandemic is the most challenging global health crisis of our times. Vaccination against COVID-19 plays a key role to control the current pandemic situation. The risk of allergic reactions to new COVID-19 vaccines is low. However, there is a debate on the safety in allergic patients following post marketing findings by different agencies. Our aim is to understand from current experiences whether children with cow’s milk or food allergy are at higher risk than a general population for allergic reactions to COVID-19 vaccines. Current data indicate that patients with a history of allergy to cow’s milk or other foods, even if severe, should receive COVID-19 vaccine in a setting with availability of treatments for anaphylactic reactions and under medical supervision. Recipients should be discharged after a protracted observation period of 30 min if no reaction developed.

Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of cortical, bulbar, and spinal motor neurons (MNs). The cardinal manifestation of ALS is a progressive paralysis which leads to death within a time span of 3 to 5 years after disease onset. Despite similar final output of neuronal death, the underlying pathogenic causes are various and no common cause of neuronal damage has been identified to date. Inflammation-mediated neuronal injury is increasingly recognized as a major factor that promotes disease progression and amplifies the MN death-inducing processes. The neuroimmune activation is not only a physiological reaction to cell-autonomous death but is an active component of nonautonomous cell death. Such injury-perpetuating phenomenon is now proved to be a common mechanism in many human disorders characterized by progressive neurodegeneration. Therefore, it represents an interesting therapeutic target. To date, no single cell population has been proved to play a major role. The existing evidence points to a complex cross talk between resident immune cells and nonresident cells, like monocytes and T lymphocytes, and to a dysregulation in cytokine profile and in phenotype commitment. After a summary of the most important mechanisms involved in the inflammatory reaction in ALS, this review will focus on novel therapeutic tools that rely on tackling inflammation to improve motor function and survival. Herein, completed, ongoing, or planned clinical trials, which aim to modify the rapidly fatal course of this disease, are discussed. Anti-inflammatory compounds that are currently undergoing preclinical study and novel suitable molecular targets are also mentioned.

The aim of this guidance is to provide recommendations to clinicians and other interested parties on chronic urticaria in children. The Italian Society for Pediatrics (SIP), the Italian Society for Allergy and Immunology (SIAIP), the Italian Society for Pediatric dermatology (SIDerP) convened a multidisciplinary panel that prepared clinical guidelines for diagnosis and management of chronic urticaria in childhood. Key questions on epidemiology, natural history, diagnosis, and management were developed. The literature was systematically searched and evaluated, recommendations were rated and algorithms for diagnosis and treatment were developed. The recommendations focus on identification of diseases and comorbidities, strategies to recognize triggering factors, improvement of treatment by individualized care.

Aim of this mini review was to analyze the main variables which should be taken into account when the decision regarding a possible treatment with L-T4 has to be considered for a child with subclinical hypothyroidism (SH). The indications of periodical monitoring and vigilance have been also discussed. It was inferred that therapy should be recommended for children with underlying Hashimoto's thyroiditis and progressive deterioration of thyroid status over time, particularly in the cases with goiter and hypothyroid symptoms and in those with associated Turner syndrome or Down's syndrome and/or other autoimmune diseases. Treatment might also be recommended for children with proatherogenic metabolic abnormalities. Treatment is not advisable in children with idiopathic and mild SH, no goiter, no hypothyroid symptoms and negative anti-thyroid autoantibodies. In the absence of any therapeutic intervention, clinical status and thyroid function tests should be periodically monitored, in order to individuate the children who might benefit from treatment. It has been suggested that children with a persistent mild elevation of TSH, who are not treated with L-T4, should undergo biochemical monitoring of thyroid function and re-assessment of clinical status every 6 months. After 2 years with stable thyroid function tests, the interval between monitoring can be extended.

BackgroundNabiximols (THC/CBD Oromucosal Spray, Sativex) is used as an add-on therapy to treat moderate to severe spasticity of Multiple Sclerosis (MS).ObjectivesTo examine the impact of physiotherapy (PT) programs on effectiveness and persistence of nabiximols treatment in people with MS-related spasticity.MethodsThis is an observational multicenter study with a follow-up period of 12 weeks, conducted in routine care settings in Italy. Patients with moderate to severe MS-related spasticity who started nabiximols were included. Spasticity was evaluated by the patient-rated 0-10 numerical rating scale (NRS). Clinical data were collected at baseline (T0), 4 weeks (T1) and 12 weeks (T2) months after enrollment.ResultsA total of 297 MS patients were selected, 290 completed the 3 months follow-up period. Mean NRS scores were 7.6 ± 1.1 at T0, 5.8 ± 1.4 at T1 and 5.5 ± 1.5 at T2. At T1, 77% of patients reached ≥20% improvement (initial response, IR); 22% reached ≥30% improvement (clinically relevant response, CRR). At T1, patients undergoing PT had a higher probability to reach CRR (Odds Ratio = 2.6 95% CI 1.3-5.6, p = 0.01). Nabiximols was discontinued in 30/290 (10.3%) patients at T1 (early discontinuers) and in 71/290 (24.5%) patients at T2 (late discontinuers). The probability of being late discontinuers was reduced in patients undergoing PT (Hazard Ratio = 0.41; 95% CI 0.23-0.69, p = 0.001).ConclusionsOur real-life study confirms nabiximols' effectiveness in MS-related spasticity and suggests that the association of a PT program may improve overall response and persistence to nabiximols treatment.

Background Currently, severe allergic asthma and food allergy in children represent an important public health problem with medical, psychosocial and economic impacts. Omalizumab is a humanized monoclonal anti-IgE antibody, approved for refractory allergic asthma and chronic urticaria. It has been widely used in clinical practice as add-on therapy in patients with severe uncontrolled allergic asthma. In recent years there has seen the emergence of an allergic epidemic with increasing food allergy, which represents the main cause of anaphylaxis in children. The standard of care for food allergy is strictly dietary allergen avoidance and emergency treatment, but recent clinical trials have suggested that omalizumab may have a role to play as an adjuvant to oral immunotherapy (OIT). We present a case series of patients treated at our institution with omalizumab for severe allergic asthma and food allergy. Methods Patients received omalizumab according to a standard reference nomogram after failing standard therapies. In children with comorbid severe food allergy, omalizumab was administered in conjunction with an oral immunotherapy protocol. Results Omalizumab was effective in controlling symptoms of allergic asthma, allergic rhinitis and rhinosinusitis, but not eosinophilic esophagitis, while aiding successful oral desensitization of comorbid severe food allergies. Conclusions Omalizumab appears to be an excellent therapeutic option in children with inadequately controlled severe allergic asthma, allergic rhinitis and rhinosinusitis, with or without food allergy.

Aim of this commentary is to analyze the relationships between genotypic bases and phenotypic expression of congenital “multiple pituitary hormone deficiency” (MPHD) syndrome and to indicate some reliable criteria for selecting the patients who should undergo genetic analyses in order to clarify the etiology of their disorder. On the basis of the most recent reports on this topic, it is possible to infer that: 1) in only few patients with congenital MPHD it is possible to detect a causative gene mutation; 2) therefore, it is fundamental to define some criteria for selecting the patients who should undergo genetic analyses; 3) such inclusion criteria should be based on the overall evaluation of hormonal clinical and neuroradiological phenotype; 4) it is crucial to consider whether the cases are sporadic or familial, since the probability of finding a causative gene mutation is distinctly higher in familial cases; 5) for PROP1 gene it is also important to consider the geographical origin of the patients, because this mutation is much more frequent in some ethnic groups.

Children who are highly sensitive to milk may also have severe allergic reactions after exposure to cow's milk proteins(CMP) through a different administration route than the oral one. We describe the case of a 16-year-old Caucasian boy with a clinical history of persistent cow's milk allergy (CMA), who developed one episode of anaphylaxis following cutaneous application of a bovine colostrum containing cream to a surgical wound. UniCAP testing showed a significant elevation in specific IgE antibodies to whey milk proteins. Until now, only three cases of anaphylaxis following cutaneous application of products containing milk proteins were available in the scientific literature.

Aim of this commentary is to report the main peculiarities that have been found to characterize the phenotypic expression of autoimmune thyroid diseases (AITDs) in children with Down’s syndrome (DS). According to recent reports, DS children are, per se, more exposed to the risk of both Hashimoto’s thyroiditis (HT) and Graves’ disease (GD), irrespective of other concomitant risk factors, such as female gender and family antecedents for AITDs. In the context of extra-thyroidal autoimmune disorders, the ones that preferentially aggregate with AITDs in DS children are alopecia areata and vitiligo. Another peculiar aspect, in DS children, is that HT presents with a more severe biochemical picture, which furtherly deteriorates over time. By contrast, GD does not demonstrate a more severe clinical and biochemical picture with respect to that generally observed in patients without DS. Finally, DS children might be at higher risk of progressing from HT toward GD over time.

IgE-mediated food allergy (FA) has been emerging as a public health priority. It is a potentially life-threatening condition with negative impact on the quality of life of patients and their family and its prevalence is increasing in westernized countries in the recent two decades. The current standard approach to FA consists of the strict avoidance of the triggering food. However, an elimination diet may be difficult and frustrating, above all for those foods (e.g. milk and egg) that are pivotal in the common diet. Oral immunotherapy (OIT) may increase the amount of food that the patient can intake without reaction and reduce the risk of potential life-threatening allergic reactions. It is currently considered the most promising treatment for FA. However, many gaps are still unsolved. Areas covered: The aim of this review is to shed light on the current evidence and the main needs in OIT in order to stimulate the development of longitudinal, prospective, and well-designed studies with the final goal of a 'precision medicine.' Expert commentary: Clinical trials for OIT conducted so far are extremely heterogeneous. The aim in the near future is to identify the most suitable candidates to OIT and algorithms for treatments tailored on well-characterized subpopulations of patients.

Background Vaccines often contain potentially allergenic material in addition to pathogen-specific immunogens that may induce allergic reactions. Parents and physicians often suspect that adverse reactions to vaccines are allergic in etiology. The concern that some of the substances contained in vaccines may trigger an anaphylactic reaction may lead to a low vaccination adherence with emergence of infectious disease epidemics. Objective To provide practical suggestions for managing children suspected to have an allergic reaction to a vaccine. Methods Information was obtained from a search of guidelines and relevant studies on allergic reactions to vaccines for infectious diseases. Results True allergic reactions elicited by a vaccine are rare. Skin testing to the vaccine and to its components may identify the triggering agent. Graded dosing desensitization is helpful in children sensitized to the offending vaccine. Conclusion All children with a suspected allergic reaction to a vaccine should be carefully evaluated by routine allergy tests. When it is necessary, further immunization should be given under strict medical surveillance, which ensures that every child can safely complete the vaccination schedule.

Allergen immunotherapy (AIT) is currently the only available disease-modifying and aetiological treatment of IgE-mediated diseases. Sublingual allergen immunotherapy (SLIT) constitutes the preferred route of administration of AIT for respiratory allergies in Europe. Recently it has also been approved in the US. Further applications are currently under evaluation, such as IgE-mediated food allergy and IgE-mediated atopic dermatitis. The SLIT safety profile is overall favourable, although local adverse events, usually mild, are described. Most of the meta-analyses confirmed the efficacy of SLIT in reducing symptoms and medication intake in children with allergic diseases. AIT, as an immune-modulating treatment, can modify the natural history of the allergic diseases: reduction of the risk of development of asthma and bronchial hyperreactivity in patients with allergic rhinitis, and reduction of the onset of new sensitizations. A great interest is now devoted to the preventive effects of AIT and, consequently, to the optimal time of initiation.

Background Cow's milk allergy is common in infancy, and total avoidance of this food is the only effective approach. In alternative, oral immunotherapy has been proposed to achieve tolerance. Once desensitization is achieved, daily intake of milk is recommended to maintain it, but this may be impractical for children/parents. We assessed whether a twice weekly maintenance regimen is effective. Methods Children who were successfully desensitized with oral immunotherapy were randomized to two maintenance regimens for 1 year: group A had to eat 150–200 ml milk daily, group B had to eat 150–200 ml milk twice weekly. Both regimens were associated to a totally free diet. Maintenance of tolerance and adverse events were recorded during 1 year. Specific IgE, IgG4 and prick-by-prick test to milk were carried out before immunotherapy (T0), before maintenance (T1), and after 1 year (T2). Results Recorded episodes included asthma, oral itching, urticaria, rhinitis, abdominal pain variously combined, usually associated with concomitant illness or exercise. The episodes were 8 in group A and 9 in group B, with no difference. None of the children discontinued the feeding maintenance. Specific IgG4 increased at T1 and remained high at T2. Specific IgE and skin reactivity significantly decreased at T2. There was no difference in those parameters between the groups. Conclusion After achieving desensitization to cow milk with oral immunotherapy, a maintenance regimen with milk given twice weekly is as effective as the daily maintenance.

Background: Eosinophilic esophagitis (EoE) has been defined as "asthma of the esophagus" for the large number of similarities between the two diseases. Omalizumab is an anti-Immunoglobulin E (IgE) antibody currently approved only in allergic IgE-mediated severe persistent uncontrolled asthma and in chronic spontaneous urticaria unresponsive to antihistamines, but it has been tried in other diseases, too. Case presentation: We present herein the case of a 13-year-old boy, affected from preschool age by severe chronic allergic asthma poorly controlled despite a generous long-term therapy, and, since he was 8 years old, by eosinophilic esophagitis, responsive to courses of strict elimination diet and semi-elemental diet, even if very burdensome for his quality of life. At the age of 11.5 years, for inadequate asthma control, he started to receive therapy with omalizumab. After the first month and for the entire duration (18 months) of omalizumab treatment, asthma was well controlled, long-term conventional therapy was gradually withdrawn and lung- function improved. Concerning EoE, after an initial clinical but not histological remission during the first few months of treatment with omalizumab, the patient experienced an exacerbation of gastrointestinal symptoms. Therefore, he started treatment with topical steroids which was effective to improve gastrointestinal symptoms. However, EoE is still steroid-dependent. Currently, he continues both treatments: omalizumab for asthma and topical steroid for EoE. Conclusions: This case report confirms that omalizumab is an effective treatment in patients with severe persistent, uncontrolled asthma. On the other hand, in our patient it did not produce persistent improvement neither on symptoms nor on biopsy findings of EoE. The outcome of this case might indicate different pathogenic mechanism(s) of the two diseases.

BACKGROUND Oral immunotherapy (OIT) for food allergy is gaining interest due to the favorable clinical results reported with cow's milk, hen egg and peanut. The safety of the procedure remains a critical aspect that can limit the introduction of OIT in clinical practice. OBJECTIVE We described herein, in detail, the occurrence and characteristics of adverse events (AE) with OIT in children who participated in controlled trials at our unit. METHODS The clinical records of 68 children who received active treatment (40 for cow's milk and 28 for hen egg) were carefully reviewed. The inclusion and exclusion criteria, and the grading of AEs were the same across the trials. Of the 68 children involved, 6 (9%) had to discontinue the OIT procedure due to severe AEs. Fifty percent of the children underwent the buildup and maintenance phases without AEs. Mild-to-moderate AEs were documented in 28 patients, who could complete the desensitization. The majority of reactions were mild or moderate, occurred during an acute intercurrent illness and required only symptomatic treatment. CONCLUSION A careful review of the patients who received food OIT in controlled trials confirmed that AEs were not rare but that ∼90% of children could achieve an effective desensitization. The procedure remains investigational and should be performed only by trained physicians, especially in the pediatric setting.

Childhood immunisation is one of the greatest public health successes of the last century. Vaccines contain an active component (the antigen) which induces the immune response. They may also contain additional components such as preservatives, additives, adjuvants and traces of other substances. This review provides information about risks of hypersensitivity reactions to components of vaccines. Furthermore, recommendations to avoid or reduce reactions to vaccine components have been detailed.

To cite this article: Pajno GB, Caminiti L, Crisafulli G, Vita D, Valenzise M, De Luca R, Passalacqua G. Direct comparison between continuous and coseasonal regimen for sublingual immunotherapy in children with grass allergy: A randomized controlled study. Pediatr Allergy Immunol 2011: 22: 803–807. Abstract Background: Pre-seasonal, pre-coseasonal and continuous regimens of immunotherapy have been proposed, but their efficacy was never compared. This phase IV open study was designed to compare the clinical efficacy of a continuous and a coseasonal sublingual immunotherapy (SLIT) for grass allergy over 3 years. Methods: Children with rhinitis/asthma because of grass were randomized to SLIT given continuously (all year long) or coseasonally. The treatment started in October 2005 in the continuous SLIT group and in March 2006 in the coseasonal group Diary cards for clinical symptoms (from 0 = none to 3 = severe), and drug intake were recorded form March to June in 2005 (baseline), 2006 2007, and 2008. Specific IgE and IgG4 were evaluated every year. Results: Eighty children (age range 8–16) were randomized and 72 completed the study. In the first year, the symptom + medication score improved by 44% in the continuous group and by 20% in the coseasonal group (p = 0.04). Symptoms, chest symptoms, and drug intake separately showed a greater decrease vs. baseline in the continuous group. In the second year, the global score decreased in both groups with no significant difference, whereas symptom score decreased more in the continuous group. In the 3rd year, there was no difference in clinical parameters between the two groups. Specific IgG4 were significantly higher vs. baseline since the 1st year in the continuous group and since the 2nd in the coseasonal group. Conclusion: In grass pollen allergy, the continuous regimen performs better than the coseasonal in the first season, whereas in the subsequent years, the two regimens are nearly equivalent.

Cow milk allergy is a common disease of infancy, often associated with atopic dermatitis (AD). Avoidance of cow milk (CM) implies the use of alternative dietary supports such as mammalian milks. In this study, we assessed the tolerability and clinical effect of ass's milk (AM), when compared with the largely used goat's milk (GM) in a single-blind, controlled, randomized crossover. Twenty-eight children with AD and ascertained allergy to CM were enrolled. The children were randomized to AM or GM for 6 months, then switched to the other milk for further 3 months. The SCORAD index (SI) and a visual analog scale (VAS) were evaluated blindly. After termination of the study, food challenges with GM and AM were performed. An SDS-PAGE analysis of different milks was performed. Two children from the GM group dropped out after randomization and 26 completed the study. Ass milk invariantly led to a significant improvement of SI and VAS of symptoms (p < 0.03 vs. baseline and inter-group), whereas GM had no measurable clinical effect. At the end of the study 23 of 26 children had a positive food challenge with GM and one of 26 with AM. Ass's milk had a protein profile closer to human milk than GM. Ass milk is better tolerated and more effective than GM in reducing symptoms of AD. It may represent a better substitute of CM than the currently used GM.

E S D A Y 842 Successful Specific Oral Tolerance Induction with Hake in an Allergic Child Detecting Fish in Cooking Steam Carmen M. Damelio, MD; Departament of Allergy Clinica Universidad de Navarra, PAMPLONA, Spain. RATIONALE: To describe a specific oral tolerance induction (SOTI) protocol with hake in a child suffering urticaria/angioedema upon fish cooking steam exposure. METHODS: A 6-year old girl who presented at 9 month of age acute urticaria after eating different types of fish (i.e. hake, sole). Skin prick test rendered positive results and since then she avoided fish. Subsequently she suffered several acute urticaria episodes after accidental intakes and even when exposed to tuna fish cooking steam. Comorbidities: mild and controlled atopic dermatitis, no bronchial asthma. A SOTI protocol was decided to apply. Sensitization was evaluated by Prick-to-prick (T1), specific IgE (sIgE) and IgG4 (sIgG4) to hake during the induction phase (T2) and when finalized (T3). SOTI to hake was performed using frozen hake loin, starting with lyophilized hake and when 20gr. were tolerated, we used cooked hake until reaching 40gr. RESULTS: The induction phase of the SOTI lasted 11 months until 40gr of hake were reached suffering one anaphylaxis, related to an infectious process and 5 episodes of abdominal pain requiring antihistamines in only 2 of them. After one month in maintenance-phase, eating 40gr of hake daily without reactions, she tolerated 50gr of bass, 50gr. of tuna, 50gr. of monkfish uneventfully. No atopic dermatitis exacerbation was observed. sIgE against hake (T1:3.31kUA/L; T2: 3.98kUA/L; T3: 2.02kUA/L) and wheal size for hake prick-to-prick (T1: 13x11mm; T2: 10x6mm; T3: 7x5mm) decreased during induction phase whereas hake sIgG4 levels increased (T2: 12.7kU/L, T3: 39.2kU/L). CONCLUSIONS: In our case, SOTI with hake induces tolerance to bass, tuna and monkfish.

OBJECTIVE: In order to ascertain the advantages of early GH treatment in Turner syndrome (TS), we started a prospective study aimed at evaluating prepubertal height gain in a cohort of 29 girls who were treated with the same pro-kilo GH dose (1.0 IU/kg per week) since they were less than 6 years old and for at least 5 years before entering puberty. PATIENTS AND DESIGN: Following a minimum of 6 months of baseline observations, 29 girls with TS were enrolled for this prospective study provided that they (a) were less than 6 years old, (b) were below -1.0 standard deviation score (SDS) for height, (c) had a projected adult height (PAH) lower than the respective target height (TH) and (d) had a height velocity (HV) lower than -1.0 SDS. All the selected girls underwent a 5-year treatment with biosynthetic GH at a stable dose of 1.0 IU/kg per week and were periodically measured during the treatment period in order to evaluate height, HV and PAH. RESULTS: After a dramatic acceleration during the 1st year, HV was attenuated during the subsequent years, reaching its nadir at the 5th year. Height deficiency under therapy progressively decreased from entry onwards, shifting from -2.4+/-0.7 to -1.0+/-1.2 SDS. In the same period, mean PAH progressively increased, although after 5 years it remained lower than the average TH. CONCLUSIONS: (a) An effective growth-promoting strategy in TS should be based on early GH treatment, as suggested by our results. (b) This strategy could result in a prepubertal normalization of height, thus allowing the appropriate timing for the induction of puberty. (c) An initial GH dose of 1.0 IU/kg per week may be suitable during the first years of therapy, as shown by our data documenting an important waning effect of GH therapy only after the 4th year of treatment. (d) No acceleration of bone maturation was observed under this treatment regimen.

OBJECTIVE: The loss of pancreatic beta-cells is thought to be one of the principal causes of diabetes mellitus (DM) in cystic fibrosis (CF), but the role of peripheral insulin resistance (IR) in the pathogenesis of DM in CF remains unclear. The aim of this study was to evaluate whether eventual changes of glucose tolerance (GT) over time were associated with modifications of insulin secretion or sensitivity. METHODS: Plasma glucose and insulin responses to an oral GT test (OGTT) were investigated and reinvestigated 13 Years later in 14 CF patients with initial and persistent fasting euglycemia and no history of insulin treatment. Insulin sensitivity (IS) at both tests was assessed on the basis of insulin and glucose levels both in the fasting state and during OGTTs. RESULTS: From the 1st to the 2nd OGTT: (a) the prevalence of DM responses significantly increased; (b) the areas beneath the respective glucose and insulin curves significantly increased and decreased respectively; (c) IR and IS indices decreased and increased respectively, even in the patients who developed DM; (d) pulmonary function significantly worsened in the entire series, especially in the patients who developed DM. CONCLUSIONS: (i) the natural history of glyco-metabolic status in CF is characterized by deteriorating GT over time; (ii) insulinopenia plays a prominent role in the pathogenesis of GT worsening; (iii) IR does not play any significant part in the pathogenesis of DM development; (iv) deterioration of lung function tests is more severe in the subjects who develop DM over time.

Background Oral immunotherapy (OIT) may be an effective treatment for food allergy in children. It is not clear if the OIT-induced effect is achieved by desensitization (transient state dependent on regular antigen exposure), or by tolerance (persistent condition where the ability to consume the food is retained even after a period of withdrawal). Objective The aim of this study was to investigate the efficacy of OIT-egg desensitization in a double-blind placebo-controlled study, and to evaluate if, after desensitization, tolerance can be maintained. Methods Children with egg allergy were randomized to OIT or placebo for 4 months. At the end of the controlled phase, a double-blind food challenge was repeated to confirm the achieved desensitization. Those subjects found to be desensitized were placed on an egg-containing diet for 6 months, followed by an egg avoidance phase for 3 months, when the food challenge was repeated to determine the maintained tolerance. Results A total of 31 children were randomized to OIT with dehydrated egg white (n = 17) or placebo (n = 14). Of the 17 active patients (1 dropout), 16 achieved desensitization and started the 6-month egg-containing diet. After 3-month of egg avoidance, 31% remained tolerant. In the control group, only 1 passed the final food challenge. Egg-specific IgG4 increased only in the active group. Five active OIT patients had side effects. Conclusion Egg OIT results in desensitization in almost all subjects, although tolerance was maintained in only 1/3 of them after a 3-month period of withdrawal. Side effects were encountered, but the procedure appeared safe. In hen egg allergy, OIT is effective for desensitization.

Resume Les donnees de la litterature mettent en evidence des resultats decevants du traitement par l'hormone de croissance recombinante (GHr) des enfants avec deficit en GH lorsque le traitement est debute tardivement. Cela incite a debuter le traitement par GHr le plus tot possible avec pour corollaire un diagnostic precoce. Cette etude a ete entreprise: 1) pour definir les principales caracteristiques cliniques du deficit en GH (DGH) au cours de la premiere annee de vie, dans le but de preciser les signes devant attirer l'attention du clinicien; 2) pour evaluer l'effet sur la croissance du traitement de GHr debute avant l'âge de l an. Seize enfants avec DGH diagnostique avant l'âge de l an, et traites par GHr des la premiere annee et pendant une duree minimale de 5 ans, ont ete etudies; quatre avaient un DGH isole secondaire a une deletion du gene de la GH (DGH de type 1A). Les principales caracteristiques anamnestiques et cliniques du DGH a revelation precoce dans cette serie sont les suivantes: pathologie perinatale frequente, petite taille a la naissance dans plus de la moitie des cas, poids de naissance relativement eleve dans tous les cas, cassure de la croissance staturale des la naissance, signes associes particuliers (hypoglycemie, dysmorphie faciale, micropenis, cryptorchidie, atteinte hepatique). L'effet du traitement de GHr (≥ 5 ans) sur la croissance: 1) a ete limite et transitoire chez les enfants avec DGH de type 1A; 2) a permis de reduire le retard statural chez les enfants avec DGH sporadique, mais leur taille moyenne est restee significativement inferieure a la taille projetee.