COVID-19 Vaccination in Patients with Inborn Errors of Immunity Reduces Hospitalization and Critical Care Needs Related to COVID-19: a USIDNET Report.

BACKGROUND: The CDC and ACIP recommend COVID-19 vaccination for patients with inborn errors of immunity (IEI). Not much is known about vaccine safety in IEI, and whether vaccination attenuates infection severity in IEI. OBJECTIVE: To estimate COVID-19 vaccination safety and examine effect on outcomes in patients with IEI. METHODS: We built a secure registry database in conjunction with the US Immunodeficiency Network to examine vaccination frequency and indicators of safety and effectiveness in IEI patients. The registry opened on January 1, 2022, and closed on August 19, 2022. RESULTS: Physicians entered data on 1245 patients from 24 countries. The most common diagnoses were antibody deficiencies (63.7%). At least one COVID-19 vaccine was administered to 806 patients (64.7%), and 216 patients received vaccination prior to the development of COVID-19. The most common vaccines administered were mRNA-based (84.0%). Seventeen patients were reported to seek outpatient clinic or emergency room care for a vaccine-related complication, and one patient was hospitalized for symptomatic anemia. Eight hundred twenty-three patients (66.1%) experienced COVID-19 infection. Of these, 156 patients required hospitalization (19.0%), 47 required ICU care (5.7%), and 28 died (3.4%). Rates of hospitalization (9.3% versus 24.4%, p < 0.001), ICU admission (2.8% versus 7.6%, p = 0.013), and death (2.3% versus 4.3%, p = 0.202) in patients who had COVID-19 were lower in patients who received vaccination prior to infection. In adjusted logistic regression analysis, not having at least one COVID-19 vaccine significantly increased the odds of hospitalization and ICU admission. CONCLUSION: Vaccination for COVID-19 in the IEI population appears safe and attenuates COVID-19 severity.

Imported allergens in Italy: an emerging issue.

Imported allergens are involved in many allergic reactions, with unexpected and unusual implications. They can be involved in developing asthma, allergic rhinoconjunctivitis, Hymenoptera venom allergies and food allergies. Imported allergens can be implied in respiratory allergies attributable to commercial practices and accidental diffusion through air currents that have introduced non-native species in new geographical contexts. Ambrosia artemisiifolia L., a plant native to North America and currently in the western part of Lombardy, represents an example. Moreover, a variation in the pollen concentration in the Northwest Tuscany area and Trentino Alto-Adige was observed. Cannabis sativa is another imported allergen used frequently by adolescents. Regarding potential imported food allergens, there is no validated list. Imported food allergens derive from ethnic foods, referring to Mexican/Latin American, Chinese/Japanese, Southeast Asian, Arab/Middle Eastern and African cuisine. Four insect flours were recently introduced to the European and Italian markets (Acheta domesticus, Alphitobius diaperinus, Tenebrio molitor and Locusta migratoria). The association between the accidental introduction through commercial traffic, climate change, and the absence of natural enemies in the destination ecosystem is related to the introduction of a specific Hymenoptera, Vespa velutina, in Italy and Europe. External events attributable to human activities, such as climate change and the introduction of non-native plants, foods and Hymenoptera through trade, have contributed to the issue of imported allergens. Making the correct diagnosis and guiding the diagnostic and therapeutic path in this particular context represent the concerns of the pediatric allergist.

Fatal food anaphylaxis in adults and children.

Anaphylaxis is a life-threatening reaction characterized by the acute onset of symptoms involving different organ systems and requiring immediate medical intervention. The incidence of fatal food anaphylaxis is 0.03 to 0.3 million/people/year. Most fatal food-induced anaphylaxis occurs in the second and third decades of life. The identified risk factors include the delayed use of epinephrine, the presence of asthma, the use of recreational drugs (alcohol, nicotine, cannabis, etc.), and an upright position. In the United Kingdom (UK) and Canada, the reported leading causal foods are peanuts and tree nuts. In Italy, milk seems to be the most common cause of fatal anaphylaxis in children < 18 years. Fatal food anaphylaxis in Italian children and adolescents almost always occurs outside and is characterized by cardiorespiratory arrest; auto-injectable adrenaline intramuscular was available in few cases. Mortality from food anaphylaxis, especially in children, is a very rare event with stable incidence, but its risk deeply impacts the quality of life of patients with food allergy and their families. Prevention of fatal food anaphylaxis must involve patients and their families, as well as the general public, public authorities, and patients' associations.

Exercise-induced bronchoconstriction, allergy and sports in children.

Exercise-induced bronchoconstriction (EIB) is characterized by the narrowing of airways during or after physical activity, leading to symptoms such as wheezing, coughing, and shortness of breath. Distinguishing between EIB and exercise-induced asthma (EIA) is essential, given their divergent therapeutic and prognostic considerations. EIB has been increasingly recognized as a significant concern in pediatric athletes. Moreover, studies indicate a noteworthy prevalence of EIB in children with atopic predispositions, unveiling a potential link between allergic sensitivities and exercise-induced respiratory symptoms, underpinned by an inflammatory reaction caused by mechanical, environmental, and genetic factors. Holistic management of EIB in children necessitates a correct diagnosis and a combination of pharmacological and non-pharmacological interventions. This review delves into the latest evidence concerning EIB in the pediatric population, exploring its associations with atopy and sports, and emphasizing the appropriate diagnostic and therapeutic approaches by highlighting various clinical scenarios.

Record of strep throat infections in Italy: what is needed to know about penicillin allergy? The point of view from the Italian Society of Pediatric Allergy and Immunology (SIAIP).

Notifications of invasive group A streptococcal (iGAS) infections have significantly increased in many European Countries compared to the previous season. In Italy, there has been an increase in streptococcal pharyngitis and scarlet fever cases since January 2023, which sparked concerns about a GAS epidemic in the pediatric population. This rise may be ascribed to the GAS infection season that began earlier than usual (off-season outbreak) and the increase in the spread of respiratory viruses and viral coinfections that raised the risk of iGAS disease. Moreover, this phenomenon was also facilitated by increased travel after reduced GAS circulation during the COVID-19 pandemic.The increase in cases of GAS disease has raised some critical issues regarding the potential reactions to administering amoxicillin, the first-line antibiotic therapy, many of which have been erroneously labeled as "allergy."For these reasons, the Italian Society of Pediatric Allergy and Immunology (SIAIP) intends to provide simple clinical indications to help pediatricians manage GAS pharyngitis, discerning the allergic from non-allergic drug hypersensitivity.

Perturbations of the T-cell receptor repertoire in response to SARS-CoV-2 in immunocompetent and immunocompromised individuals.

BACKGROUND: Functional T-cell responses are essential for virus clearance and long-term protection after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas certain clinical factors, such as older age and immunocompromise, are associated with worse outcome. OBJECTIVE: We sought to study the breadth and magnitude of T-cell responses in patients with coronavirus disease 2019 (COVID-19) and in individuals with inborn errors of immunity (IEIs) who had received COVID-19 mRNA vaccine. METHODS: Using high-throughput sequencing and bioinformatics tools to characterize the T-cell receptor ß repertoire signatures in 540 individuals after SARS-CoV-2 infection, 31 IEI recipients of COVID-19 mRNA vaccine, and healthy controls, we quantified HLA class I- and class II-restricted SARS-CoV-2-specific responses and also identified several HLA allele-clonotype motif associations in patients with COVID-19, including a subcohort of anti-type 1 interferon (IFN-1)-positive patients. RESULTS: Our analysis revealed that elderly patients with COVID-19 with critical disease manifested lower SARS-CoV-2 T-cell clonotype diversity as well as T-cell responses with reduced magnitude, whereas the SARS-CoV-2-specific clonotypes targeted a broad range of HLA class I- and class II-restricted epitopes across the viral proteome. The presence of anti-IFN-I antibodies was associated with certain HLA alleles. Finally, COVID-19 mRNA immunization induced an increase in the breadth of SARS-CoV-2-specific clonotypes in patients with IEIs, including those who had failed to seroconvert. CONCLUSIONS: Elderly individuals have impaired capacity to develop broad and sustained T-cell responses after SARS-CoV-2 infection. Genetic factors may play a role in the production of anti-IFN-1 antibodies. COVID-19 mRNA vaccines are effective in inducing T-cell responses in patients with IEIs.

Selective IgM Deficiency: Evidence, Controversies, and Gaps.

Selective Immunoglobulin M deficiency (SIgMD) has been recently included in the inborn errors of immunity (IEI) classification by the International Union of Immunological Societies Expert Committee. The understanding of SIgMD is still extremely limited, especially so in cases of SIgMD in the pediatric population. The epidemiology of SIgMD in the pediatric population is still unknown. The pathogenesis of SIgMD remains elusive, and thus far no genetic nor molecular basis has been clearly established as a definitive cause of this primary immunodeficiency. Recurrent respiratory infections represent the main clinical manifestations in children, followed by allergic and autoimmune diseases. No conclusive data on the correct therapeutic management of SIgMD are available. Although, for most SIgMD patients, Ig replacement therapy is not required, it may be recommended for patients with significantly associated antibody deficiency and recurrent or severe infections. Prophylactic antibiotics and the prompt treatment of febrile illness are crucial. There is insufficient evidence on the prognosis of this condition. Therefore, further studies are required to define the disease trajectories and to increase our understanding of the molecular mechanisms underlying SIgMD in order to facilitate a better clinical, immunological, and prognostic characterization of the condition and develop tailored therapeutic management strategies.

Clinical and immunological phenotypes of selective IgM deficiency in children: Results from a multicenter study.

BACKGROUND: A few studies assessed the clinical and immunological features of selective IgM deficiency (SIgMD), especially in the pediatric age. We aimed to characterize the clinical and immunological phenotypes of a cohort of pediatric patients with SIgMD according to the different diagnostic criteria available. METHODS: In this multicenter study, we evaluated pediatric SIgMD patients diagnosed at the Pediatric Clinic in Pavia, Italy, or through the Italian Primary Immunodeficiency NETwork (IPINET) and monitored changes in their diagnosis over a time frame that ranges from several months to several years. RESULTS: Forty-eight patients with SIgMD were included (mean serum IgM: 33 mg/dL). The most common clinical manifestations were recurrent infections (67%) and allergies (48%). Subgroup analysis according to SIgMD definition criteria of the European Society for Immunodeficiencies (ESID) showed no significant difference in clinical manifestations, also considering the group with additional immunological abnormalities. Sixteen patients had long-term follow-up, during which 87% preserved their SIgMD diagnosis, while two patients showed a reduction in IgA in addition to low IgM. CONCLUSIONS: Our data suggest that the identification of a reduction in serum IgM in children should lead to a complete immunological work-up to obtain a comprehensive clinical and immunological characterization of the patient. The follow-up of these patients is fundamental to define the disease evolution and appropriate management.

Allergic Proctocolitis: Literature Review and Proposal of a Diagnostic-Therapeutic Algorithm.

Allergic proctocolitis (AP) is a benign condition, frequent in childhood, that is classified as a non-IgE-mediated food allergy. The prevalence is unknown; however, its frequency appears to be increasing, especially in exclusively breastfed infants. Clinical manifestations typically begin in the first few months of life with the appearance of bright red blood (hematochezia), with or without mucus, in the stool of apparently healthy, thriving infants. Most cases of AP are caused by cow's milk proteins; however, other allergens, such as soy, egg, corn, and wheat, may be potential triggers. Diagnosis is based on the patient's clinical history and on the resolution of signs and symptoms with the elimination of the suspected food antigen from the diet and their reappearance when the food is reintroduced into the diet. The treatment of AP is based on an elimination diet of the trigger food, with resolution of the symptoms within 72-96 h from the beginning of the diet. The prognosis of AP is good; it is a self-limiting condition, because most children can tolerate the trigger food within one year of life, with an excellent long-term prognosis. The purpose of this review is to provide an update on the current knowledge and recommendations in epidemiological, diagnostic, and therapeutic terms to the pediatricians, allergists, and gastroenterologists who may find themselves managing a patient with AP.

The role of basophil activation test and component-resolved diagnostics in the workup of egg allergy in children at low risk for severe allergic reactions: A real-life study.

BACKGROUND: The gold standard for diagnosing egg allergy in children is the oral food challenge (OFC). However, OFCs are time-consuming and risky procedures. Our study aimed to evaluate the utility of the basophil activation test (BAT) and component-resolved diagnostic in the diagnostic workup of children with egg allergy. METHODS: Overall, 86 children aged 6 months to 17 years, suspected of egg allergy, underwent OFC with boiled egg according to international standardized protocols. BAT and specific immunoglobulin E (sIgE) testing to component egg proteins (Gal d 1-4) were also performed. RESULTS: Of the 22 children who reacted to boiled egg, only one experienced anaphylaxis during the challenge. BAT was performed in samples obtained by 75 of the 86 patients of our cohort. Egg white and yolk protein extracts induced CD63 upregulation in the egg-allergic (EA) children compared with sensitized children that tolerated boiled egg (we registered an overall mean of CD63 expression in the EA population of 44.4% [SD 34.1] for egg white and 34.7% [SD 31.3] for egg yolk vs. 12.5% [SD 19.1] and 10.0% [SD 16.0] in sensitized children). BAT could discriminate between true egg allergy and egg sensitization in our population. As a second-line diagnostic step, the positivity of BAT for egg white or Gal d 1-sIgE resulted in a 40.9% OFC reduction, especially for those with a positive outcome. CONCLUSION: The BAT may be implemented in the diagnostic workup of egg allergy in children and, in a stepwise approach, separately or combined with Gal d 1-sIgE, may predict the allergic status and reduce the number of positive OFCs in children with egg allergy at low risk for severe reactions.

New approaches in childhood asthma treatment.

PURPOSE OF REVIEW: This review aims to summarize the most recent advances in asthma management, focusing on novel approaches to pediatric asthma. RECENT FINDINGS: In recent years, the therapeutic tools for pediatric asthma have expanded significantly for both the nonsevere and severe forms. The use of anti-inflammatory treatment, even for the mildest cases, and the withdrawal of symptomatic bronchodilation as monotherapy have been included in the most recent guidelines. Also, different biological therapies have revolutionized the therapeutical approach for severe uncontrolled asthma in children and adolescents. SUMMARY: With the expanding landscape of novel therapeutic approaches for pediatric asthma, further evidence is needed to help clinicians choose the best option for patients, particularly those with severe asthma. The identification of novel predictive biomarkers may also help pediatricians in selecting children and adolescents for innovative therapies.

Pediatric Angioedema without Wheals: How to Guide the Diagnosis.

Angioedema (AE) is a vascular reaction of subcutaneous and submucosal tissues that identifies various clinical pictures and often is associated with wheals. AE without wheals (AEwW) is infrequent. The ability to distinguish between AEwW mediated by mast cells and bradykinin-mediated or leukotriene-mediated pathways is often crucial for a correct diagnostic-therapeutic and follow-up approach. AEwW can be hereditary or acquired. Factors typically correlated with hereditary angioedema (HAE) are a recurrence of episodes, familiarity, association with abdominal pain, onset after trauma or invasive procedures, refractoriness to antiallergic therapy, and lack of pruritus. The acquired forms of AE can present a definite cause based on the anamnesis and diagnostic tests. Still, they can also have an undetermined cause (idiopathic AE), distinguished according to the response to antihistamine in histamine-mediated and non-histamine-mediated forms. Usually, in childhood, AE responds to antihistamines. If AEwW is not responsive to commonly used treatments, it is necessary to consider alternative diagnoses, even for pediatric patients. In general, a correct diagnostic classification allows, in most cases, optimal management of the patient with the prescription of appropriate therapy and the planning of an adequate follow-up.

Immune tolerance breakdown in inborn errors of immunity: Paving the way to novel therapeutic approaches.

Up to 25% of the patients with inborn errors of immunity (IEI) also exhibit immunodysregulatory features. The association of immune dysregulation and immunodeficiency may be explained by different mechanisms. The understanding of mechanisms underlying immune dysregulation in IEI has paved the way for the development of targeted treatments. In this review article, we will summarize the mechanisms of immune tolerance breakdown and the targeted therapeutic approaches to immune dysregulation in IEI.

COVID-19 and autoimmune diseases: is there a connection?

PURPOSE OF REVIEW: This review summarizes current evidence on the potential link between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and autoimmunity. RECENT FINDINGS: Several viral infections are potential triggers of reactive and autoimmune diseases by inducing type II and type IV hypersensitivity reactions. Recent evidence demonstrated that SARS-CoV-2 infection is not an exception, triggering the production of tissue-specific autoantibodies during the acute phase of coronavirus disease 2019 (COVID-19) and leading to autoimmune diseases development as long-term complication. The significant immune dysregulation with cytokine storm and organ damage observed in patients with severe to critical COVID-19 is considered the main mechanism explaining the high levels of autoantibodies, which are also implicated in disease severity and the need for an intensive care assessment. Multisystem inflammatory syndrome in children (MIS-C) is an immune-mediated disease where the recent viral infection leads to systemic inflammation, as already observed in other reactive and autoimmune diseases. SUMMARY: Autoimmunity may be a complication of SAR-CoV-2 infection. Understanding the pathogenesis of autoimmune manifestations in COVID-19 might help prevent the incidence or exacerbation of autoimmune disorders and design better and more efficient treatment strategies in children and adult populations.

Omalizumab may protect allergic patients against COVID-19: A systematic review.

Omalizumab, which downregulates the immunoglobulin E (IgE) receptor site on plasmacytoid dendritic cells and thereby increases interferon-α (INF-α) production, may shorten the duration of viral infections by enhancing the antiviral immunity. A systematic review was conducted to investigate whether previous anti-IgE treatment with omalizumab could protect against SARS-CoV-2 disease ("COVID-19") (infection, disease duration, and severity), and whether IFN-α upregulation could be involved. The research included articles published from March 2020 to January 2022. An accurate search was performed on bibliographic biomedical database (MEDLINE - Pubmed, SCOPUS, EMBASE, BIOMED CENTRAL, Google scholar, COCHRANE LIBRARY, ClinicalTrial.gov) including cohorts, case reports and reviews. Different methods were used, based on the study design, to assess the quality of eligible studies. Several authors link omalizumab to a possible protection against viruses, but they often refer to studies carried out before the pandemic and with viruses other than SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) (eg, rhinoviruses -RV). Few cases of COVID-19 patients treated with omalizumab have been recorded, and, in most of them, no increased susceptibility to severe disease was observed. According to these data, the current indication is to continue omalizumab therapy during the pandemic. Moreover, although omalizumab may enhance the antiviral immune response even for SARS-CoV-2, further studies are needed to confirm this hypothesis. It would be helpful to establish a registry of omalizumab-treated (or in treatment) patients who have developed COVID-19. Finally, randomized controlled trials could be able to demonstrate the effect of omalizumab in protecting against severe SARS-CoV-2, through IFN-α upregulation or other immunological pathways.

A compilation answering 50 questions on monkeypox virus and the current monkeypox outbreak.

The current monkeypox disease (MPX) outbreak constitutes a new threat and challenge for our society. With more than 55,000 confirmed cases in 103 countries, World Health Organization declared the ongoing MPX outbreak a Public Health Emergency of International Concern (PHEIC) on July 23, 2022. The current MPX outbreak is the largest, most widespread, and most serious since the diagnosis of the first case of MPX in 1970 in the Democratic Republic of the Congo (DRC), a country where MPX is an endemic disease. Throughout history, there have only been sporadic and self-limiting outbreaks of MPX outside Africa, with a total of 58 cases described from 2003 to 2021. This figure contrasts with the current outbreak of 2022, in which more than 55,000 cases have been confirmed in just 4 months. MPX is, in most cases, self-limiting; however, severe clinical manifestations and complications have been reported. Complications are usually related to the extent of virus exposure and patient health status, generally affecting children, pregnant women, and immunocompromised patients. The expansive nature of the current outbreak leaves many questions that the scientific community should investigate and answer in order to understand this phenomenon better and prevent new threats in the future. In this review, 50 questions regarding monkeypox virus (MPXV) and the current MPX outbreak were answered in order to provide the most updated scientific information and to explore the potential causes and consequences of this new health threat.

Eosinophilic Gastrointestinal Diseases in Inborn Errors of Immunity.

Inborn errors of immunity (IEI) are disorders mostly caused by mutations in genes involved in host defense and immune regulation. Different degrees of gastrointestinal (GI) involvement have been described in IEI, and for some IEI the GI manifestations represent the main and characteristic clinical feature. IEI also carry an increased risk for atopic manifestations. Eosinophilic gastrointestinal diseases (EGIDs) are emerging disorders characterized by a chronic/remittent and prevalent eosinophilic inflammation affecting the GI tract from the esophagus to the anus in the absence of secondary causes of intestinal eosinophilia. Data from the U.S. Immunodeficiency Network (USIDNET) reported that EGIDs are more commonly found in patients with IEI. Considering this element, it is reasonable to highlight the importance of an accurate differential diagnosis in patients with IEI associated with mucosal eosinophilia to avoid potential misdiagnosis. For this reason, we provide a potential algorithm to suspect an EGID in patients with IEI or an IEI in individuals with a diagnosis of primary EGID. The early diagnosis and detection of suspicious symptoms of both conditions are fundamental to prevent clinically relevant complications.