Hypersensitivity reactions to vaccines in children: from measles to SARS-CoV-2.

Allergic individuals at risk for hypersensitivity reactions to measles vaccine marketed for a long time are well established. On the other hand, risk factors for hypersensitivity reactions to the new mRNA COVID-19 vaccines currently include a history of allergy, allergy to excipient of the vaccine, or hypersensitivity reactions to the first dose of COVID-19 vaccine. In the last two cases, the recipient should be assessed by an allergist before vaccination to share a decision on the choice of vaccination. Studies on skin testing accuracy and desensitization protocols to the COVID-19 vaccines and the efficacy of potential alternatives in patients with confirmed hypersensitivity reactions to the first COVID-19 vaccine are necessary to improve the safety of COVID-19 vaccines.

Radiocontrast Media Hypersensitivity Reactions in Children.

Hypersensitivity reactions to radiocontrast media seem to be rare in children. Furthermore, the use of radiocontrast media in children remains quite safe in terms of the severity of reactions. Since pediatric guidelines are lacking, the diagnostic workup employed in adults could be adapted to children, taking into account that results have not yet been validated in this age group. Specific protocols for risk stratification and management of severe reactions have been proposed so far.

Hypersensitivity reactions to proton pump inhibitors in childhood.

Hypersensitivity reactions (HRs) to proton pump inhibitors (PPIs) are mainly described in adults. Anyway, increased use of PPIs in childhood has been observed in recent years. In the literature, only case reports are published on children. Most of the PPI HRs are IgE-mediated. Skin test concentrations and allergy workup protocols used for adults are also applied in children. This study underlies that multicentric pediatric studies focusing on PPI reactions in children are needed.

Hypersensitivity Reactions to Monoclonal Antibodies in Children.

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.

Evaluating children with suspected allergic reactions to vaccines for infectious diseases.

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.

The Legacy of Hg Contamination in a Past Mining Area (Tuscany, Italy): Hg Speciation and Health Risk Assessment.

The mercury cell manufacturing process, which has been extensively used in chlor-alkali plants to produce chlorine and caustic soda by electrolysis, represents a major source of Hg environmental pollution. At Saline di Volterra (Tuscany, Italy), solution mining by pumping water into halite deposits was applied to produce brines for a mercury-cell chlor-alkali plant. The Hg-contaminated, exhausted brines were pumped back at depth into the rock salt field in order to renew the available resources. Activities ceased in 1994, following the leakage dispersion of highly contaminated Hg(0)-bearing brines into the environment. The mercury content in the soil, measured during a survey conducted in 2000, reached 334 mg/kg, highlighting diffuse contamination in the floodplain. By 2009, the Hg concentration had generally decreased and was mostly confined to the topsoil layer. In order to evaluate the present Hg soil pollution, a geochemical survey was carried out in 2023, almost thirty years after the contamination event. The obtained data indicated the occurrence of legacy Hg, which reached 25.5 mg/kg in some soil samples. Speciation analysis for the most contaminated soil revealed that Hg(0) represented about 17.3% of the total Hg and that water-soluble and organic Hg fractions were negligible. These results suggest that the originally released metallic mercury has volatilized and likely oxidized, becoming practically immobile in the soil. A risk assessment, performed by applying Hg speciation analysis, indicated that the mercury in the soil does not carry a risk of non-cancerous effects for different exposure routes in case of subsequent use of the site and that the formerly contaminated area can now be converted into a leisure area.

Risk factors for drug hypersensitivity reactions in children.

Drug hypersensitivity reactions are common in children. Risk factors predisposing to IgE-mediated drug allergies and delayed drug reactions are a matter of debate. Gender, age, previous reactions to the same drug or to another drug, reduced drug metabolism, chronic diseases, polypharmacy, drug doses are linked with the onset of hypersensitivity reactions in some children. Novel advances in genetic polymorphisms can rapidly change the approach to the prevention of reactions since gene testing can be a useful screening test for severe cutaneous adverse reactions. Viral infections may act as cofactors in susceptible individuals. Polypharmacy, high doses, repeated doses and parental route of administration are also risk factors. Clinicians should take into account risk factors to allow the risk-benefit balance to be maintained.

Drug-Induced Anaphylaxis in Children.

Drug-induced anaphylaxis in children is less common than in adults and primarily involves beta-lactams and nonsteroidal anti-inflammatory drugs. Epidemiological studies show variable prevalence, influenced by age, gender, and atopic diseases. The pathophysiology includes IgE-mediated reactions and non-IgE mechanisms, like cytokine release reactions. We address drug-induced anaphylaxis in children, focusing on antibiotics, nonsteroidal anti-inflammatory drugs, neuromuscular blocking agents, and monoclonal antibodies. Diagnosis combines clinical criteria with in vitro, in vivo, and drug provocation tests. The immediate management of acute anaphylaxis primarily involves the use of adrenaline, coupled with long-term strategies, such as allergen avoidance and patient education. Desensitization protocols are crucial for children allergic to essential medications, particularly antibiotics and chemotherapy agents.

Local Anesthetic Hypersensitivity Reactions in Pediatric Patients: Recognition and Management.

Local anesthetics (LAs) are commonly used in all medical specialties, particularly in association with surgery, obstetrics, dentistry, and emergency departments. Most individuals, starting from young children, are exposed to LAs during life. LA hardly induces adverse events when used in recommended doses and with proper injection techniques. However, immediate anaphylactic reactions to LA injections may be a rare but life-threatening manifestation. A comprehensive report of the event and performing a specialist examination are crucial to prevent further episodes. The diagnosis should be based on history, medical records, skin and challenge tests.

Aetiological factors associated with chronic urticaria in children: a systematic review.

Chronic urticaria is a distressing condition with high costs. The aim of this literature review was to assess the relative frequency of causes of chronic urticaria in childhood and to provide guidance on which laboratory tests should be performed. Using PubMed, EMBASE and Cochrane databases, the literature from 1966 to 2010 (week 25) was systematically reviewed. Data from studies conducted on children who had had urticaria for at least 6 weeks, and assessing at least 3 different causes of urticaria, were analysed by reviewers using independent extraction. Six studies, all of low quality, met the inclusion criteria. Idiopathic and physical urticaria were common. Infections, autoimmunity and allergy were also reported. We conclude that children with chronic urticaria not caused by physical stimuli should undergo tests for allergy or infections only when there is a history of cause-effect correlation. High-quality trials are warranted to evaluate the causes of chronic urticaria in childhood.

Hexavalent chromium release over time from a pyrolyzed Cr-bearing tannery sludge.

Pyrolysis in an inert atmosphere is a widely applied route to convert tannery wastes into reusable materials. In the present study, the Cr(III) conversion into the toxic hexavalent form in the pyrolyzed tannery waste referred to as KEU was investigated. Ageing experiments and leaching tests demonstrated that the Cr(III)-Cr(VI) inter-conversion occurs in the presence of air at ambient temperature, enhanced by wet environmental conditions. Microstructural analysis revealed that the Cr-primary mineral assemblage formed during pyrolysis (Cr-bearing srebrodolskite and Cr-magnetite spinel) destabilized upon spray water cooling in the last stage of the process. In the evolution from the higher to the lower temperature mineralogy, Cr is incorporated into newly formed CrOOH flakes which likely react in air forming extractable Cr(VI) species. This property transforms KEU from an inert waste to a hazardous material when exposed to ordinary ambient conditions.

Drugs and Vaccines Hypersensitivity in Children with Mastocytosis.

Mastocytosis, a heterogeneous mastcell disease, include three different entities: cutaneous mastocytosis, systemic mastocytosis (SM) and mast-cell sarcoma. Tryptase levels can differentiate cutaneous mastocytosis from SM. In mastocytosis, quick onset drug hypersensitivity reactions (DHRs) that are facilitated by mastcell mediators, are investigated in adults. Due to the limited number of children with mastcell disease and increased serum tryptase levels, the role of drugs in this age group is less studied. In this review, we critically assessed relevant papers related with immediate DHRs in children with mastocytosis and discuss practical issues of the management. In childhood mastocytosis, anaphylaxis is frequently idiopathic, and elevated level of basal tryptase, and high burden of disease may increase the risk. Among drugs, antibiotics, NSAIDs and opioids can potentially induce anaphylaxis, anyway avoidance should be recommended only in case of previous reactions. Moreover, vaccinations are not contraindicated in patients with mastocytosis. The risk of severe systemic reactions after drugs intake seems to be extremely low and in general lower in children than in adults. Anyway, studies on this topic especially focusing on children, are missing to state final recommendations.

Hypersensitivity to Intravenous Iron Preparations.

Intravenous iron is widely used for the treatment of iron deficiency anemia when adherence to oral iron replacement is poor. Acute hypersensitivity reactions during iron infusions are very rare but can be life threatening. Major risk factors for hypersensitivity reactions include a previous reaction to an iron infusion, a fast iron infusion rate, multiple drug allergies, atopic diseases, high serum tryptase levels, asthma, and urticaria. The management of iron infusions requires meticulous observation, and, in the event of an adverse reaction, prompt recognition and severity-related interventions by well-trained medical and nursing staff. Avoidance of IV iron products in patients with iron hypersensitivity reactions may not be considered as a standard practice.

COVID-19 Vaccines in Children with Cow's Milk and Food Allergies.

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.

Hypersensitivity to polyethylene glycol in adults and children: An emerging challenge.

Hypersensitivity reactions to polyethylene glycol (PEG) is an emerging challenge and the interest about this disease is growing since PEG is considered one of the possible causes of coronavirus disease 2019 (COVID 19) vaccine-associated anaphylaxis. PEG is used in a wide variety of pharmaceutical, medical, industrial, cosmetic, and food products and can be an active ingredient or used as an excipient. PEG is present in several medications, and it may or may not be present in different formulations and dosages of the same drug. Lack of standardization nomenclature, inadequate labelling of products and lack of knowledge about PEG involvement in hypersensitivity reactions expose patients at risk of presenting multiple reactions before a diagnosis could be made. In this review we describe the main cases published in literature and propose an allergy work-up and management.

Management of the child with allergy to non-antibiotic drugs.

Non-steroidal anti-inflammatory drugs, perioperative drugs, radio contrast media and chemotherapeutics drugs are, after the non-antibiotic drugs, the drugs most commonly responsible for allergic reactions in children. Management is different depending on the drug involved.

Mild cutaneous reactions to drugs.

Adverse reactions to drugs are not frequent in childhood. Cutaneous reactions are the most frequent in this age group. Mild cutaneous reactions are immediate or delayed adverse reactions that do not seriously compromise the clinical condition of children. The patients usually early improve and recover the state of health. Although it is difficult to define the prevalence accurately, we could affirm that the rate adverse reaction to drugs are often over estimated by both the families and the physicians. Therefore, children may be prone to loss of school days and inappropriate or sub-optimal treatments. However, the identification of a true adverse reaction to drugs allows adequate treatment and alert to further exposure to harmful drugs.

Mechanisms of hypersensitivity reactions induced by drugs.

Adverse drug reactions include drug hypersensitivity reactions (DHRs), which can be immunologically mediated or non-immunologically mediated. The high number of DHRs unconfirmed and/or self-reported is a frequent problem in daily clinical practice, with considerable impact on future prescription choices and patient health. It is important to distinguish between hypersensitivity and non-hypersensitivity reactions by adopting a structured diagnostic approach to confirm or discard the suspected drug, not only to avoid life-threatening reactions, but also to reduce the frequent over-diagnosis of DHRs.

Clinical features, outcomes and treatment in children with drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be considered a late-onset allergic reaction, can cause serious long-term sequelae. SJS/TEN are considered a spectrum of life-threatening adverse drug reactions. They have the same clinical manifestations and the only difference is in the extent of epidermal detachment. These conditions are associated with high mortality, although incidence of SJS/TEN is rare in children. SJS/TEN is an adverse drug reaction influenced by genes that involve pharmacokinetics, pharmacodynamics and immune response. Infective agents are additional influencing factors. Anticonvulsants and antibiotics, and especially sulphonamides and non-steroidal anti-inflammatory drugs, are among the drugs that were predominantly suspected of triggering SJS/TEN. No evidence-based standardized treatment guidelines for SJS or TEN are currently available. The usual treatment is mainly founded on the withdrawal of the suspected causative agent and supportive therapy. In pediatric patients, the specific therapeutic strategies are controversial and comprise systemic corticosteroids and the use of intravenous immunoglobulin (IVIG). More recently, new therapeutic approaches have been used, such as immunosuppressive therapies, including cyclosporine and TNF-α inhibitors.

Pediatric drug hypersensitivity: which diagnostic tests?

Along with the anamnesis and clinical evaluation, diagnostic tests are one of the mainstream key points in the evaluation and management of drug hypersensitivity reactions (DHR). A wide knowledge gap, both in diagnosis and management of pediatric DHR, must be filled.  Only a few published studies evaluated sensitivity and specificity of skin and in vitro tests in children. However, selected case series show that diagnostic work-up for adults could be useful, with some limitations, in pediatric age. Indeed, despite improvement in in vivo and in vitro diagnosis, drug provocation test remains the gold standard in pediatric age, too. Unmet needs in children include multi-centric studies on incidence of DHR, utility and feasibility of in vivo and in vitro diagnostic tests and specifically dedicated guidelines for the diagnosis and management of DHR in children.