Safety and adverse reactions in subcutaneous allergen immunotherapy: a review.

BACKGROUND: Allergen immunotherapy (AIT) is the only treatment which acts on the causes of allergic diseases by modifying their natural history. In the eighties subcutaneous immunotherapy (SCIT) with high biological power allergen extracts caused a number of severe systemic reactions and also fatalities in the UK and the US, resulting in its limitation and in the introduction of other routes of administration. A decisive advance for SCIT safety was understanding that the major cause of mortality was injecting the allergen extract to patients with uncontrolled asthma at the time of injection. AREAS COVERED: This awareness resulted in a significant decrease in fatalities, but not in their abolition. In 2019, an increase in SCIT-related mortality was observed, suggesting to continue the research for still unidentified factors favoring severe reactions, such as the administration of a wrong extract or of allergen doses higher than listed, unintentional intravenous administration, and missed dose reduction after protracted interruption. Moreover, in the context of the improving of the safety, the role played in tolerance-promoting by adjuvants such as CpG oligodeoxynucleotides has to be taken into account, as well as the potential preventive effect performed by the monoclonal anti-IgE antibody omalizumab against the exacerbation of severe reactions during SCIT. CONCLUSION: The safety of SCIT is good, but the research to improve it further must continue. In particular, the pathophysiological mechanisms related to AIT for inhalants and for Hymenoptera venom should be studied, based on the evident diversity demonstrated by the complete absence of fatal reactions to Hymenoptera venom immunotherapy from its introduction in comparison with the history of serious and fatal offenses examined in this review.

Two decades with omalizumab: what we still have to learn.

From its availability for clinical use nearly two decades ago for severe asthma, omalizumab has gained strong evidence of efficacy and safety in the treatment of severe asthma not controlled by standard-of-care therapy. It has been acknowledged by Global Initiative on Asthma guidelines as add-on therapy against severe uncontrolled asthma. Thanks to controlled trials supporting its efficacy, omalizumab has also been licensed for the treatment of chronic spontaneous urticaria. The optimal duration of treatment in either disease has not been established. Despite its high price, omalizumab appears to be cost-effective in severe uncontrolled asthma as well as in chronic urticaria. The literature suggests a wide range of applications for omalizumab in various disorders regardless of allergic or non-allergic pathophysiology.

Adherence to Sublingual Immunotherapy.

Adherence is a major issue in any medical treatment. Allergen immunotherapy (AIT) is particularly affected by a poor adherence because a flawed application prevents the immunological effects that underlie the clinical outcome of the treatment. Sublingual immunotherapy (SLIT) was introduced in the 1990s, and the early studies suggested that adherence and compliance to such a route of administration was better than the traditional subcutaneous route. However, the recent data from manufacturers revealed that only 13% of patients treated with SLIT reach the recommended 3-year duration. Therefore, improved adherence to SLIT is an unmet need that may be achieved by various approaches. The utility of patient education and accurate monitoring during the treatment was demonstrated by specific studies, while the success of technology-based tools, including online platforms, social media, e-mail, and a short message service by phone, is currently considered to improve the adherence. This goal is of pivotal importance to fulfill the object of SLIT that is to modify the natural history of allergy, ensuring a long-lasting clinical benefit, and a consequent pharmaco-economic advantage, when patients complete at least a 3-year course of treatment.

May chronic rhinosinusitis in children be diagnosed by clinical symptoms?

OBJECTIVES: Chronic rhinosinusitis (CRS) is a common disease in childhood but is often underdiagnosed because the symptoms are subtle and similar to other nasal pathologies. No clinical symptom is pathognomonic, and consensus documents suggest nasal fibroendoscopy (NF) or imaging criteria (computed tomography, magnetic resonance imaging) as the gold standards for diagnosis of CRS. However, considering the frequent unavailability of such tools to physicians, we designed this study to evaluate whether combinations of symptoms may achieve a clinical diagnosis of CRS in children as confirmed by NF. METHODS: The study population consisted of 275 children with a clinical diagnosis of CRS, in 228 of whom diagnosis of CRS was confirmed by NF, while in 47 diagnosis was not confirmed by NF and they served as the control group. The symptoms considered were nasal obstruction, nasal discharge, cough, facial pain, and halitosis, using for statistical analysis multivariate logistic regression, Wald tests, and receiver operating characteristic (ROC) curve. RESULTS: The multivariate logistic regression for CRS symptoms indicated rhinorrea as the strongest predictor of CRS. With three symptoms the probability of CRS was from 60% to 75% without rhinorrea and 77-91% in the presence of this symptom, with four symptoms the probability was over 93%, and with all the five symptoms the probability of having CRS was virtually 100%. CONCLUSIONS: These findings suggest that an initial symptoms assessment may help to recognize children with a high probability of CRS, thus reducing the need of NF or imaging techniques.

A role for Waldeyer's ring in immunological response to allergens.

OBJECTIVE: Adenoids, tubal tonsil, palatine tonsil, and lingual tonsil are immunological organs included in the Waldeyer's ring, the basic function of which is the antibody production to common environmental antigens. Adenoidal hypertrophy (AH) is a major medical issue in children, and adenoidectomy is still the most used treatment worldwide. The response of adenoids to allergens is a good model to evaluate their immunological function. This report assessed the immunological changes in adenoid tissues from children with allergic rhinitis (AR) undergoing sublingual immunotherapy (SLIT). METHODS: Adenoid samples from 16 children (seven males, nine females, mean age 7.12 years) with AH and clinical indication to adenoidectomy were collected. Of them, five children were not allergic and 11 had house dust mite and grass pollen-induced AR. Among allergic children, in four AR was treated by antihistamines while in seven AR was treated by high-dose SLIT during 4-6 months. The evaluation addressed the T helper 1 (Th1), Th2, and Th3 cells by performing a PCR array on mRNA extracted from adenoid samples. RESULTS: In non-allergic children, a typical Th1 pattern was found. SLIT induced a strong down-regulation of genes involved in Th2 and Th1 activation and function. In particular, in SLIT-treated allergic children IL-4, CCR2, CCR3, and PTGDR2 (Th2 related genes) and CD28, IL-2, and INHA (Th1 related genes) expression was reduced, compared with children treated with antihistamines. CONCLUSIONS: These preliminary findings warrant investigation in trials including larger numbers of patients, but indicate that hypertrophic adenoids of allergic children have the typical response to the specific allergen administered by SLIT. This should suggest that one should reconsider the immunological role of adenoids.

Pathophysiology, favoring factors, and associated disorders in otorhinosinusology.

The pathogenesis of rhinosinusitis (RS) is related to inflammation, caused by infections in the acute form of the disease but also by other agents in the chronic forms. Cytology allows to evaluate the defensive components, such as hair cells and muciparous cells, while the presence in the nasal mucosa of eosinophils, mast cells, bacteria and/or fungal hyphae, or spores indicates the nasal pathology. The anatomic and physiologic characteristics of the otorhinosinusal system account for the frequent concomitant involvement of the different components. The pivotal pathophysiologic sites are the ostiomeatal complex, the spheno-ethmoidal recess, and the Eustachian tube. The latter is the link with acute otitis media (AOM), which is the most common disease in infants and children and has major medical, social, and economic effects. Moreover, because of the strict relationship between upper and lower airways, nasal sinus disease may contribute to asthma and sinusitis may be considered as an independent factor associated with frequent severe asthma exacerbations. Concerning the role of allergy, the available data do not permit to attribute a central role to atopy in sinusitis and thus allergy testing should not be a routine procedure, while an allergologic evaluation may be indicated in children with OM, especially when they have concomitant rhinitis.

Diagnosis of chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a rather common disease in children, but its symptoms are often subtle and non-specific and this may result in overlooking a correct diagnosis. In turn, a missed diagnosis of CRS prevents a correct management to be performed and is associated with uneffective investigations and improper treatments. Actually, when CRS symptoms, which are mainly nasal congestion and obstruction, nasal discharge, facial pain, cough, and halitosis, are correctly assessed, the clinical diagnosis of CRS may be achieved, and confirmation may be obtained by imaging criteria or nasal fibroendoscopy. In imaging, computed tomography (CT) is the first choice technique for the evaluation of CRS and is able to provide an anatomic road map when surgery is required. Magnetic resonance imaging (MRI) of the sinuses, orbits, and brain should be performed whenever extensive or multiple complications of sinusitis are suspected. Also for middle ear disorders, CT is the first choice because it detects opacification of the middle ear cavity and mastoid cells, presence of fluids or debris, and allows the ossicular chain and the cortical bone of the mastoid to be evaluated. Another important diagnostic issue is the need to look for disorders that are frequently associated with CRS, such as obstructive sleep apnea syndrome (OSAS), that has some recognized risk factors in adenotonsillar hypertrophy, craniofacial anomalies, obesity, and neuromuscular disorders. Other associated disorders requiring investigation are recurrent or persistent otitis media and difficult asthma.

Sinus imaging for diagnosis of chronic rhinosinusitis in children.

Chronic rhinosinusitis (CRS) is a relatively common disease in children but is often overlooked because at times the clinical symptoms are subtle and nonspecific. This makes imaging very important in the diagnosis. Among the different techniques, plain radiography has limited utility,whereas CT scan and MRI have a major role in evaluating the modifications caused by the disease. In particular, a CT scan provides higher resolution of bone and soft tissue and removes the overlapping structures that are present in conventional radiography. CT is recommended in isolated sphenoid sinusitis, is essential in diagnosing fungal sinusitis, and is the technique of choice when orbital complications are suspected. MRI allows investigation of not only the morphology of structures, but their intrinsic biophysical and biochemical properties, such as water content, cellular density, lipid or blood product deposits, and fibrosis. MRI allows better soft tissue differentiation and high spatial resolution images depicting fine details. When indicated, MRI with contrast gadolinium-based agents may better characterize the local disease extension or its diffusion beyond paranasal and nasal cavities and has excellent contrast resolution. A combination of CT and MRI is useful in cases of diagnostic difficulties,especially when complications are involved.

New applications for sublingual immunotherapy in allergy.

Specific immunotherapy is the only treatment targeting the causes, and not only the symptoms, of allergic diseases. Sublingual immunotherapy (SLIT) was introduced and developed to solve the problem of the adverse reactions, uncommon but possibly severe and rarely fatal, to the traditional subcutaneous immunotherapy (SCIT). The evidence of SLIT efficacy concerns rhinitis and asthma caused by sensitization to pollens and to house dust mites, but there are increasing data suggesting that SLIT could be applied in forms of allergy hardly feasible for SCIT because of its poor safety (this is true for food allergy and latex allergy) or could be considered for new applications, such as atopic dermatitis or baker's asthma. In particular, there are placebo-controlled trials indicating good efficacy and safety of SLIT in patients allergic to latex and to foods and in children with atopic dermatitis, that indicate SLIT as a real treatment option in such clinical entities. This article also discusses some patent related to the field.

Diagnosis and management of acute rhinosinusitis in children.

Rhinosinusitis is a common disease in children that is often overlooked. The clinical symptoms of acute rhinosinusitis are nasal blockage or congestion, nasal discharge or postnasal drip (often mucopurulent), facial pain, headache, and reduction in/loss of smell. Direct vision by nasal fibroendoscopy may aid the diagnosis. Regarding imaging criteria, recent consensus documents state that plain sinus x-rays are of limited utility, and CT remains the technique of choice, particularly in children with complications or very persistent or recurrent infections that are unresponsive to medical management. Antibiotics are the primary form of medical treatment for acute bacterial rhinosinusitis, but they should be used when acute bacterial rhinosinusitis presents as persistent or severe disease. This will minimize the number of children with uncomplicated viral upper respiratory tract infections who are treated with antimicrobials. Topical corticosteroids may reduce nasal edema and improve ostial drainage and ventilation of the sinus.

Prevalence of tympanometric alterations in children with chronic sinusitis.

OBJECTIVE: Due to its anatomical and functional connections, middle ear disorders frequently occur in sinusitis. Its prevalence, however, is likely to be underestimated. We evaluated the prevalence of middle ear dysfunction, as assessed by tympanometry, in children with chronic sinusitis in a large group of patients with chronic respiratory symptoms, and its possible relationship with respiratory allergy. METHODS: From a population of 1,810 children with respiratory symptoms referred to our Pediatric Allergy center, subjects with chronic sinusitis diagnosed by clinical criteria were selected. Children underwent testing of middle ear function by tympanometry and of allergy by skin tests with environmental allergens. Patients were divided into three groups according to age. RESULTS: Two hundred and eighty-eight children (15.9%) had clinical diagnosis of chronic sinusitis according to the established criteria. Twenty-four patients were in group 1, 220 in group 2, and 44 in group 3. Altered middle ear pressure was found in 76.4% of patients, with a significantly higher rate of altered tympanograms in younger children (p<0.001). A positive skin prick test was found in 29.9% of children, with a significantly higher rate of positivity in older children (p=0.01). CONCLUSIONS: The decrease with age in the rate of tympanometric alterations is likely to be associated to the anatomic development of the upper airways, while the presence of atopy does not seem to play a role in their occurrence.

Clinical tolerance to lactose in children with cow's milk allergy.

OBJECTIVE: Adverse reactions following the ingestion of lactose have been reported in children with cow's milk (CM) allergy. Whether this is attributable to the contamination of lactose with CM proteins is unknown. In this paper, we assessed clinical tolerance of lactose derived from CM whey in children hypersensitive to CM from 2 university hospital pediatric departments. DESIGN: Twenty-four children (5 girls and 19 boys, median 25 months old; range: 2-107 months) with immediate CM allergy confirmed at history or during double-blind, placebo-controlled food challenge (DBPCFC) were enrolled. DBPCFC with CM could be conducted in 11 of 24 patients. Children with a history of immediate/delayed reactions to soy formula (SF) were excluded. Clinical tolerance to CM, SF, and SF + lactose was assessed by: 1) skin prick test with casein, lactalbumin, soy commercial allergen preparations, fresh CM, SF, SF and lactose, lactose (Official Pharmacopoeia) in 4 concentrations (0.01%, 0.1%, 1%, 10%); 2) specific serum immunoglobulin E determination by CAP system technology; 3) DBPCFC in 8 incremental doses of SF + lactose and using SF as a placebo to make up a total of 240 mL of reconstituted formula. RESULTS: With a positive cutoff point of > or = 3 mm wheal diameter at SPT, all patients were sensitized to fresh CM, lactalbumin, and/or casein. Twenty-three of 24 patients (95.8%) were SPT-positive to CM formula, 16 of 24 to lactalbumin (66.6%), 14 of 24 to casein (58.3%), and none to SF, SF + lactose, or lactose alone at all dilutions. Complexed immunoglobulin E determinations were positive for CM in 23 of 24 cases and negative in all cases for soy. Challenge with SF + lactose was negative in all cases. CONCLUSIONS: Even children hypersensitive to CM are clinically tolerant to lactose and can safely consume foods and drugs with lactose from bovine sources as an ingredient. Lactose exclusion is unwarranted from soy preparations on grounds of potential allergic reactions to CM protein residue.

[Alternative tests in the diagnosis of food allergies]. / Test alternativi nella diagnostica delle allergie alimentari.

In the last years an increase of allergic diseases has been observed whose prevalence is about 20-30% in general population of western countries. However there is a risk of an over diagnosis of allergic diseases as many different diseases (migraine, chronic urticaria, chronic inflammatory bowel diseases, chronic-fatigue syndrome etc.) are considered due to food allergy or intolerance. In many patients the diagnosis is based on the results of alternative diagnostic tests such as the cytotoxic test, the provocation/neutralization sublingual or subcutaneous test, the heart-ear reflex test, the kinesiology, the biorisonance, the electro-acupuncture, and the hair analysis, or on immunological tests (immunocomplex or specific food IgG). We reviewed the scientific evidences of these tests (specificity, sensibility, rationale, reproducibility). According to most studies none of them had to be recommended as useful for the diagnosis of food allergy or intolerance. Physicians should alert patients about the risk of an indiscriminate use of these test in the diagnosis of food allergy. In fact the use of an incorrect diet could be dangerous, particularly in childhood, as recently shown.