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

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

The clinical relevance of molecular diagnosis in children allergic to grass pollen and treated with allergen immunotherapy

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The growing importance of real-life studies in allergen immunotherapy.

Summary: Real-life studies offer the opportunity of obtaining outcomes suitable in clinical practice, as controlled trials do not mirror the real patients' population observed in clinical practice. This concept is particularly appropriate for allergen immunotherapy (AIT). Therefore, the current review will present and discuss the most recent and relevant studies published on this topic. Globally, 15 real-life studies on AIT efficacy are available until now, the total of patients amounts to 9090, with an average number of 699 patients per study. This high number significantly decrease the possibility that the observations from real-life study are casual, and confers to such studies a key role in the next years to assess issues other than efficacy and safety, especially those scantly investigated thus far.

Nasal cytology in children: scraping or swabbing?

Nasal cytology has become a valuable tool in the assessment of a multitude of nasal pathologies in children. Collection methods differ significantly and even though the use of the nasal curette is regarded as the most reliable in adults, most practitioners use the nasal swab in children. However, no studies have validated the reliability and supposed better tolerability of the latter. We have compared these two sampling methods regarding their tolerability and analysed the diagnostic accuracy of the cotton nasal swab (NSW) to identify nasal cytotypes and rhinitis phenotypes, using nasal scraping (NSC) for comparison. In a multicentric prospective study we recruited 208 children and performed nasal cytology by means of NSW and NSC. Microscopic evaluating of the nasal cytotypes was performed and tolerability of NSW and NSC was tested. Our data revealed a significantly inferior diagnostic accuracy of NSW compared to NSC regarding reliability and cell counts. Our study is the first to shed light on the role of the sampling tools for pediatric nasal cytology. We documented a poor diagnostic accuracy of NSW, thus suggesting using only the nasal curette in clinical practice. Furthermore, tolerability did not differ between the two, refuting the common thesis that swabs are to be preferred when doing nasal cytology in children.

Isotonic saline in children with perennial allergic rhinitis.

Children with HDM allergy suffer from perennial allergic rhinitis (PAR). The present pilot study evaluated nasal lavage with isotonic saline (0.9%) in 25 children (mean age 8.9 years; 13 males) with HDM-dependent PAR, assessing: nasal symptoms severity and parental perception of rhinitis control, sleep, and school performance. Nasal symptoms, rated by total symptom score, parental perception of PER control, sleep quality, and school performance, measured by visual analogue scale, were significantly improved by nasal lavage (p < 0.001) after treatment. The effects tended to persist also during the follow-up. In conclusion, the present pilot study provides the first evidence that nasal lavage with isotonic saline relieved the nasal symptoms of children with PAR and improved the parental perception of the disease.

Hypertonic saline monotherapy in children with perennial allergic rhinitis: a pilot study.

Perennial allergic rhinitis (PAR) is very common in children and has a relevant impact on their families. House dust mites (HDM) are the most relevant cause of PAR. The present pilot study aimed to evaluate whether hypertonic saline (3%) nasal spray as monotherapy is able to improve: nasal symptom severity and parental perception of rhinitis control, sleep, and school performance in HDM-mono-sensitized children with PAR. Globally, 25 children (13 males and 12 females; mean age 9.5±3.1 years) were treated for 3 weeks. They were visited at baseline, at the end of treatment, and after a 2-week follow-up. Hypertonic saline significantly reduced total symptom score, and improved the perception, according to their parents, of rhinitis control, sleep, and school performance. In conclusion, the present pilot study provided the first evidence that 3% hypertonic saline monotherapy was able to relieve nasal symptoms and parental perception of PAR impact as well as being safe and well tolerated.

Nose-bronchi link: does an asthma march exist?

Allergic rhinitis is considered a strong risk factor for the onset of asthma. However, few studies have addressed this issue from a functional point of view. In this work the close link between upper and lower airways is highlighted, suggesting that spirometry should be precociously performed on patients with allergic rhinitis.

Allergen immunotherapy may exert an extra-anti-allergic activity in children.

Allergic patients frequently suffer from infections. Allergen immunotherapy (AIT) usually improves respiratory symptoms, mainly in allergic rhinitis (AR). This study was aimed at evaluating the possible impact of AIT on extra-allergic outcomes in a cohort of Italian children with respiratory allergy patients. The study was performed on 77 children (43 males, mean age 10.5 years) with AR. The kind and the number of prescribed allergen extracts, type of diagnosis, severity of symptoms, and use of drugs were evaluated at baseline and after 2 year AIT. Globally 40 patients were treated with AIT, the remaining 37 children served as control. AIT-treated children had lower symptoms, drug use, and less severe extra-allergic surrogate markers of infection in comparison with children untreated with AIT. In conclusion, this study provides the first evidence that 2-year SLIT is able of exerting an adjunctive anti-allergic activity in AR children.

Immunological modifications induced from products used during the perioperative period.

Anesthetics and other products used during the perioperative period may influence immune function not only merely by reducing the HPA-axis stress response but also by directly modulating innate and adaptive immune responses. Most of the literature on the immune effects of anesthetics has been derived from in vitro or animal studies, due to the number of confounding variables in real life surgical settings. These immunosuppressive effects might not normally have clinical consequences for an immune-competent patient, but may act as important modifiers in postoperative morbidity and mortality. Furthermore, some inhibitory effects on neutrophil functions may provide a therapeutically beneficial effect under specific surgical clinical conditions, such as ischemia-reperfusion injury.

Ovarian carcinoma presenting with axillary lymph node metastasis: a case report.

Ovarian cancer is usually limited to the abdomen and frequently remains confined. The occurrence of extrabdominal mestastases is unusual. In this report we describe a rare case of axillary involvement at initial presentation of ovarian cancer in a 48-year-old woman. The axillary mass was the only clinical abnormality. Cytological and histological findings, performed on axillary lymph nodes, showed the presence of psammoma bodies and specific immunohistochemical tumor markers (OC-125 and WT1), supporting the evidence of a metastatic axillary lymphadenopathy from ovarian cancer. Subsequently, chest and abdominopelvic computed tomography showed a right ovarian complex mass of 30 x 25 mm and biochemical tests showed high levels of CA125. Surgical therapy was performed. Histology confirmed the diagnosis, evidencing a poorly differentiated serous-papillary carcinoma of the right ovary. In conclusion, cytological and histological findings can play a crucial role in suggesting the correct origin of a metastatic adenocarcinoma when the clinical presentation is atypical.

Immune response to sublingual immunotherapy in children allergic to mites.

Allergic rhinitis (AR) is characterized by Th2 polarized immune response. Specific immunotherapy modifies this arrangement restoring a physiologic Th1 profile. Sublingual immunotherapy (SLIT) is widely prescribed, but there is no early marker of response. The aim of this study is to investigate possible marker of SLIT effectiveness. Thirty children with mite allergy were studied: 15 were treated with drugs alone, 15 with SLIT and drugs on demand. The study lasted 2 years. Visual analogue scale (VAS) for symptoms and medication score were evaluated. Serum cytokines (IL-2, IL-4, IL-6, IL-8, IL-10, IFN-gamma, MCP-1, and TNF-alpha) were assessed by ELISA before and after 1 and 2 year SLIT. SLIT-treated children obtained a significant improvement of symptoms and a reduction of drug use, whereas children treated with a drug alone did not obtained any change. IL-10 significantly increased, whereas Th2-dependent and pro-inflammatory cytokines significantly decreased. In conclusion, the present study demonstrates that 2-year SLIT is capable of inducing immunologic hyporeactivity to mites.

The history of sublingual immunotherapy.

The sublingual route of administration of allergen (SLIT) has emerged as an effective treatment. Other non-injective route of administration of vaccines failed their goals; oral immunotherapy (OIT), local nasal immunotherapy (LNIT), local bronchial immunotherapy (LBIT) were reported as too expensive or unsafe or ineffective. Oral regimens were used in the first half of the 20th century but then they lost ground to injection immunotherapy. SLIT is suitable for home treatment and it has not to be regarded not only as a substitute of subcutaneous immunotherapy (SCIT), but also as a complementary or additional therapeutic tool in conventional medical practice. Currently, the balance sheet for SLIT is improving: with the steadily increasing number of patients with IgE mediated disorders, looking for a "cheap, safe and effective therapy" becomes a priority.

Reproducibility of atopy patch tests with food and inhalant allergens.

Although atopy patch tests (APT) seem a valuable additional tool in the diagnostic work-up for food allergy in children with atopic eczema/dermatitis syndrome, the immunopathology and some technical aspects of testing remain controversial. Few published data are available on the reproducibility of APT with inhalants and only two studies include fresh food allergens. In this study we therefore investigated the reproducibility of duplicate APT (left versus right side of the back) with native and commercially available food (cow s milk, hen s egg, tomato, wheat flour) and with inhalant allergens (Dermatophagoides pteronyssinus and mixed grasses) in a large unselected population of children. We tested a population of 277 Italian school children with three APT allergens: fresh food (cow s milk, hen s egg, tomato and wheat flour), standardised food allergens in petrolatum (the same four foods) and standardised inhalant allergens routinely used for skin prick testing. For the four food allergens (applied in the natural form or as the standardised commercial preparation) from one- to three quarters of the APT gave positive results on one side and negative reactions on the opposite side (Cohen s K coefficient between 0.38, fresh tomato and 0.81, fresh cow s milk). Conversely, APT with inhalant allergens were invariably reproducible (Cohen s K = 1.00). The possible technical and immunologic reasons explaining why reproducibility of APT differed for the two types of allergens await an answer from extensive controlled studies.

Antibiotic treatment alone for acute rhinosinusitis gives a poor response in allergic children.

Acute rhinosinusitis (ARS) is frequent in children. Patients with allergic rhinitis show signs of more impaired paranasal sinus functioning than normal subjects during viral colds. This study evaluated the effectiveness of administering antibiotics alone to treat ARS in both allergic and non-allergic children. We obtained informed consent from the parents of each patient enrolled in the study. 97 children, 55 males and 42 females aged between 4 and 9 years (46 of whom were allergic), suffering from ARS, were treated with amoxicilline-clavulanate (50 mg/Kg bid) for 14 days. Symptoms and endoscopic signs of illness were evaluated at baseline and immediately after treatment. Symptoms improved significantly (p<0.001) after treatment in 84 patients, equally distributed between allergic and non-allergic subjects. On the contrary, endoscopic signs disappeared only in 49 children, 9 of whom were allergic (OR 14.9, 95%CI 4.6-40.1, p<0.001). Slight to fair agreement was observed between clinical symptoms and endoscopic signs (agreement 64% , Kappa=0.28, McNemar test p<0.001). Antibiotic therapy alone in the treatment of ARS may be generally insufficient to resolve symptoms, mainly endoscopic signs. Moreover, in allergic children this issue appears to be more evident.

Tahini, a little known sesame-containing food, as an unexpected cause of severe allergic reaction.

We describe the case of a young woman with asthma and confirmed food allergy to sesame who had 2 severe systemic reactions after the inadvertent ingestion of tahini, a paste made with ground sesame seeds that is not generally known by physicians and patients as a sesame-containing food. A double-blind placebo-controlled food challenge confirmed the allergy to tahini in our patient. As new products and recipes are being introduced from around the world on a regular basis, it is essential that at-risk patients are able to obtain information about allergens used as ingredients and as potential contaminants. This should be applied not only to packaged food but also to freshly made foods, such as those served in restaurants.

Non-invasive assessment of airway inflammation in ship-engine workers.

Smoking is harmful for respiratory function. In young to middle-aged men the damage is insidious and difficult to demonstrate. The respiratory impairment could increase under specific stressful conditions in the professional environment. On the hypothesis that exhaled markers are useful for assessing airway susceptibility to inhaled irritants, we measured exhaled markers and lung function in smoking and non-smoking engine-driver military coastguards before and after a patrol at sea. Eighteen men, mean age 39 yrs (range 23-58 yrs), 8 smokers, underwent spirometry, exhaled and nasal nitric oxide (eNO, nNO), exhaled carbon monoxide (CO) and exhaled breath condensate (EBC) for measures of hydrogen peroxide (H2O2), leukotriene B4 (LTB4), proteins (Prots), 8-isoprostanes (8-IsoPs), nitrite (NO2-) and nitrosothiols (RS-NOs) at baseline and after an 8-hour patrol navigation on board small, high-speed diesel-powered ships. At baseline, the smokers showed higher middle flows and CO levels, lower eNO and nNO than non-smokers, but similar levels of EBC markers; geometric means (95% confidence interval), CO: 23.6 (14.5 to 38.3) vs. 3.5 (2.5 to 5.3) ppm; eNO: 7.9 (4.8 to 12.9) vs. 26.7 (15.7 to 45.5) ppb, p=0.000. After navigation, Prots, 8-IsoPs and RS-NOs (but not lung function variables or other markers) significantly increased only in smokers; baseline vs post-navigation RS-NOs: 0.27 (0.11 to 0.65) vs. 1.30 (0.58 to 2.89) micromol, p=0.012. The respiratory consequences of a stressing environment in engine-driver military coastguards who actively smoke are better assessed by measuring EBC markers than by eNO, nNO or lung function. By increasing airway inflammation from oxidative-stress, tobacco smoking appears to interact with other chemical or physical factors elicited during sea navigation. Precisely what these factors are deserves further investigation.

Differences in serum GH cut-off values for pharmacological tests of GH secretion depend on the serum GH method. Clinical validation from the growth velocity score during the first year of treatment.

BACKGROUND: The serum GH cut-off value for pharmacological tests of GH secretion (PhT GH) depends on the type of test and also on the method used for determining serum GH. Cut-off serum GH values as different as 5-10 ng/ml, have been reported, and have been validated biochemically. We have used the growth velocity (GV)-standard deviation score (SDS) during the first year of treatment with rhGH to validate these cut-offs on a biological basis. METHODS: Fifty pre-pubertal patients with short stature (height < or =-2 SDS and GV < or =-1.2 SDS) were studied. GH deficiency (GHD) was diagnosed in 39 patients, on the basis of clinical and auxological parameters and on the serum concentration of IGF-1, and non-GHD in the other 11 patients. Two PhT GH (arginine and clonidine) were carried out in the 50 patients. Serum GH was determined by two different methods: one detecting most of serum GH isoforms, named Total GH (HGH Bio-Tech, MAIA Clone), and another one, only detecting the 22 kDa GH, named 22K GH (GH-22K IFMA, Wallac). RESULTS: Basal data: all patients with GHD and with non-GHD had maximal serum GH response (MaxR) values below and above the cut-off, respectively, for the serum Total GH and 22K GH. The mean 22K GH/Total GH ratio was similar to previous publications. Post-rhGH treatment data: the two groups improved their height SDS during the first year of treatment, particularly patients with GHD. A receiver-operator curve was used to define the best threshold for post-treatment GV-SDS that separates GHD from non-GHD patients. This value was 1.91 GV-SDS. A negative correlation between first year treatment GV-SDS and pre-treatment serum GH MaxR was found for the two assays (p < 0.001). Then, the best cut-off GV-SDS, previously calculated with the receiver-operator curve (1.91 SDS) was used to interpolate the corresponding serum GH values, as determined by the two methods. For Total GH, the value was 10.8 ng/ml, and for 22K GH, it was 5.4 ng/ml. CONCLUSION: The cut-off values calculated by biological means to separate GHD from non-GHD were remarkably similar to those calculated biochemically (10.0 and 4.8 ng/ml, respectively) for Total and 22K GH. This is a biological validation for using different cut-off values, appropriate for each assay, to diagnose GHD.

[Role of uric acid in hypertension and in the progression of chronic renal disease]. / Ruolo dell'acido urico nell'ipertensione arteriosa e nella progressione delle nefropatie.

In humans, uric acid (UA) is the main urinary metabolite of purines, whereas in other species (avians) it is the chief nitrogen compound excreted in the urine. The absence of uricase, due to nonsense or splice mutations occurring during the evolution of primates, results in blood urate levels much higher in humans than in other mammalians. This could have favorable implications, including protection from oxidative damage, as well as possibly allowing better blood pressure (BP) control in settings of low dietary Na+ intake. UA is a stimulus of the renin-angiotensin system (RAS). Moreover, blood UA levels are a major marker of proximal tubular function and overall volume status. On the other hand, hyperuricemia is a co-factor in Na+ -sensitive arterial hypertension, a marker and perhaps itself responsible for microvascular and systemic damage through RAS stimulation, inhibitory effects on endothelial cells, and the proliferation of perivascular smooth muscle cells. Recent studies in rats rendered hyperuricemic through administration of oxonic acid demonstrate the induction of hypertension and severe microvascular damage when associated with subtotal nephrectomy or chronic cyclosporine treatment. The opportunity to pharmacologically manipulate blood UA levels through inhibitors of synthesis (allopurinol), uricosuric agents (benziodarone), or recombinant urate oxidase (rasburicase) provides a relevant therapeutic potential in UA metabolism disorders, tumor lysis syndrome, and possibly in essential hypertension, as well as chronic progressive renal disease.