Simonetta Masieri

Specific immunotherapy by the sublingual route for respiratory allergy

Specific immunotherapy is the only treatment able to act on the causes and not only on the symptoms of respiratory allergy. Sublingual immunotherapy (SLIT) was introduced as an option to subcutaneous immunotherapy (SCIT), the clinical effectiveness of which is partly counterbalanced by the issue of adverse systemic reactions, which occur at a frequency of about 0.2% of injections and 2-5% of the patients and may also be life-threatening. A large number of trials, globally evaluated by several meta-analyses, demonstrated that SLIT is an effective and safe treatment for allergic rhinitis and allergic asthma, severe reactions being extremely rare. The application of SLIT is favored by a good compliance, higher than that reported for SCIT, in which the injections are a major factor for noncompliance because of inconvenience, and by its cost-effectiveness. In fact, a number of studies showed that SLIT may be very beneficial to the healthcare system, especially when its effectiveness persists after treatment withdrawal because of the induced immunologic changes.

Furosemide protective effect against airway obstruction.

Furosemide (frusemide) is mainly employed as a powerful diuretic that inhibits Na and K reabsorption in renal tubules. However other valuable pharmacological effects have been discovered that include a protective action from bronchospasm. The effects of furosemide on airways have been recognized to be more and more complex as far as an increasing amount of studies have been produced on this subject. The drug shows no acute bronchodilator effect, but prevents or attenuates bronchospasm caused by many factors, such as hyperpnea, drugs (metabisulphite, bradykinin, AMP), physical agents (hypo- and hypertonic aerosols), and allergen challenge in asthmatic patients. Furosemide is also active on upper airway mucosa, on which the drug decreases nasal resistance in patients affected by non-allergic rhinitis and exhibits a protective effect on nasal mucosa reactivity to the specific allergen in atopic subjects. The mechanism of action of furosemide on airways has not yet been fully cleared and interference with electrolyte epithelial transport, prostaglandins, inflammatory cell activity, vascular and neural regulation has been hypothesized. The interest for clinical application of inhaled furosemide has grown in last years. Some Authors have investigated whether the drug is effective in acute asthma attacks or not. Furosemide is one of the drugs currently used to prevent exercise-induced asthma. More recently, inhaled furosemide has been observed to decrease the sensation of experimentally-induced dyspnea. Apart from possible therapeutic application, studies about furosemide effects on respiratory mucosa can contribute to better understand the physiology of upper and lower airways.

Exposure to noise during continuous positive airway pressure: influence of interfaces and delivery systems.

Background: We measured noise intensity and perceived noisiness during continuous positive airway pressure (CPAP) performed with two interfaces (face‐mask, helmet) and four delivery systems.

A role for Waldeyer’s ring in immunological response to allergens

Abstract 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.

Nasal obstruction improvement induced by topical furosemide in subjects affected by perennial nonallergic rhinitis.

Inhaled furosemide decreases bronchial response to several physical and chemical irritants. To evaluate the effect of topical furosemide on nasal resistance in patients affected by perennial nonallergic rhinitis, we studied 12 patients. This diagnosis of perennial nonallergic rhinitis was based on the history of rhinorrhea, sneezing, and nasal obstruction, on anterior rhinoscopy and endoscopy, on negative allergic tests, and on the absence of eosinophilia in nasal secretion. The study was performed on two nonconsecutive days. On the first day, one puff (100 μl) of 0.9% saline was sprayed into both nostrils and nasal resistance was measured by anterior rhinomanometry before the puff and 15 and 30 minutes later. On the second day, one puff (100 μl) of a solution of furosemide (10 mg/mL) was sprayed into both nostrils and nasal resistance was measured before the puff and 15, 30, 45, 60, 90, 120, and 180 minutes later. Initial nasal resistance was abnormally high in all patients on both days. A slight but significant increase was observed after spraying isotonic saline (base: 1.38 ± .69; 15 minutes: 1.47 ± 0.72; 30 minutes: 1.44 ± 0.73); by contrast a marked decrease was observed after spraying the furosemide solution. Nasal resistance was lowest between 30 and 90 minutes after giving furosemide. Then it progressively increased, but values at 180 minutes were still lower than the initial ones (base: 1.43 ± 0.67; 15 minutes: 0.70 ± 0.47; 30 minutes: 0.48 ± 0.24; 45 minutes: 0.49 ± 0.21; 60 minutes: 0.50 ± 0.20; 90 minutes: 0.56 ± 0.23; 120 minutes: 0.62 ± 0.32; 180 minutes: 0.67 ± 0.30). After topical furosemide, all patients had subjective relief of nasal obstruction that lasted more that 12 hours in 9 subjects.

The current role of sublingual immunotherapy in the treatment of allergic rhinitis in adults and children.

Allergic rhinitis is a very common disease affecting about 20% of people. It may be treated by allergen avoidance when possible, by antiallergic drugs such as antihistamines and topical corticosteroids, and by allergen-specific immunotherapy. The latter is the only treatment able to act on the causes and not only on the symptoms of respiratory allergy and is able to maintain its efficacy even after stopping, provided an adequate duration of treatment of 3–5 years is ensured. Sublingual immunotherapy (SLIT) was introduced in the 1990s as a possible solution to the problem of adverse systemic reactions to subcutaneous immunotherapy and has been demonstrated by more than 50 trials and globally evaluated thus far by five meta-analyses as an effective and safe treatment for allergic rhinitis. Life-threatening reactions are extremely rare. However, it is important to note that clinical efficacy occurs only if SLIT meets its needs, ie, sufficiently high doses are regularly administered for at least 3 consecutive years. This is often overlooked in the current practice and may prevent the same success reported by trials from being achieved.

Characteristics of candidates for allergen immunotherapy

Allergic rhinitis (AR) may be cured by allergen immunotherapy (AIT). However, patient characteristics for prescribing AIT are not well defined. This study aimed at evaluating the patients profile to be a candidate for AIT in a cohort of patients suffering from AR, evaluated in 20 Italian Allergy or Ear, Nose, and Throat Centers. The study has been performed on 198 patients (98 men; mean age, 26.8 years) with AR (assessed by Allergic Rhinitis and Its Impact on Asthma [ARIA] criteria). The kind and the number of prescribed allergen extracts, type of diagnosis, severity of symptoms, and patients perception of symptoms and drug use were evaluated. Patients were subdivided in AIT-treated and without AIT (as controls) subgroups. Most of the patients (69.7%) had persistent AR with moderate–severe symptoms. The mean number of sensitization was 3.4. ARIA classification and sensitization number did not affect AIT choice, but the type of allergen was relevant. AIT-treated patients had milder symptoms than controls if assessed by doctors, but AIT patients perceived more severe symptoms and larger drug use than controls. This study shows that the choice of AIT is based on patients perception and type of allergen, but number of sensitizations, symptom severity assessed by doctors, and ARIA classification are not relevant factors. The key message might be that it is always relevant to pay attention to the complaints referred by the patient.

Carbonic anhydrase in human nasal epithelium: Localization and effect of the inhibition by dichlorphenamide

Carbonic anhydrase has not hitherto been reported in nasal mucosa. In the first part of this study, five specimens of human nasal mucosa from the inferior turbinate were obtained from five healthy subjects and tested for this enzyme with a histochemical reaction. Carbonic anhydrase was identified in the columnar ciliated respiratory epithelium, but was absent in the adjacent stratified squamous epithelium. The effect of the inhibition of this enzyme on the pH values and Na, K, and Cl activity in nasal secretion was subsequently investigated. Fifteen patients, affected by endocranial hypertension and to whom dichlorphenamide—an inhibitor of carbonic anhydrase—was administered, were studied. The pH value, determined with a surface electrode before giving the drug and 30, 60, and 90 minutes later, significantly increased and reached a peak at 60 minutes. Na, K, and Cl concentration was assessed by indirect potentiometry in the nasal secretion and in the plasma both before giving dichlorphenamide and 60 minutes later. Although no change was observed in the plasma, in the nasal secretion Na and Cl concentration increased and K concentration decreased. As a consequence, the gradients of Na and K between plasma and secretion decreased, and that of Cl increased. We assume analogous changes in the rate of transport through the mucosa to occur. These results thus suggest that carbonic anhydrase is involved in control of the pH of nasal secretions as well as in the electrolyte transport through the epithelium.

The best allergen immunotherapy choice for mite allergic patients

Allergic rhinitis and asthma are very common and are characterized by an IgE-dependent reaction. Allergen exposure typically causes inflammation occurrence that in turn is the condicio sine qua non to induce symptoms’ appearance. Thus, there is a vicious circle that starts from allergen presence in the environment, and proceeds with its inhalation, inflammatory response, and symptoms happening: all these actors are necessarily linked in the allergy scenario. House dust mites (HDM) are common cause of allergic rhinitis and asthma.[1] HDM belong to the Arachnidae family and are worldwide ubiquitous; HDM highly grow in humid and warm environments up to 2000 m above sea level. HDM consist of many species, but the most relevant are Dermatophagoides pteronyssinus and Dermatophagoides farinae. The IgE response to HDM appears very early in life, reaching a peak during adolescence–young adulthood to progressively diminishing with ageing.[2] The HDM molecular allergen components are well defined and cloned: the major allergens are Group 1 (Der p 1 and Der f 1) and Group 2 (Der p 2 and Der f 2) proteins.[3] HDM allergens require an airstream to be dispersed and inhaled, as they are relatively heavy and so tend to lay down. Typically, HDM-allergic patients usually have symptoms while dusting, opening wardrobe, putting on sweaters, handling old books. HDM allergy is characterized by bothersome symptoms, mainly concerning nasal obstruction. This symptom is closely depending on allergic inflammation caused by allergen exposure.[4] In addition, HDM allergy has a negative impact on quality of life.[5] On the basis of these considerations, a recent cross-sectional study investigated the clinical characteristics of HDM-related allergy in 499 Italian patients using a questionnaire-based method.[6] The findings showed that 42% had rhinitis alone, 13% asthma alone, and 45% had asthma and rhinitis. Rhinitis was moderate–severe in 51%; asthma was intermittent in 36%, mild persistent in 37%, moderate in 27%. In addition, about 50% of patients were unsatisfied of prescribed treatments. Finally, the study reported that HDM-allergic patients had more symptoms during the fall–winter period. This issue is intriguing as this autumnal peak of allergic symptoms may be contemporary with the so-called ‘September epidemic’ due to viral infections, mainly in allergic children.[7] Moreover, it has been reported that HDM-allergic children have more frequent and severe respiratory infections than healthy ones and this attitude may be reduced by allergen immunotherapy (AIT).[8] Therefore, fall–winter tends to be the worst season for HDM allergic patients. In addition, the HDM concentration at home is not constant during the whole year, but periodically varies with two peaks: fall–winter, the main, and spring.[9] Similarly, nasal inflammation is closely related to mite variations as well as patients with HDM allergy exactly present more severe symptoms in these specific year periods, and there was a significant relationship between nasal eosinophil count and nasal obstruction perception.[10] Thus, mite allergy should be considered not as a pure ‘perennial’ (i.e. continuous) allergy, but as a ‘seasonal’ allergy, although characterized by long periods of symptoms occurrence and inflammation persistence. This concept could have practical consequence, mainly concerning the AIT schedule. In other words, new therapeutic strategy could be defined: for example, prescribing two pre-co-seasonal courses along the year instead a continuous schedule. In this regard, a previous study demonstrated that intermittent (2 months on treatment and 2 off) AIT schedule was equivalent to a continuous regimen in patients with mite allergy treated for one year.[11] On the basis of these considerations, a group of 50 Italian allergists, particularly expert in AIT management, met to discuss these issues and to define a shared point of view about HDM allergy management, mainly concerning AIT prescription and schedule. The meeting was organized by the authors of this paper with an unconditional fund provided by Stallergenes Italia. Five issues were discussed and voted. The first issue concerned the question: what is the best treatment for patients with mite allergy? Eighty per cent of allergists answered the AIT, whereas 16% preferred environmental prevention. Therefore, the large majority of these allergists retain that AIT is the best option for treating HDM allergy. The second point evaluated the inclusion criteria for prescribing AIT. Intermittent asthma, mild and moderate persistent asthma, and/or persistent moderate–severe allergic

pH and electrolytes in nasal secretum of intensive care unit patients

Na, K and Cl levels and pH were determined in 26 samples of nasal secretum and plasma obtained from orally intubated intensive care unit patients. In nasal secretum K and Cl were higher and Na lower than in plasma: pH was higher in secretum than in plasma, probably because of the fall of CO2, which freely diffuses to the air. The epithelial activities of lowering pH, secreting K, and reabsorbing Na appeared closely linked together. The chloride difference (DCl) probably balanced the decrease of other anions, such as bicarbonate. Finally, some influences of plasmatic values on ion active transport rates may be hypothesized on the ground of the correlations of chloride and potassium values in nasal secretion and plasma.