Asthma and COVID-19: a dangerous liaison?

The coronavirus disease 2019 (COVID-19) pandemic, caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), provoked the most striking international public health crisis of our time. COVID-19 can cause a range of breathing problems, from mild to critical, with potential evolution to respiratory failure and acute respiratory distress syndrome. Elderly adults and those affected with chronic cardiovascular, metabolic, and respiratory conditions carry a higher risk of severe COVID-19. Given the global burden of asthma, there are well-founded concerns that the relationship between COVID-19 and asthma could represent a "dangerous liaison".Here we aim to review the latest evidence on the links between asthma and COVID-19 and provide reasoned answers to current concerns, such as the risk of developing SARS-CoV-2 infection and/or severe COVID-19 stratified by asthmatic patients, the contribution of type-2 vs. non-type-2 asthma and asthma-COPD overlap to the risk of COVID-19 development. We also address the potential role of both standard anti-inflammatory asthma therapies and new biological agents for severe asthma, such as mepolizumab, reslizumab, and benralizumab, on the susceptibility to SARS-CoV-2 infection and severe COVID-19 outcomes.

Oral health in asthmatic patients: a review : Asthma and its therapy may impact on oral health.

Different drugs used to treat asthma, such as beta 2 agonists and inhaled steroids, may promote a higher risk of caries, dental erosion, periodontal disease and oral candidiasis. This article reviews the evidences of mechanisms involved in oral diseases in patients affected by asthma. The main mechanism involved is the reduction of salivary flow. Other mechanisms include: acid pH in oral cavity induced by inhaled drugs (particularly dry powder inhaled), lifestyle (bad oral hygiene and higher consumption of sweet and acidic drinks), gastroesophageal reflux, and the impairment of local immunity. In conclusion asthma is involved in the genesis of oral pathologies both directly and indirectly due to the effect of the drugs used to treat them. Other cofactors such as poor oral hygiene increase the risk of developing oral diseases in these patients. Preventive oral measures, therefore, should be part of a global care for patients suffering from asthma.

The Characteristics of Severe Chronic Upper-Airway Disease (SCUAD) in Patients with Allergic Rhinitis: A Real-Life Multicenter Cross-Sectional Italian Study.

BACKGROUND: There are few studies regarding severe chronic upper-airway disease (SCUAD) that represents an important socioeconomic problem for the treatment of rhinitis and associated comorbidities, particularly asthma. OBJECTIVES: The aim of our study is to evaluate the prevalence of this pathology in patients with allergic rhinitis (AR) in real life, to phenotype allergic patients with SCUAD, and to identify which factors are related to the severity of the disease. METHODS: We studied 113 patients with uncontrolled AR despite optimal adherence to therapy according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines in a multicenter Italian study, analyzing comorbidity, use of additional drugs, not scheduled visits, and the number of emergency room admissions. RESULTS: Our data suggest that polysensitization is the only statistically significant factor correlating with SCUAD. Asthma does not seem to represent a correlating factor. An important finding is the poor use (20%) of allergy immunotherapy (AIT), although patients were suffering from AR and the ARIA guidelines recommend the use of AIT in moderate/severe AR. CONCLUSIONS: The SCUAD population seems not to have a specific phenotype; there is a greater presence of SCUAD in polysensibilized patients, perhaps a sign of greater inflammation.

The control of allergic rhinitis in real life: a multicenter cross-sectional Italian study.

BACKGROUND: Allergic Rhinitis (AR) is a high-prevalence disease. In Europe about 25% of the general population is affected, and in Italy the prevalence is estimated to be 19.8%. The Allergic Rhinitis and its Impact on Asthma (ARIA) international document underlined that the prevalence of severe or refractory or overlapping rhinitis is increasing and represents a non-negligible socio-economic burden. In general, despite the social healthcare costs, allergic rhinitis remains underestimated, not sufficiently controlled and often undertreated. AIM OF THE STUDY: In this multi-center Italian observational and prospective study we assessed the control of AR in patients (> 16 years) without previous asthma diagnosis, referred to Allergy Centers. METHODS: Patients of both sexes and older than 16 with rhinitis symptoms and without asthma were studied. A Visual Analogue Scale (VAS) and the CARAT (Control of Allergic Rhinitis and Asthma Test) were used as patient reported outcome. The possible causes of poor control of AR, as per protocol, were assessed accordingly. RESULTS: We observed 250 patients in a real-life setting: more than 60% of them had an uncontrolled AR, only about 50% used multiple medications, and only a minority were receiving allergen immunotherapy. CONCLUSION: This survey, conducted in a real-life setting, confirmed that AR is overall poorly controlled. The VAS assessment well correlates with the structured CARAT questionnaire and with the relevant symptoms of AR.

Development and validation of an UHPLC-MS/MS method for ß2-agonists quantification in human urine and application to clinical samples.

A fast analytical method for the simultaneous detection of 24 ß2-agonists in human urine was developed and validated. The method covers the therapeutic drugs most commonly administered, but also potentially abused ß2-agonists. The procedure is based on enzymatic deconjugation with ß-glucuronidase followed by SPE clean up using mixed-phase cartridges with both ion-exchange and lipophilic properties. Instrumental analysis conducted by UHPLC-MS/MS allowed high peak resolution and rapid chromatographic separation, with reduced time and costs. The method was fully validated according ISO 17025:2005 principles. The following parameters were determined for each analyte: specificity, selectivity, linearity, limit of detection, limit of quantification, precision, accuracy, matrix effect, recovery and carry-over. The method was tested on real samples obtained from patients subjected to clinical treatment under chronic or acute therapy with either formoterol, indacaterol, salbutamol, or salmeterol. The drugs were administered using pressurized metered dose inhalers. All ß2-agonists administered to the patients were detected in the real samples. The method proved adequate to accurately measure the concentration of these analytes in the real samples. The observed analytical data are discussed with reference to the administered dose and the duration of the therapy.

Identification of IL-17F/frequent exacerbator endotype in asthma.

BACKGROUND: Severe asthma might be associated with overexpression of Th17 cytokines, which induce neutrophil recruitment via neutrophil-mobilizing cytokines in airways. OBJECTIVE: To study IL-17-related cytokines in nasal/bronchial biopsies from controls and mild asthmatics (MAs) to severe asthmatics (SAs) in relation to exacerbation rate. METHODS: Inflammatory cells and IL-17A+, IL-17F+, IL-21+, IL-22+, and IL-23+ cells were examined by immunohistochemistry in cryostat sections of bronchial/nasal biopsies obtained from 33 SAs (21 frequent exacerbators [FEs]), 31 MAs (3 FEs), and 14 controls. IL-17F protein was also measured by ELISA in bronchial/nasal lysates and by immunohistochemistry in bronchial tissue obtained from subjects who died because of fatal asthma. Immunofluorescence/confocal microscopy was used for IL-17F colocalization. RESULTS: Higher number (P < .05) of neutrophils, IL-17A+, IL-17F+, and IL-21+ cells in bronchial biopsies and higher numbers (P < .01) of IL-17F+ and IL-21+ cells in nasal biopsies were observed in SAs compared with MAs. Bronchial IL-17F+ cells correlated with bronchial neutrophils (r = 0.54), exacerbation rate (r = 0.41), and FEV1 (r = -0.46). Nasal IL-17F+ cells correlated with bronchial IL-17F (r = 0.35), exacerbation rate (r = 0.47), and FEV1 (r = -0.61). FEs showed increased number of bronchial neutrophils/eosinophils/CD4+/CD8+ cells and bronchial/nasal IL-17F+ cells. Receiver operating characteristic curve analysis evidenced predictive cutoff values of bronchial neutrophils and nasal/bronchial IL-17F for discriminating between asthmatics and controls, between MAs and SAs and between FEs and non-FEs. IL-17F protein increased in bronchial/nasal lysates of SAs and FEs and in bronchial tissue of fatal asthma. IL-17F colocalized in CD4+/CD8+ cells. CONCLUSIONS: IL-17-related cytokines expression was amplified in bronchial/nasal mucosa of neutrophilic asthma prone to exacerbation, suggesting a pathogenic role of IL-17F in FEs.

Patients with asthma and comorbid allergic rhinitis: is optimal quality of life achievable in real life?

OBJECTIVES: Asthma trials suggest that patients reaching total disease control have an optimal Health Related Quality of Life (HRQoL). Moreover, rhinitis is present in almost 80% of asthmatics and impacts asthma control and patient HRQoL. We explored whether optimal HRQoL was reachable in a real-life setting, and evaluated the disease and patient related patterns associated to optimal HRQoL achievement. METHODS AND FINDINGS: Asthma and rhinitis HRQoL, illness perception, mood profiles, rhinitis symptoms and asthma control were assessed by means of validated tools in patients classified according to GINA and ARIA guidelines. Optimal HRQoL, identified by a Rhinasthma Global Summary (GS) score ≤20 (score ranging from 0 to 100, where 100 represents the worst possible HRQoL), was reached by 78/209 (37.32%). With the exception of age, no associations were found between clinical and demographic characteristics and optimal HRQoL achievement. Patients reaching an optimal HRQoL differed in disease perception and mood compared to those not reaching an optimal HRQoL. Asthma control was significantly associated with optimal HRQoL (χ(2) = 49.599; p<0.001) and well-controlled and totally controlled patients significantly differed in achieving optimal HRQoL (χ(2) = 7.617; p<0.006). CONCLUSION: Approximately one third of the patients in our survey were found to have an optimal HRQoL. While unsatisfactory disease control was the primary reason why the remainder failed to attain optimal HRQoL, it is clear that illness perception and mood also played parts. Therefore, therapeutic plans should be directed not only toward achieving the best possible clinical control of asthma and comorbid rhinitis, but also to incorporating individualized elements according to patient-related characteristics.

Pitfalls in respiratory allergy management: alexithymia and its impact on patient-reported outcomes.

OBJECTIVES: Alexithymia is a personality trait characterized by a limited ability to identify and express emotions and it represents a possible risk factor for disease development and management. The objective of the study is to evaluate alexithymia in patients with persistent asthma and comorbid rhinitis and its relation with patient-reported outcomes (PROs). METHODS: Alexithymia, quality of life, illness perception, and stress were assessed, as well as rhinitis symptoms and asthma control in out-patients classified according to GINA and ARIA guidelines. RESULTS: Out of 115 patients, 19% turned out to be alexithymic (TAS-20 ≥ 61). Concerning alexithymia level, no difference was detected between males and females (χ(2) = 0.317) and among GINA levels (χ(2) = 0.22). Alexithymics had significantly lower Asthma Control Test scores when compared with non-alexithymics (15.86 vs. 19; p = .02). Alexithymics had a worse quality of life (p< .001) and, concerning illness perception, they ascribed to respiratory allergy symptoms that are not strictly disease related and referred to asthma and rhinitis more serious negative consequences (p < .001) and emotional representations (p < .035). Moreover, they had lower illness coherence (p < .001) and lived their disease as a cyclical rather than a chronic disorder (p < .035). As regards stress, alexithymics reported less energy (p < .001), higher levels of tension (p < .001), depression (p < .001), confusion (p > .001), and inertia (p < .001). CONCLUSION: Alexithymia is present in a relevant percentage of subjects and, as it can modulate illness perception, quality of life, and stress, it should be considered in disease management.

[Exercise-induced anaphylaxis]. / Anafilassi da sforzo.

Exercise-induced anaphylaxis (EIA) was defined for the first time in 1980. EIA is associated with different kind of exercise, although jogging is the most frequently reported. The clinical manifestations progress from itching, erythema and urticaria to some combination of cutaneous angioedema, gastrointestinal and laryngeal symptoms and signs of angioedema and vascular collapse. Mast cell participation in the pathogenesis of this syndrome has been proved by the finding of an elevated serum histamine level during experimentally-induced attacks and by cutaneous degranulation of mast cells with elevated serum tryptase after attacks. As predisposing factors of EIA, a specific or even aspecific sensitivity to food has been reported and such cases are called "food-dependent EIA". Many foods are implicated but particularly wheat, vegetables, crustacean. Another precipitating factor includes drugs intake (non steroidal anti-inflammatory drugs), climate variations and menstrual cycle factors. Treatment of an attack should include all the manoeuvres efficacious in the management of conventional anaphylactic syndrome, including the administration of epinephrine and antihistamines. Prevention of the attacks may be achieved with the interruption of the exercise at the appearance of the first premonitory symptoms. To prevent the onset of EIA it is also suitable to delay the exercise practice after at least 4-6 hours from the swallowing of food.

[New treatments for bronchial asthma]. / Nuove terapie dell'asma bronchiale.

Nowadays asthma treatment is based on topical beta2 short-acting and topical and systemic corticosteroids. Topical drugs do not control completely peripheral airways inflammation and also they are not able to control other disease frequently associated to asthma as rhinitis. Systemic steroids instead are very useful but not specific antinflammatory drug and can induce important side effects. For the reasons mentioned above it is important to use systemic drugs, acting on the numerous mediators typical of asthma, without modifying human physiological functions. We actually can use antileucotriens, but anti-IgE will be available also in Italy soon. Antileucotriens are effective and safe and are actually used in persistent asthma not completely controlled by inhaled steroids. They are administered per os; some of them are used once a day and can be used in paediatric age. In USA antileucotriens are also indicated in allergic rhinitis treatment. In atopic asthma, Omalizumab, an anti IgE drug, is safe and useful. It reduces the use of the systemic and inhaled steroids and the number of asthma exacerbations, in selected treated patients, without inducing important side effects. It is also useful in the treatment of rhinitis. Some proinflammatory cytochines, antiinflammatory cytochines and phosphodiesterasis inhibitor could be useful in the treatment of asthma but actually the use of these new drugs is still experimental.

IFN-gamma inhibits the proliferation of allergen-activated T lymphocytes from atopic, asthmatic patients by inducing Fas/FasL-mediated apoptosis.

The defect in interferon-gamma (IFN-gamma) production that results in a T helper cell type 2-dominated response may be responsible for a decrease in the apoptosis of allergen-activated T cells in asthma. We investigated the effect of recombinant IFN-gamma on proliferation, Fas/Fas ligand (FasL) expression, and apoptosis in allergen-stimulated peripheral blood mononuclear cells obtained from atopic, asthmatic patients and nonatopic, control subjects. The addition of IFN-gamma at the start of cultures markedly inhibited the proliferative response to a specific allergen in cells from all asthmatic patients, whereas no change was observed in cells from nonatopic, control subjects. IFN-gamma induced an increase in the expression of Fas and FasL by allergen-stimulated CD4+ T cells from asthmatic patients and caused the apoptosis of these cells. A Fas-blocking monoclonal antibody prevented the inhibitory effect of IFN-gamma on allergen-induced proliferation. These results suggest that IFN-gamma inhibits the proliferation of allergen-stimulated CD4+ T cells from atopic, asthmatic patients by inducing the surface expression of Fas and FasL, which in turn triggers their apoptotic program. The defect in IFN-gamma production involved in the allergic, immune response may therefore be responsible for a decrease in apoptosis of allergen-activated T lymphocytes in the airways of atopic, asthmatic patients.

Clinical and therapeutic aspects of allergic asthma in adolescents.

Little is known about the management of asthma in adolescents. We aimed at evaluating these aspects, through a specific questionnaire, in the real life of adolescents with allergic asthma. The questionnaire was administered to a group of adolescents after a diagnosis of allergic asthma. The diagnosis was based on history, clinical examination, pulmonary function tests and allergy tests. One hundred and fifteen adolescents (65 males, mean age 16.5 years) fulfilled the criteria for allergic asthma. The questionnaire explored demography, family history, clinical history, previous diagnosis, therapy, attitude towards therapy and social aspects. The mean actual FEV1 was 87 +/- 10%. Methacholine challenge was carried out in 79 patients and was always positive (PD20 < 1,200 microg), whereas 36 patients underwent reversibility test. According to GINA guidelines, severity of asthma resulted intermittent in 62, mild persistent in 31, moderate in 19 and severe in three patients. In 61% of cases teachers were not aware of the disease. Asthma was managed by general practitioners, allergists and pulmonologists, but PFT/allergy tests had never been performed in 14% of patients. Forty-two per cent of the adolescents received no therapy at all, and only 15% of those with persistent asthma were receiving a stable treatment. Seventy-four per cent of adolescents preferred the inhaled, as against the oral, route. From a clinical and functional point of view, asthma in adolescents did not differ from other age ranges. Nevertheless, the management (diagnosis and therapy) emerged to be unsatisfactory from many points of view.

[Asthma and aspirin]. / Asma ed aspirina.

Aspirin (ASA) is an important cause of asthma so that ASA induced asthma (AIA) is considered a disease. Its prevalence is of 0.3-0.6 in the general population but it raises to 21% in the asthmatic one. Middle aged female are the most affected. AIA generally begins with a non allergic rhinitis, complicated sometimes with polyps, that evolves secondarily in asthma. The disease is often so severe to need oral corticosteroids to be controlled. It persists independently to the intake of ASA. From a pathogenetic point of view the interaction of ASA with the arachidonic acid metabolism seems to be important. The inhibition of cyclo-oxygenase (COX) induces an activation of lypo-oxygenase with an increased synthesis of leukotrienes. In ASA intolerant patients there is also an activation of LTC4 synthetase, enzyme responsible for the synthesis of leukotrienes. Clinical history is very important to diagnose the disease but to confirm the diagnosis sometimes the provocation test is mandatory. Oral and bronchial challenges can be dangerous, while nasal challenge is safer even if must be better standardized. Patients must not use antiinflammatory drugs with the same mechanism of action of ASA; COX-2 inhibitors are generally well tolerated. Antileukotrienes are useful to treat asthma, in association with steroids. Desensitization can be used in very selected patients.

[Rhinitis, asthma and sports]. / Rinite, asma e sport.

Over the last few years, the importance of sport in everyday life has rapidly increased. Asthma and allergic rhinitis are among the most common problems to be afforded in those practising sports. It is believed that allergy represents a limitation to sport activity, but many elite athletes suffer from respiratory allergy: within those participating in the Olympic Games, 49% suffered from allergic rhinitis, and 20% of winter sport athletes suffered from asthma. Exercise is a potent trigger factor for asthma both in allergic and non allergic subjects. About 70% of asthmatic patients experience asthma symptoms during exercise; skiing and running in particular can elicit bronchospasm. Swimming is usually considered a non asthmogenic sport, but the inhalation of chloride derivatives and irritants can favor asthma onset. From a pathogenic point of view, exercise induced asthma seems to be due to sudden changes of osmolarity in the mucus layer on bronchial walls induced by hyperventilation and low temperature of inspired air. Athletes also suffer from non allergic rhinitis that can influence their performance. Rhinitis in fact modify the correct ventilation and can induce lower respiratory disorders, like asthma. Recently, cold-induced rhinitis has been described in those athletes practicing winter sports, especially skiers. This rhinitis is characterized mainly by rhinorrhea, and responds to topical anti-cholinergic agents. In conclusion, sport can exacerbate or induce asthma and rhinitis but this fact does not represent a limitation to physical activity. A deep knowledge of the diseases occurring during exercise, a detailed education and a correct therapy, allow to perform sports even at high levels also in presence of respiratory allergy.

[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.