Predictors of response to omalizumab and relapse in chronic spontaneous urticaria: a study of 470 patients.

BACKGROUND: Chronic spontaneous urticaria (CSU) is defined as spontaneous occurrence of wheals and/or angioedema for ≥6 weeks. Omalizumab is a monoclonal anti-IgE antibody effective in refractory CSU, but its mechanism of action and markers predictive of response remain not completely defined. OBJECTIVES: To correlate baseline levels of two proposed biomarkers, total IgE (bIgE) and d-dimer (bd-dimer), and clinical parameters to omalizumab response and to relapses after drug withdrawal. METHODS: In this retrospective Italian multicentre study, clinical data were collected in 470 CSU patients, and bIgE and bd-dimer were measured in 340 and 342 patients, respectively. Disease activity was determined by Urticaria Activity Score 7 (UAS7) at week 1 and 12 after omalizumab starting. Relapses were evaluated during a 2- and 3-month interval after a first and a second course of treatment, respectively. RESULTS: bIgE correlated to a good response to omalizumab since levels were significantly higher in responders than non-responders (P = 0.0002). Conversely, bd-dimer did not correlate to response. There was no correlation between both bIgE and d-dimer and either first or second relapse. Disease duration was significantly longer in patients who experienced either first or second relapse (P < 0.0001 and P = 0.0105, respectively), while baseline UAS7 correlated only to first relapse (P = 0.0023). CONCLUSIONS: Our study confirms bIgE as a reliable biomarker predicting response to omalizumab in CSU, while it does not support the usefulness of bd-dimer unlike previous findings. CSU duration before omalizumab and baseline UAS7 may be clinical markers of relapse risk.

Idiopathic pulmonary fibrosis: a disease with similarities and links to cancer biology.

Several clinical trials have recently targeted specific pathways implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, IPF remains plagued by a median survival of 3 yrs and emphasises the need for further research with new insights and perspectives. The prevailing pathogenic hypotheses assume that either an inflammatory process or an independent epithelial/fibroblastic disorder may propagate the disease process. Based on knowledge developed with considerable scientific evidence, we provide our perspectives with an alternative point of view that IPF be considered as a neoproliferative disorder of the lung. Genetic alterations, response to growth and inhibitory signals, resistance to apoptosis, myofibroblast origin and behaviour, altered cellular communications, and intracellular signalling pathways are all fundamental pathogenic hallmarks of both IPF and cancer. The concept of IPF as a lethal malignant disorder of the lung might extend beyond the pathogenic link between these two diseases and disclose new pathogenic mechanisms leading to novel therapeutic options, adopted from cancer biology. Moreover, this vision might dawn the awareness of the public, political and scientific community of this devastating disease from an angle different from the current perception and provoke new ideas and studies to get a better understanding to control the otherwise relentless progressive disease.

Vitamin D and disease severity in bronchiectasis.

BACKGROUND: Bronchiectasis is a complex respiratory disease characterised by permanent dilatation of bronchi. Vitamin D plays a role in infective disease by modulating the inflammation. Patients affected by bronchiectasis are frequently Vitamin D deficient and it correlates with lung function decline. We want to understand if there is a correlation between Vitamin D and clinical and radiological severity of bronchiectasis. METHODS: We included 57 patients (17 males/40 female with mean age 60 ±â€¯12 years) between October 2017 and March 2018. We excluded patients with cystic fibrosis, traction bronchiectasis and reporting Vitamin D supplementation. Bronchiectasis severity index (BSI) and Bhalla score were calculated, blood inflammatory markers and Vit. D were measured and lung function tests were performed. RESULTS: Vitamin D is deficient in 64% of patients, sufficient in 36% and normal in 7%. Mean BSI is 7.5 ±â€¯5 and mean Bhalla score is 16 ±â€¯4. Vitamin D levels correlate with Bhalla score (R2 = 0.68, p < 0.001) and BSI (R2 = 0.58, p < 0.0001). The correlation appears to be stronger than other markers of inflammation such as ESR and CRP [R2 = 0.33, p = 0.001 and R2 = 0.39, p = 0.001 respectively]. CONCLUSIONS: We consider Vitamin D as a good predictor of clinical and radiological severity of bronchiectasis.

In vitro antiproliferative effect of trastuzumab (Herceptin(®)) combined with cetuximab (Erbitux(®)) in a model of human non-small cell lung cancer expressing EGFR and HER2.

Lung cancer is the leading cause of cancer death. For this reason, new therapies are needed for the treatment of this devastating disease. In this study, we investigated the effects of combining cetuximab and the trastuzumab on the growth of a model of human non-small cell lung carcinoma cell line (A549). The results were compared with those obtained from a human lung squamous carcinoma cell line (NCI-H226). Both cell lines were treated with cetuximab and trastuzumab, alone or in combination, at various concentrations, for 24, 48 and 72 h. Cell proliferation was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. EGFR and HER-2 mRNA expression was detected by reverse transcription polymerase chain reaction, and the gene amplification status of receptors was evaluated by fluorescence in situ hybridisation. The colorimetric proliferation assay showed that trastuzumab combined with cetuximab significantly inhibited A549 cells at a dose of 40 µg/ml after 72 h of treatment (p < 0.05), while no time-dose dependent inhibition was observed in NCI-H226 cells. The combined treatment influenced both levels of EGFR and HER-2 mRNA in A549 cells and only EGFR mRNA levels in NCI-H226 cells. Fluorescence in situ hybridisation showed that both cell lines were aneuploid for the two genes with equally increased EGFR and CEN7 signals, as well as HER-2 and CEN17 signals, indicating a condition of polysomy without amplification. The preliminary results of this study encourage further investigations to elucidate the downstream events involved and to understand how these mechanisms influence non-small cell lung cancers growth.

Higher serum levels of periostin and the risk of exacerbations in moderate asthmatics.

BACKGROUND: In asthma, exacerbations and poor disease control are linked to airway allergic inflammation. Serum periostin has been proposed as a systemic biomarker of eosinophilic inflammation. This pilot study aims at evaluating whether in patients with moderate asthma, higher baseline levels of serum periostin are associated with a greater risk of exacerbation. METHODS: Fifteen outpatients with moderate allergic asthma were recruited. Serum concentrations of periostin were assessed (ELISA) at baseline, and the frequency of asthma exacerbations was recorded during a one-year follow-up. RESULTS: Patients (M/F: 10/5, mean age of 47.6 ± 11.0 years) had mean ACQ score of 5.5 ± 4.2 and FEV1%pred of 81.9 ± 21.7 %. Baseline serum levels of periostin did not correlate with lung function parameters, nor with the ACQ score (p ≥0.05 for all analyses). Five subjects (33 % of the study group) reported one or more exacerbations during the following year. Baseline serum levels of periostin were significantly higher in subjects who experienced one or more exacerbations during the one year period of follow-up, compared with subjects with no exacerbations: median serum periostin level was 4047 ng/ml (range: 2231 to 4889 ng/ml) and 222 ng/ml (range 28.2 to 1631 ng/ml) respectively; p = 0.001. CONCLUSION: The findings of the present pilot study could form the basis for the design of larger studies aiming at developing strategies to identify asthmatic patients at risk for exacerbations.

[Prevalence of respiratory symptoms, reduction in lung function and allergic sensitization in a group of traffic police officers exposed to urban pollution]. / Prevalenza di sintomi respiratori, riduzione della funzionalità polmonare e sensibilizzazione allergica in un gruppo di vigili urbani esposti al traffico urbano.

BACKGROUND: Environmental factors are believed to play a critical role in the development of allergic respiratory diseases, such as asthma and rhinitis. Particularly, the role of urban pollution in the pathogenesis of these diseases is debated. OBJECTIVES: The aim of the study was to investigate whether subjects with a well-defined occupational history of exposure to road traffic fumes presented an increased prevalence of respiratory symptoms of chronic bronchitis (cough), asthma (wheeze), and allergic sensitisation to the most common allergens and reduced lung function compared with an unexposed control group. METHODS: The study was conducted on 484 traffic police in Catania (465 men and 19 women), with a mean age of 45 +/- 7.9 years, who were subdivided into three groups. The first group included traffic police assigned to traffic direction, the second group included traffic police working in administrative offices, the third group included all traffic police who did not fall into the previous groups. In the first group, "truly exposed" subjects were identifed as police officers assigned to traffic direction in the last 8 years. Similarly, in the second group, "truly non-exposed" subjects were identified as police officers working in offices in the last 8 years. RESULTS: Statistical analysis showed a significant difference in mean age between the truly exposed group and the truly non-exposed group (p < 0.01). The truly exposed group showed a greater prevalence of symptoms (cough, wheeze and dyspnoea), and positive reaction to skin allergy tests compared with the "truly non-exposed group", but this increase did not reach statistical significance. Alterations of the respiratory function tests were more frequent in the non-exposed (14.3%) compared to the exposed group (9.6%). The highest prevalence of cough, dyspnoea and wheezing was detected in smokers compared to non-smokers and to ex-smokers within each group. CONCLUSIONS: Our results show a major prevalence of respiratory symptoms and allergic sensitisation in exposed traffic police compared with non-exposed police, although this did not reach statistical significance. Further epidemiological studies conducted on larger samples are required to better understand the role of road traffic pollution in inducing allergic respiratory diseases.

Nuclear factor-kappaB activation in human monocytes stimulated with lipopolysaccharide is inhibited by fibroblast conditioned medium and exogenous PGE2.

The nuclear factor kappaB (NF-kappaB) is thought to be crucially involved in the gene activation of several cytokines, including tumor necrosis factor alpha (TNF). Previously, we showed that fibroblast conditioned medium (FCM) is able to inhibit both TNF mRNA accumulation and protein release in peripheral blood-derived human monocytes (PBM) stimulated with lipopolysaccharide (LPS). In this study we have investigated the effect of FCM on the LPS-induced DNA-binding activity of NF-kappaB, by means of electrophoretic shift assay (EMSA). We provide evidence that FCM strongly inhibits the LPS-induced NF-kappaB activation in PBM. Furthermore, we show that exogenous PGE2 mimics the NF-kappaB inhibitory effect of FCM. On the other hand, FCM produced in the presence of indomethacin does not inhibit NF-kappaB activation by LPS. Our results lend further support to the hypothesis that inflammatory and immune responses of monocytes/macrophages may be modulated at the molecular level by signals originating from tissue structural cells such as fibroblasts.

Pulmonary tuberous sclerosis in a woman of child-bearing age with no mental retardation.

Tuberous sclerosis is a rare disease characterized by epilepsy, mental retardation and adenoma sebaceum. We describe the case of a 29-year-old woman with a clinical history of tuberous sclerosis who also had severe hypoxaemia, multifocal hamartoma-like lesions of various extrapulmonary organs, massive hypersplenism and coagulation defects. This case emphasizes the value of high resolution computed tomography (HRCT) in patients with pulmonary tuberous sclerosis.

The long-term antimicrobial prophylaxis of chronic bronchitis exacerbations.

Infectious exacerbations are the major cause of mortality in patients with chronic bronchitis, particularly in elderly subjects. Considering that the preventive use of antibiotics has provided no clear-cut evidence of real efficacy, it has become quite common to use treatments potentially able to stimulate the immune system for prevention of exacerbations of chronic bronchitis. This treatment, based on the oral administration of bacterial extracts, should, at least in theory, stimulate the immune defenses and reduce the incidence of recurring respiratory tract infections. Although during the last few years a good effort to define better the real efficacy and role played by bacterial extracts in chronic bronchitis has been made, their clinical effectiveness is still the subject of debate and the results of some clinical trials are controversial. Particularly, its mechanism of action remains poorly understood, although a huge effort has been made in this direction.

Once-daily tobramycin therapy in lower respiratory tract infections.

In a multicenter Italian study of 104 adult patients with severe bacterial lower respiratory tract infections, the safety and efficacy of a regimen of high dose, once-daily tobramycin alone or in combination with antipseudomonas betalactams was assessed. The overall bacteriological response was an elimination of the original pathogen in 70% of the patients while the overall clinical response mirrored the bacteriological results with a successful clinical outcome in 78% of patients. Adverse experiences were, in general, few and mild without oto- or nephrotoxicity. The once-daily, high dose regimen of tobramycin proved to be a safe and efficacious therapy for severe lower respiratory tract infections in adult patients.

Evaluation of the activity of the carbocysteine-sobrerol combination on mucus spinnability.

Among the rheological properties of bronchial mucus, "spinnability", i.e. the ability to form threads under the effect of traction, should be regarded as the most closely related to the mucociliary transport function. In the present study the "spinnability" parameter was included in the functional tests aimed at evaluating the efficacy of the carbocysteine-sobrerol combination in 16 patients suffering from chronic abstructive lung disease with bronchial hypersection. Treatment was administered for ten days under double-blind conditions compared with a placebo. The results obtained showed the tested combination to be able to favourably affect all the most important rheological parameters of mucus, including spinnability, leading to a rapid disappearance of signs and symptoms and to the improvement of the most important respiratory function indexes.

Azelastine in the prophylactic treatment of bronchial asthma: an Italian multicentre comparison with ketotifen.

The prophylactic effectiveness of the phthalazinone derivative, azelastine was compared with ketotifen. A total of 111 patients, aged 18-65 years, from 10 centres was entered into this randomized, double-blind study. All patients had reversible asthma. After 1 week on placebo, patients were allocated to either 8 mg/day azelastine once or twice daily, or to 1 mg ketotifen, twice daily, for a further 12 weeks. Azelastine was more effective in improving respiratory function (forced expiratory flow in 1 s and peak expiratory flow rate) when given in the once daily regimen, whereas clinical measures (number of weekly asthma attacks) were most improved by twice daily dosing. There was no significant difference between the effectiveness of azelastine and that of ketotifen. Treatments were equally well tolerated and a low incidence of side-effects was reported. In conclusion, 8 mg/day azelastine, in either a single or twice daily dosage regimen may be regarded as providing effective prophylaxis against bronchial asthma.

[Guidelines for the treatment of acute asthma. A critical retrospective analysis]. / Linee guida in tema di trattamento dell'episodio acuto di asma. Retrospettiva critica.

Acute asthma attacks are frequently observed in common medical practice. However a unified and scientifically proven directive which advises objectively on the best management strategy for patients with acute asthma attacks is still lacking. In the present review we have accurately assessed various important points addressed in the recent international guidelines for acute asthma. This work has enabled us to derive precise and documented suggestions of practical importance which may be useful to the physician for a correct and judicious approach to the management of those patients with acute asthma attacks.

[Controlled clinical study of the treatment of chronic bronchitis with guacetisal]. / Studio clinico controllato sul trattamento della bronchite cronica con guacetisal.

Controlled clinical research has been carried out on the activity and tolerance of a new active principle, guacetisal (Broncaspin) obtained from the esterification of acetylsalicylic acid with guaiacol, in the treatment of chronic bronchitis. The drug's therapeutic response was evaluated with respect to that of bromexine. Guacetisal was generally well tolerated. It had no unwanted side-effects on the main haematochemical parameters or on the function of organs and systems. It was found to have considerable therapeutic effectiveness, at times even superior to that of the control drug, with respect to general symptomatology and at respiratory system level. It produced early, lasting reduction in temperature, heart frequency, dyspnoea, duration of expirium and in the intensity and number of coughing attacks. It also led to an appreciable improvement in thoracic objectivity and the X-ray picture. Variations in respiratory functional parameters were of considerable interest and from these it is concluded that guacetisal exerts its polyvalent activity to a proportionately higher extent in the bronchial districts more seriously involved in the inflammatory process, inducing an elective improvement in bronchial permeability, a reduction in total pulmonary resistances--with consequent tendency for ventilation-perfusion relations to normalise--as well as an improvement in gas exchanges and patient oxygenation.

Modulation of non-specific bronchial reactivity.

There are several drugs that can modify non-specific reactivity induced by various stimuli. Disodium cromoglycate (DSCG) is able to reduce bronchial hyperreactivity status, but its mechanism has not yet been demonstrated. It would be expected to exert its activity either by mastocyte stabilization or by other actions that are not related to mastocyte mediator release. It has been suggested that DSCG has a calcium channel blocking activity. Its possible role as a calcium antagonist suggest a general modifying effect of calcium antagonists against hyperreactivity, although their use in therapy cannot be foreseen. In exercise-induced bronchospasm, numerous beta 2-adrenergic drugs have proved more effective than other drugs studied in several investigations. It is unknown whether their effects are to be attributed to a bronchodilator activity or to another mechanism of action. Anticholinergic drugs have a lower protective effect against several stimuli. Theophylline has protective action on histamine bronchospasm which is dependent on the blood levels of theophylline attained. Many drugs currently available can modify bronchial hyperreactivity, but only in a transient way. Several anti-asthmatic drugs cause a decrease of the bronchial hyperreactivity, reducing the release of inflammatory mediators and inhibiting reflex bronchoconstriction. However, at present there are no specific drugs which are able to modify bronchial hyperreactivity with a direct action.

Influence of asthmatic and rhinitic symptomatology duration on bronchial responsiveness to histamine.

Our Study aimed to investigate the influence of the time in years elapsed from the onset of symptoms on bronchial nonspecific responsiveness in rhinitic and asthmatic patients. The study was performed on 83 asthmatic patients and on 46 patients with allergic rhinopathy. The beginning of the symptoms and years of asthmatic or rhinitic history were particularly investigated. A histamine challenge was performed. The dose of histamine producing at 20% change in FEV1 (forced expiratory volume in one second) was calculated from the individual semilogarithmic dose-response curve (PD20). Bronchial responsiveness to histamine showed wide variability in subjects of two groups, and an overlap of the distribution curves was observed between asthmatic and rhinitic patients. A significant relationship (p less than 0.01) between the years elapsed from the onset of symptoms and bronchial responsiveness to histamine was observed in each group of patients. We noticed that the number of the years passed heightened the bronchial responsiveness to histamine in both groups of patients.

Exposing the mast cell: its novel integrated role in allergy.

New discoveries have suggested that the mast cell has the potential to regulate allergic inflammation by inducing IgE synthesis from B cells. Under allergic inflammatory conditions, "primed" mast cells appear to express higher levels of the high affinity receptor for IgE and the ligand for the surface antigen CD40, involved in T/B cell interactions leading to immunoglobulin production, as well as Th2-type cytokines, IL-4 and IL-13. The critical role of these cells in the induction of IgE synthesis is supported by the findings that anti-ligand for the surface antigen CD40, anti-IL-4, and anti-IL-13 monoclonal antibodies inhibit IgE production. Mast cells also have the potential to function as antigen presenting cells with the ability to shift T cells into Th2 subtypes. These recent findings suggest that mast cells can modulate important regulatory functions of the allergic response by acting directly on B cells and inducing IgE production.

Histamine releasability after adenosine challenge in subjects with allergic and non-allergic rhinitis: possible implications for mast cell priming.

Nasal provocation with adenosine 5'-monophosphate elicits nasal symptoms in subjects with rhinitis. Histamine released from airway mast cells may play a role in adenosine-induced nasal responses. To investigate the possible role of histamine in mediating adenosine-induced nasal responses, we measured its release in the fluid obtained by nasal lavage after adenosine 5'-monophosphate, guanosine 5'-monophosphate, and placebo instillations. Nasal lavages were performed before and 3, 5, 10, 15, 30 and 45 min after challenge with adenosine 5'-monophosphate, guanosine 5'-monophosphate, and normal saline in 11 patients with rhinitis and 7 normal subjects in a double-blind randomized placebo-controlled cross-over study to evaluate symptoms and to monitor changes in histamine levels. No symptoms or significant increases in histamine were observed after guanosine 5'-monophosphate and placebo challenge. Symptom scores increased in response to adenosine 5'-monophosphate challenge in the rhinitic subjects but not in the normal controls. Nasal provocation with adenosine elicited a significant release of histamine in the nasal lavage fluids with an immediate peak response: its median (range) concentration increased from the baseline value of 1.33 (0.16-14.54) ng/mL to 2.68 (0.31-61.11) ng/mL at 3 min. However, increased histamine levels were not associated with nasal symptom scores. When compared to non-atopic subjects, significantly higher levels of histamine were seen in the nasal lavage fluids of the atopic subjects following adenosine challenge. In the atopic subjects, the median (range) histamine concentration increased from the baseline value of 1.54 (0.16-14.54) ng/mL to that of 4.21 (0.70-61.11) ng/mL at 3 min, whereas no increment was seen in the non-atopic subjects, their histamine concentration being 0.81 (0.29-5.56) ng/mL and 0.74 (0.31-14.25) ng/mL at baseline and 3 min after adenosine challenge respectively. These findings indicate that adenosine elicits nasal responses in patients with rhinitis but not in normal controls. Moreover, adenosine elicits an immediate rise in histamine levels in the nasal lavage fluid, with the highest rise in atopic compared to non-atopic volunteers, suggesting that the nasal responses to adenosine may be an index of mast cell priming.

[Mast cell mediator release after endobronchial challenge with adenosine 5'-monophosphate in asthmatic subjects]. / Liberazione di mediatori mastocitari dopo challenge endobronchiale con adenosina 5'-monofosfato in soggetti asmatici.

Mediator release from activated mast cells is also likely to take place in the asthmatic airways in vivo during adenosine-induced bronchoconstriction. To test this hypothesis, we evaluated mast cell mediator release directly into the airways of 9 asthmatic subjects after endobronchial challenge with adenosine by bronchoalveolar lavage (BAL). The mediators measured were histamine, tryptase, and PGD2. When compared to the saline-challenged segment, the response to AMP instillation was characterized by a prompt reduction in airway calibre paralleled by a significant 4.2-fold increase in PGD2 levels in the BAL fluid (p = 0.004). There were also increases in median histamine (from 200.1 to 433.6 pg/mL) and tryptase levels (from 0.31 to 0.46 ng/mL) recovered after AMP challenge, although they were not significant. These findings support the view that acute bronchospastic response to AMP in asthmatic airways is paralleled by the local release of mast cells derived products, particularly PGD2.