Reliability of automatic detection of AHI during positive airway pressure treatment in obstructive sleep apnea patients: A "real-life study".

INTRODUCTION: Automatic event detection (AED) of residual apnea-hypopnea index (AHI) by ventilators is a current practice in sleep and mechanical ventilation Units but this methodology has not been validated in an unselected population of OSA patients. Aim of the present study was to assess in a "real-life" condition the reliability of AED during PAP therapy by the in-built software compared to full polysomnography during follow-up. METHODS: We enrolled 300 OSA patients (105 F; AHI 45.3 ± 27.8) already on Positive airway pressure (PAP) therapy: 53% of the patients were on CPAP while other modalities were used in the rest of the sample. RESULTS: Overall, the built-in software identified residual obstructive AHI (AHIPAP) > 5, 10 or 15 in 18.7, 8.6 or 4.6% of patients, respectively. By using AHIPAP, 28.4% of patients were wrongly classified as "well controlled" despite a residual AHIPSG>5 (6% considering a residual AHIVENT >15); 7% of patients were classified as not controlled while AHIPSG was <5 (1.4% considering a residual AHIVENT >15). Type of ventilation, ventilator parameters, adherence to treatment and level of baseline or follow-up Epworth Sleepiness Scale score were similar between groups. The sensitivity and positive predicted values were very low. Positive likelihood ratio appears adequate only for residual AHIPAP ≥10, but negative likelihood ratio was inconclusive for all the cut-off considered. DISCUSSION: The results of the present study suggest a more cautious approach in the follow-up of OSA patients, since a protocol based only on AED detection and symptoms assessment may not be accurate especially for AHIPAP<15.

Chronic obstructive pulmonary disease and obstructive sleep apnea. Association, consequences and treatment.

Obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD) are two diseases that often co-exist within an individual. This co-existence, known as overlap syndrome (OS), is the result of chance rather than a pathophysiological linkage and epidemiological studies indicate a prevalence of 1% in adult males. Patients vith OS have a more important sleep-related O2 desaturation than COPD patients with the same degree of bronchial obstruction and show an increased risk of developing hypercapnic respiratory failure and pulmonary hypertension when compared with patients affected by only one of he diseases. COPD and OSAS are independent risk factors for cardiovascular events and their co-existence in OS probably increases this risk. Evidence of systemic inflammation in COPD and sleep apnea and consequentely OS, is interesting because it may contribute to the pathogenesis of cardiovascular diseases. Treatment consists of continuous positive airway pressure (CPAP) or non-invasive positive pressure ventilation (NIPPV), with or without associated O2, for correction of the upper airway obstructive episodes and hypoxemia during sleep.

Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite-induced rhinoconjunctivitis.

BACKGROUND: Non-injective routes of immunotherapy are thought to be valuable therapeutic options for respiratory allergy. We investigated the clinical efficacy and the effects of sublingual/oral immunotherapy on conjunctival allergic inflammation in patients with mite-induced respiratory allergy. METHODS: We used a double-blind placebo-controlled design. 20 patients with mite-induced rhinoconjunctivitis (six of whom also had mild asthma) were randomly assigned sublingual/oral immunotherapy (n=10) or placebo (n=10) for 2 years. We assessed symptom score by diary cards and inflammatory-cell infiltrate, and expression of intercellular adhesion molecule 1 (ICAM-1) in the conjunctiva after specific allergen challenge at enrollment and after 12 and 24 months of treatment. FINDINGS: We found significantly lower symptom scores in the immunotherapy group than in the placebo group in most of the winter months (p=0.05). Compared with the placebo group, inflammatory-cell infiltration after conjunctival challenge, and ICAM-1 expression on conjunctival epithelium decreased significantly in the first year of treatment in the immunotherapy group (p=0.04 and p=0.02, respectively). These effects were also seen for the minimum persistent inflammation, in symptom-free patients exposed constantly to allergens (p=0.02). Serum concentrations of eosinophil cationic protein decreased significantly (p=0.04). Immunotherapy was well tolerated and compliance was good. INTERPRETATION: Our results suggest that this immunotherapy is clinically effective in rhinoconjunctivitis and that it decreases the immune-mediated inflammatory responses to the allergen.

Loratadine treatment of rhinitis due to pollen allergy reduces epithelial ICAM-1 expression.

BACKGROUND: Loratadine and cetirizine are new generation antihistamines, which are clinically effective in the treatment of allergic rhinitis. OBJECTIVE: The aim of the study was to evaluate antiallergic activity of loratadine compared with cetirizine, over a 2 week period under natural allergen exposure, in a double-blind parallel groups, randomized, controlled trial. METHODS: Twenty patients, sensitized to grass and/or Parietaria pollen, were subdivided into two groups, one receiving loratadine the other cetirizine respectively. Both were dosed at 10 mg/day. Evaluated parameters were: clinical symptoms, nasal inflammatory cell (such as neutrophil, eosinophil and metachromatic cells) counts, ICAM-1 expression on nasal epithelial cells, and nasal mediators (e.g. histamine, ECP, EPO and MPO). RESULTS: Loratadine and cetirizine significantly improved symptoms (P < 0.002), significantly reduced eosinophil (P < 0.016) and metachromatic cell (P < 0.01) infiltration, levels of ECP (P < 0.002), EPO (P < 0.006) and histamine (P < 0.01) and ICAM-1 expression on nasal epithelial cells (P < 0.02). No difference was demonstrated between the two drugs. CONCLUSION: The antiallergic activity of loratadine and cetirizine is documented by their actions on the inflammatory and clinical parameters, especially ICAM-1 modulation.

Long-term follow-up of nasal immunotherapy to Parietaria: clinical and local immunological effects.

BACKGROUND: Local nasal immunotherapy (LNIT) with extracts in powder has been demonstrated clinically effective and devoid of side-effects in several controlled trials; nevertheless, no data concerning the long-term effects of LNIT are presently available. METHODS: In a recent double-blind, placebo-controlled study of LNIT to Parietaria pollen we observed, by means of specific nasal provocation test (SNPT) that LNIT is able to modify the local allergic inflammatory response. In the present study we followed up the same patients in open fashion for 2 further years. RESULTS: The results confirmed the clinical efficacy of LNIT and showed that it is strictly dependent on pre-seasonal administration: in fact, after LNIT discontinuation a clinical relapse was observed. A certain long-lasting protective effect on SNPT parameters (nasal symptoms and neutrophils infiltration) was also observed, whereas an increase of eosinophils count and ICAM-1 expression on nasal epithelial cells appeared as possible markers of clinical relapse. CONCLUSION: The present study suggests that pre-seasonal LNIT can be taken in consideration in selected subjects as prophylactic treatment for pollen-induced rhinitis. In addition, the results obtained provide informations about the duration of clinical efficacy and add data about the local allergic inflammation and its modulation.

Topical azelastine reduces eosinophil activation and intercellular adhesion molecule-1 expression on nasal epithelial cells: an antiallergic activity.

BACKGROUND: It is well known that allergen-specific nasal challenge (ASNC) is a fruitful tool with which to evaluate antiallergic activity exerted by a drug. Azelastine is a new antihistamine also available in topical form (i.e., nasal spray). OBJECTIVE: The aim of the study was to evaluate the effects of azelastine nasal spray on inflammatory changes after ASNC in both the early-phase reaction and the late-phase reaction. METHODS: The study had a double-blind, placebo-controlled, randomized, and parallel-group design. Twenty patients with pollen allergy were enrolled out of pollen season. ASNC was performed at baseline (TO) and after 1 week of washout (T7). At T7, 10 patients sprayed azelastine (1 puff) into their nostrils, and 10 patients used placebo. ASNC was performed after 30 minutes. The considered parameters (evaluated during early- and late-phase reactions) were: (1) clinical signs and symptoms, (2) cytologic assessment (neutrophils and eosinophils), (3) assay-of mediators (eosinophil cationic protein and myeloperoxidase), and (4) expression of intercellular adhesion molecule-1 (ICAM-1) on nasal epithelial cells. We focused our attention on ICAM-1 because it is the natural ligand of leukocyte functional associated antigen-1 and Mac-1, expressed on eosinophils. In addition, ICAM-1 is expressed on epithelial cells only on allergen exposure (both natural and experimental). RESULTS: Placebo did not exert any modification on the considered parameters. After azelastine administration, significant decreases in total symptom score, eosinophilic and neutrophilic infiltration, and ICAM-1 expression were observed during both early- and late-phase reactions. Furthermore, serum eosinophil cationic protein levels decreased during the late-phase reaction, whereas myeloperoxidase was not affected by the treatment. These findings were confirmed by the powerful Koch's split-plot statistical analysis. CONCLUSION: Azelastine exerts antiallergic activity, mainly affecting eosinophil function and downregulating ICAM-1 expression, on nasal epithelial cells.

Cetirizine reduces ICAM-I on epithelial cells during nasal minimal persistent inflammation in asymptomatic children with mite-allergic asthma.

It has been recently demonstrated that individuals who suffer from mite allergy present mucosal inflammation even when asymptomatic. This situation is characterized by infiltration of inflammatory cells (eosinophils and neutrophils) and by ICAM-I expression on epithelial cells. It has been called 'minimal persistent inflammation' (MPI) for its relationship with natural exposure to allergen, which is continuous in the case of mite allergy. ICAM-I (or CD54) expression on epithelial cells is relevant for several reasons: (a) healthy individuals and patients with pollen allergy out of the pollen season do not express this molecule; (b) ICAM-I is the natural ligand of LFA-1 (an integrin expressed on granulocytes), and (c) ICAM-I is also receptor for rhinoviruses. It is well known that viral infections precede asthmatic attacks; consequently, this correlation is more frequent in cases of mite allergy. Cetirizine is an antiallergic drug that can reduce both inflammatory infiltrate and ICAM-I expression induced by allergen-specific conjunctival challenge. The aim of this study was to evaluate the effect of cetirizine on MPI in 20 children (5-14 years old) with mite allergy. All the children suffered from mild asthma and 9 also had rhinitis (they had been asymptomatic, and thus not treated, for 2 months). The study was double-blind, placebo controlled and randomized and children took Cetirizine or placebo for 15 days. At the beginning and end of the study, nasal scrapings were performed to evaluate inflammatory cell infiltration (eosinophils and neutrophils) and ICAM-I expression on epithelial cells. Cetirizine-treated children showed a significant reduction (or even total absence) of ICAM-I expression on epithelial cells (p less than 0.002) and a reduction trend in inflammatory cell counts compared with placebo. In conclusion, Cetirizine might be envisaged as fruitful for the prolonged treatment of allergic children, including during clinical latency, to prevent possible relapse or rhinovirus infections.

Minimal persistent inflammation is present at mucosal level in patients with asymptomatic rhinitis and mite allergy.

The natural exposure to house dust mites causes sensitization in genetically susceptible patients. Persistent exposure of sensitized patients causes chronic inflammation, and consequently, hyperreactivity, thus promoting the development of clinical features. Recently, intercellular adhesion molecule-1 (ICAM-1)/CD54 expression on epithelial cells triggered by allergen has been demonstrated and related to the inflammation caused by the allergic reaction. Therefore we evaluated the possible presence of inflammation (i.e., inflammatory cell infiltrate and ICAM-1/CD54 expression on epithelium) at conjunctival and nasal levels in patients with asymptomatic allergic rhinitis caused by mites, in their relatives living in the same environment, and in healthy volunteers. In addition, the possible relationship between inflammation and house dust mite allergen exposure was evaluated. Conjunctival and nasal scrapings of allergic subjects enrolled in the study showed many inflammatory cells. A mild ICAM-1/CD54 expression on conjunctival and nasal epithelium was detectable in allergic subjects, whereas relatives and healthy volunteers showed few inflammatory cells and no ICAM-1/CD54 expression on epithelial cells. A detectable level of house dust mite, sufficient to cause sensitization, was found in all houses. This study demonstrates a minimal persistent inflammation at conjunctival and nasal levels constantly detectable in patients without symptoms who are sensitized to mites and continuously exposed to the natural allergens.

Oxatomide reduces inflammatory events induced by allergen-specific conjunctival challenge.

BACKGROUND: Allergen-specific conjunctival challenge is a safe and reproducible experimental model to evaluate effectiveness and possible mechanism(s) of action of drugs employed in the treatment of allergic diseases. OBJECTIVE: The protective effect of oxatomide on inflammatory changes that follow allergen-specific conjunctival challenge was assessed in 20 patients with rhinoconjunctivitis due to Parietaria judaica in a double-blind study. METHODS: After a screening allergen-specific conjunctival challenge, patients were randomized into two treatment groups, each being given oxatomide (oral tablets) at 60 mg daily or matching placebo for seven days during off-pollen season. Clinical evaluation, cytologic assessment (number of inflammatory cells and ICAM-1 expression on epithelial cells) were assessed at baseline, 30 minutes, 6 hours, and 24 hours after allergen-specific conjunctival challenge, before and after treatment. In addition, electrocardiograms were obtained before and after treatment. RESULTS: Early phase reaction clinical events as well as total numbers of inflammatory cells were significantly reduced by oxatomide compared with placebo. Late phase reaction clinical events as well as total numbers of inflammatory cells were significantly reduced by oxatomide compared with placebo. ICAM-1 expression was significantly reduced by oxatomide in early phase reactions and late phase reactions compared with placebo. No pathologic cardiac events were detected in any subject. CONCLUSIONS: Oxatomide has a protective effect on clinical and cellular early phase reactions and late phase reactions (including ICAM-1 expression on epithelium) induced by allergen-specific conjunctival challenge and is safe and well tolerated.

Terfenadine exerts antiallergic activity reducing ICAM-1 expression on nasal epithelial cells in patients with pollen allergy.

BACKGROUND: Rhinoconjunctivitis caused by pollen allergy is characterized by typical signs and symptoms and mucosal infiltration by inflammatory cells during the pollen season. It has recently been demonstrated that the adhesion molecule system is deeply involved in cell-to-cell interaction during the inflammatory response which follows allergic reactions. OBJECTIVE: The aim of the present study (placebo-controlled, double-blind, randomized) was the evaluation of the antiallergic activity of Terfenadine in the model of the allergic rhinitis due to natural pollen exposure. METHODS: Two groups of patients with pollen allergy were enrolled in this study. Ten patients were treated with Terfenadine (120 mg/die) for 7 days and 10 with placebo. Evaluation criteria were: (a) clinical: signs and symptoms (recorded daily in a diary card by patients); (b) cytological: inflammatory cell count (neutrophils, eosinophils, metachromatic cells) from nasal lavage at T0 and T7; (c) immunocytochemical: ICAM-1/CD54 expression on nasal epithelial cells at T0 and T7; and (d) mediators dosage (ECP-MPO) on nasal lavage at T0 and T7. RESULTS: As opposed to the placebo group, patients treated with Terfenadine showed a significant improvement of both symptoms (P < 0.022) and signs P < 0.001), a significant reduction of inflammatory cells infiltrate (P < 0.005), of ECP levels (P < 0.002) and ICAM-1 expression on nasal epithelial cells (P < 0.005). CONCLUSIONS: In conclusion, these data demonstrate that Terfenadine exerts antiallergic activity since it is able to reduce inflammatory cell infiltrate and downregulates ICAM-1 expression.

Nasal immunotherapy to Parietaria: evidence of reduction of local allergic inflammation.

Studies over 10 yr have demonstrated local nasal immunotherapy (LNIT) to be an effective treatment for rhinitis due to pollens and mites. The aim of our work was to investigate the effects of LNIT on the local inflammatory phenomena, employing the model of nasal allergenic challenge, since no evidence has been yet provided about LNIT effects on the events due to allergic reactions. We evaluated, in addition, the possible effects of LNIT on some systemic immunologic parameters and its clinical efficacy. The study involved a double-blind, placebo-controlled trial of preseasonal immunotherapy with Parietaria in 20 adults. A significant reduction of symptoms, inflammatory infiltration, and intercellular adhesion molecule-1 (ICAM-1) expression on epithelial cells after nasal challenge was evidence as long-lasting effect. No changes in serum allergen-specific IgE, IgG, and soluble eosinophil cationic protein were detected, whereas an unexpected increase of soluble ICAM-1 was found in the placebo group only. The treatment was well tolerated and a significant clinical improvement under natural allergenic exposure was observed in the active group. The present study provides, for the first time, evidence that LNIT is able to modulate the nasal allergic inflammation.

Follicular thyroid cells of autoimmune thyroiditis may coexpress ICAM-1 (CD54) and its natural ligand LFA-1 (CD11a/CD18).

The leukocyte functional associated antigen-1 (LFA-1)-intercellular adhesion molecule-1 (CD11a-CD18/CD54) intercellular adhesion system plays a crucial role in several immunologic phenomena, including adhesion between lymphocytes and epithelial cells. In previous studies evidence for CD54 expression on thyroid follicular cells in Hashimoto's thyroiditis was provided. In this study we evaluated the possible expression of CD11a and CD18 antigens on thyrocytes of patients with Hashimoto's thyroiditis and on thyrocytes of patients with Graves' disease and simple goiter as controls; we used both alkaline phosphatase immunostaining and indirect immunofluorescence on cryostatic tissue sections. The results showed that LFA-1 (both CD11a and CD18) positivity on thyroid follicles may occur in glands of patients with Hashimoto's disease, with a pattern very similar to that of CD54: this was observed in five of seven specimens. Conversely, no positivity was observed in tissues from patients with Graves' disease or goiter: notably, isolated follicular cells from Graves' goiter tissues are induced in culture to express CD54, but not LFA-1. Using double-staining techniques, we were able to show that in specimens from patients with Hashimoto's disease, the same follicular structures coexpressed LFA-1 and CD54. Such a coexpression of the two ligands further emphasizes the possible role of this adhesion system in the pathogenesis of epithelial damage, through bidirectional interactions between thyroid epithelial cells and infiltrating LFA-1 or CD54-positive mononuclear cells.

Infiltrating gamma/delta T-cell receptor-positive lymphocytes in Hashimoto's thyroiditis, Graves' disease and papillary thyroid cancer.

In the present study we have evaluated the expression of different molecular forms of the antigen receptor (TcR) on lymphocytes derived from thyroid tissue of patients with Graves' disease, Hashimoto thyroiditis and papillary cancer both in situ by APAAP technique and on isolated lymphocytes by indirect immunofluorescence. A panel of monoclonal antibodies (mAbs) recognizing alpha/beta and gamma/delta TcR-positive subsets was used. The results showed that the large majority of T-cells in thyroid infiltrates were alpha/beta TcR+, gamma/delta TcR+ ones being very rare or nearly absent, whatever the disease (autoimmune or neoplastic). No difference between gamma/delta TcR+ T-cell subsets (V delta 1+ or V delta 2+) was observed. Thus, neither in autoimmune thyroid diseases nor in papillary cancer gamma/delta TcR+ cells are likely to be a major effector-T cell population.

Fibrous invasive (Riedel's) thyroiditis with critical response to steroid treatment.

The Riedel's thyroiditis is an uncommon form of chronic thyroiditis characterized by an invasive fibrosclerosis of the gland, often involving the surrounding tissues. Usually, the only possible treatment is the surgical decompression of the tissues. We describe a case of aggressive Riedel's thyroiditis with severe compression and dislocation of trachea and esophagus. The surgical approach was uneffective, while an "ex juvantibus" steroid treatment, resulted in a dramatic regression of fibrosclerosis and a complete clinical remission. This report points out the possible effectiveness of corticosteroids in the treatment of selective disorders involving increased fibrogenesis.

Allergen-specific challenge induces intercellular adhesion molecule 1 (ICAM-1 or CD54) on nasal epithelial cells in allergic subjects. Relationships with early and late inflammatory phenomena.

Intercellular adhesion molecule 1 (ICAM-1 or CD54) expression on epithelial cells (EC) has been demonstrated to play a role in the local molecular events of inflammation following allergen-specific conjunctival challenge. In the light of these observations, we evaluated the possible expression of ICAM-1 on nasal EC after allergen-specific challenge. Three groups of subjects were studied: (1) 14 symptomless patients sensitized to mites, (2) 15 symptomless patients sensitized to pollen, and (3) 10 healthy volunteers as controls. The study was performed during winter. At baseline we found that both pollinosic and healthy subjects did not express CD54 on epithelial cells, whereas mite-sensitive patients showed a mild expression (possibly caused by a persistent natural allergen exposure). In addition, clinical and cellular responses were induced by lower allergen dosages in mite-sensitive patients compared with pollen-sensitive patients. CD54 was detectable in all the allergic patients but not in the control subjects 30 min after challenge. At 6 h all patients showed a marked inflammatory infiltration and CD54 persistence on EC: such an infiltration was more relevant in patients developing clinical late-phase reaction (LPR). Finally, 24 h after challenge EC CD54 expression persisted, as well as a cellular infiltrate mainly caused by eosinophils (the latter being more pronounced in mite-sensitive individuals). CD54 should be regarded as an early and sensitive marker of inflammation in both LPR-positive and LPR-negative patients. A cellular inflammatory infiltrate was detectable in both LPR-positive and LPR-negative subjects, although relevant differences in eosinophil counts were observed between the two groups. The study emphasizes the importance of the different events of inflammation in allergy.

Evidence of intercellular adhesion molecule-1 expression on nasal epithelial cells in acute rhinoconjunctivitis caused by pollen exposure.

Rhinoconjunctivitis caused by pollen allergy is characterized by typical signs and symptoms and mucosal infiltration by inflammatory cells during pollen season. It has been recently demonstrated that the adhesion molecule system is deeply involved in cell-to-cell interaction during inflammatory response consequent to allergic reactions. The aim of this study was to evaluate the expression of intercellular adhesion molecule-1 (ICAM-1 or CD54) on nasal epithelial cells, before and during natural seasonal exposure, in 10 allergic patients (Parietaria judaica-sensitized) and in 10 healthy volunteers, correlating this parameter with clinical and cytologic involvement. Nasal epithelial cells of allergic subjects showed a significant expression of CD54 during pollen season (p < 0.001). On the contrary, no CD54 expression was observed out of pollen season. In healthy volunteers no CD54 expression was observed both before and during pollen season. Cytologic evaluation demonstrated an infiltration by eosinophils (mainly activated [EG2+]), (p < 0.001), neutrophils (p < 0.001), and metachromatic cells (p < 0.001) during pollen season only in allergic subjects. Therefore results indicate that seasonal allergic rhinitis is characterized by an infiltration of inflammatory cells correlated with CD54 expression on nasal epithelial cells. This phenomenon is specific, being restricted only to allergic patients during pollen season.