Severe hypereosinophilia in a patient treated with dupilumab and shift to mepolizumab: the importance of multidisciplinary management. A case report and literature review.

Type 2 inflammation is a heterogeneous condition due to the complex activation of different immunological pathways. Rapid progress in research to evaluate the efficacy of biologics for chronic rhinosinusitis with nasal polyps and asthma has led to the availability of effective therapeutic options. These drugs are safe, but temporary iatrogenic hypereosinophilia may sometimes be associated with clinical symptoms or organ damage. Here, we describe a case of severe hypereosinophilia in a patient with chronic rhinosinusitis with nasal polyps and asthma treated with dupilumab and a subsequent therapeutic shift to mepolizumab that led to maintenance of symptom control and concomitant normalization of blood eosinophil count.

Tezepelumab: patient selection and place in therapy in severe asthma.

Asthma is a disease characterised by heterogeneous and multifaceted airway inflammation. Despite the availability of effective treatments, a substantial percentage of patients with the type 2 (T2)-high, but mainly the T2-low, phenotype complain of persistent symptoms, airflow limitation, and poor response to treatments. Currently available biologicals target T2 cytokines, but no monoclonal antibodies or other specific therapeutic options are available for non-T2 asthma. However, targeted therapy against alarmins is radically changing this perspective. The development of alarmin-targeted therapies, of which tezepelumab (TZP) is the first example, may offer broad action on inflammatory pathways as well as an enhanced therapeutic effect on epithelial dysfunction. In this regard, TZP demonstrated positive results not only in patients with severe T2 asthma but also those with non-allergic, non-eosinophilic disease. Therefore, it is necessary to identify clinical features of patients who can benefit from an upstream targeted therapy such as anti-thymic stromal lymphopoietin. The aims of this narrative review are to understand the role of alarmins in asthma pathogenesis and epithelial dysfunction, examine the rationale underlying the indication of TZP treatment in severe asthma, summarise the results of clinical studies, and recognise the specific characteristics of patients potentially eligible for TZP treatment.

Comparison between clinical trials and real-world evidence studies on biologics for severe asthma.

In recent years, the more widespread availability of biological drugs with specific mechanisms of action has led to significant breakthroughs in the management of severe asthma. Over time, numerous randomised clinical trials have been conducted to evaluate the efficacy and safety of these biologics and define the eligibility criteria of patients suitable for various therapeutic options. These studies were conducted under controlled conditions not always applicable to real life. For this and other reasons, real-world evidence and pragmatic studies are required to provide useful information on the effectiveness of biological drugs and their safety, even in the long term. Because differences in outcomes have sometimes emerged between clinical trials and real-life studies, it is important to clarify the causes of these discrepancies and define the significance of the results of studies conducted in the course of daily clinical practice. Thus, a scientific debate is ongoing, and no consensus has been reached. The purpose of this narrative review is to analyse the differences between randomised trials and real-world evidence studies, focusing on their roles in guiding clinicians among different therapeutic options and understanding the reasons for the large discrepancies often found in the results obtained.

SFRP4 Expression Is Linked to Immune-Driven Fibrotic Conditions, Correlates with Skin and Lung Fibrosis in SSc and a Potential EMT Biomarker.

Secreted Frizzled Receptor Protein 4 (SFRP4) has been shown to be increased in Scleroderma (SSc). To determine its role in immune-driven fibrosis, we analysed SSc and sclerotic Chronic Graft Versus Host Disease (sclGVHD) biosamples; skin biopsies (n = 24) from chronic GVHD patients (8 with and 5 without sclGVHD), 8 from SSc and 3 healthy controls (HC) were analysed by immunofluorescence (IF) and SSc patient sera (n = 77) assessed by ELISA. Epithelial cell lines used for in vitro Epithelial-Mesenchymal-Transition (EMT) assays and analysed by Western Blot, RT-PCR and immunofluorescence. SclGVHD skin biopsies resembled pathologic features of SSc. IF of fibrotic skin biopsies indicated the major source of SFRP4 expression were dermal fibroblasts, melanocytes and vimentin positive/caveolin-1 negative cells in the basal layer of the epidermis. In vitro studies showed increased vimentin and SFRP4 expression accompanied with decreased caveolin-1 expression during TGFß-induced EMT. Additionally, SFRP4 serum concentration correlated with severity of lung and skin fibrosis in SSc. In conclusion, SFRP4 expression is increased during skin fibrosis in two different immune-driven conditions, and during an in vitro EMT model. Its serum levels correlate with skin and lung fibrosis in SSc and may function as biomarker of EMT. Further studies are warranted to elucidate the role of SFRP4 in EMT within the pathogenesis of tissue fibrosis.

Usefulness of sleep events detection using a wrist worn peripheral arterial tone signal device (WatchPAT™) in a population at low risk of obstructive sleep apnea.

Due to the high prevalence of obstructive sleep apnea (OSA), it is recommended to use in-laboratory polysomnography (PSG) or a home sleep apnea test (HSAT) in uncomplicated adult subjects at high risk of OSA. The aims of the present study were to compare a HSAT device, a wrist worn peripheral arterial tone signal device (WatchPAT™-200 [WP]) with PSG and respiratory polygraphy (RP) in a low-risk population of OSA. A total of 47 adult subjects at low risk of OSA were simultaneously examined with the three different approaches in a single night. The sleep studies were scored independently and in a blinded fashion, then the results and the parameters (Respiratory Disturbance Index, apnea-hypopnea index [AHI] and oxygen desaturation index of 3%) were compared with several statistical analyses. The agreement between the sleep tools and correlation for the assessed parameters were analysed and compared with Bland and Altman plots and Pearson's coefficient (WP versus PSG, r = 0.86). For the severity of OSA ranked according to PSG, the Cohen's k was 0.60 and 0.82 for WP and RP, respectively. Specificity was higher for RP compared to WP for identifying the presence of OSA (AHIPSG cut-off ≥5 events/hr: 0.85 versus 0.73), while was quite similar in identifying patients who were more likely to be treated (AHIPSG cut-off ≥15 events/hr: 0.94 versus 0.96). Assessing the costs and the simplicity of the examination, the results of our present study demonstrate the usefulness of WP compared to PSG, especially in screening and follow-up for the ability to exclude subjects from treatment with continuous positive airway pressure (AHI <15 events/hr) in a population with a low pre-test risk of moderate-to-severe OSA.

Expression of the atypical chemokine receptor D6 in human alveolar macrophages in COPD.

BACKGROUND: D6 is an atypical chemokine receptor involved in chemokine degradation and resolution of acute inflammatory responses in mice. Emerging evidence suggests that D6 might behave differently in human chronic inflammatory conditions. We, therefore, investigated the involvement of D6 in the immune responses in COPD, a chronic inflammatory condition of the lung. METHODS: D6 expression was quantified by immunohistochemistry in surgical resected lung specimens from 16 patients with COPD (FEV(1), 57% ± 6% predicted) and 18 control subjects with normal lung function (nine smokers and nine nonsmokers). BAL was also obtained and analyzed by flow cytometry, immunofluorescence, and molecular analysis for further assessment of D6 involvement. RESULTS: D6 expression in the lung was mainly detected in alveolar macrophages (AMs). The percentage of D6(+) AMs was markedly increased in patients with COPD as compared with both smoker and nonsmoker control subjects (P < .0005 for both). D6 expression was detected at both transcript and protein level in AMs but not in monocyte-derived macrophages. Finally, D6 expression was positively correlated with markers of immune activation (CD8(+) T lymphocytes, IL-32, tumor necrosis factor-α, B-cell activating factor of the tumor necrosis factor family, phospho-p38 mitogen-activated protein kinase) and negatively with lung function (FEV(1), FEV(1)/FVC). CONCLUSIONS: D6 is expressed in AMs from patients with COPD, and its expression correlates with the degree of functional impairment and markers of immune activation. Upregulation of D6 in AMs could indicate that, besides its known scavenger activity in acute inflammation, D6 may have additional roles in chronic inflammatory conditions possibly promoting immune activation.

Deficient antiviral immune responses in childhood: distinct roles of atopy and asthma.

BACKGROUND: Impaired immune response to viral infections in atopic asthmatic patients has been recently reported and debated. Whether this condition is present in childhood and whether it is affected by atopy per se deserves further investigation. OBJECTIVE: We sought to investigate airway interferon production in response to rhinovirus infection in children who are asthmatic, atopic, or both and its correlation with the airway inflammatory profile. METHODS: Bronchial biopsy specimens and epithelial cells were obtained from 47 children (mean age, 5 ± 0.5 years) undergoing bronchoscopy. The study population included asthmatic children who were either atopic or nonatopic, atopic children without asthma, and children without atopy or asthma. Rhinovirus type 16 induction of IFN-λ and IFN-ß mRNA and protein levels was assessed in bronchial epithelial cell cultures. The immunoinflammatory profile was evaluated by means of immunohistochemistry in bronchial biopsy specimens. RESULTS: Rhinovirus type 16-induced interferon production was significantly reduced in atopic asthmatic, nonatopic asthmatic, and atopic nonasthmatic children compared with that seen in nonatopic nonasthmatic children (all P < .05). Increased rhinovirus viral RNA levels paralleled this deficient interferon induction. Additionally, IFN-λ and IFN-ß induction correlated inversely with the airway T(H)2 immunopathologic profile (eosinophilia and IL-4 positivity: P < .05 and r = -0.38 and P < .05 and r = -0.58, respectively) and with epithelial damage (P < .05 and r = -0.55). Furthermore, total serum IgE levels correlated negatively with rhinovirus-induced IFN-λ mRNA levels (P < .05 and r = -0.41) and positively with rhinovirus viral RNA levels (P < .05 and r = 0.44). CONCLUSIONS: Deficient interferon responses to rhinovirus infection are present in childhood in asthmatic subjects irrespective of their atopic status and in atopic patients without asthma. These findings suggest that deficient immune responses to viral infections are not limited to patients with atopic asthma but are present in those with other T(H)2-oriented conditions.

Mast cell infiltration discriminates between histopathological phenotypes of chronic obstructive pulmonary disease.

RATIONALE: COPD is a complex disease with heterogeneous manifestations. Attempts have been made to define different phenotypes that could guide toward better disease understanding. We described before that smokers can develop either panlobular (PLE) or centrilobular emphysema (CLE). The latter has worse small airways remodeling and narrowing, which account for the airflow obstruction similar to asthma. OBJECTIVES: Because of the small airways involvement in CLE similar to asthma, we hypothesized a role for mast cells in CLE but not in PLE. Hence, we investigated mast cell infiltration, along with overall inflammation, and their relation with hyperreactivity and emphysema type in COPD. METHODS: We studied lung function, emphysema type, mast cells, and overall inflammation in small airways and alveolar walls, along with alveolar wall thickening in 67 subjects undergoing lung resection (59 smokers, 8 nonsmokers). MEASUREMENTS AND MAIN RESULTS: Twenty-seven smokers had CLE, 24 had PLE, and 8 had no emphysema. Mast cells were significantly increased in CLE compared with PLE and control subjects. Especially relevant was the mast cell increase in airway smooth muscle in CLE, which related significantly to airway hyperreactivity. CD4(+)T cells, neutrophils, and macrophages, but not eosinophils and CD8(+)T cells, were significantly higher in CLE than PLE. Alveolar wall thickness was increased in all smokers, but significantly more in CLE. CONCLUSIONS: The pathological phenotypes of COPD CLE and PLE show important differences in their overall inflammation with a protagonism of mast cells, which are related to airway reactivity. These findings highlight the distinctness of these COPD phenotypes and the role of mast cells in the pathophysiology of COPD.

Correlation of computed tomography densitometry and pathological grading of emphysema with the variation of respiratory function after lobectomy for lung cancer.

The presence of emphysema may lead to an underestimation of postoperative respiratory function after lobectomy when evaluated by standard functional assessment. The aim of the study was to assess the correlation between computed tomography (CT) densitometry, pathological grading of emphysema and variation of pulmonary function after lobectomy for lung cancer. Forty-one patients entered the study. Respiratory function was assessed preoperatively and after a mean period of 4.04 months following surgery. Postoperative function remained unchanged or increased after surgery in nine patients (Group A). In the remaining 32 patients (Group B) postoperative function was reduced after surgery. Preoperative forced expiratory volume in 1 s (FEV(1))% was 68.5+/-13.1% in Group A and 91.7+/-21.0% in Group B. CT densitometry of the lobe to be resected was -877.8+/-57.6 HU in Group A and -827.5+/-64.4 HU in Group B. Pathological grading of emphysema of the resected lobe (range 0-10) was 4.1+/-2.2 in Group A and 3.1+/-1.2 in Group B. A significant correlation was observed (Spearman rank correlation) between the variation of FEV(1) and preoperative FEV(1) (P=0.003; r=-0.455), CT quantitative assessment (P=0.036; r=-0.430) and pathological grading (P=0.008; r=0.673). Patients with a higher degree of emphysema had a lower reduction of respiratory function after lobectomy and CT densitometry and pathological grading of emphysema correlated with the variation in respiratory function.

[Sentinel lymph-node biopsy for breast cancer. Analysis of 235 cases and review of the literature]. / Lo studio del linfonodo sentinella nel carcinoma della mammella. Analisi di 235 casi e revisione della letteratura.

Sentinel lymph-node biopsy for breast cancer has been rapidly adopted in clinical practice. At the present time few prospective randomised studies exist, the false negative rate is variable and its role with regard to prognosis is not well known. The aim of this study was to evaluate the elements of sentinel lymph-node biopsy that have yet to be clearly defined, by reference to the literature and our own experience. From September 1999 to July 2005, we considered 235 consecutive patients undergoing sentinel lymph-node biopsy. We used the radioactive tracer in 143 cases, and the radiotracer combined with vital blue dye in 89 cases. Vital blue dye was used alone in only 3 cases. In 224 cases the sentinel lymph-node biopsy was performed in a single session, using frozen sections to evaluate the sentinel node. The identification rate obtained was 97.9% with the radiotracer, 100% with the combined procedure and 66.7% with vital blue alone. The sentinel node proved positive in 52 cases. The frozen sections correctly predicted the positive result of the definitive histopathological analysis in 26 cases and correctly predicted a negative result in 172. We discuss the indications and methods of sentinel lymph-node biopsy, analysing our own data and those reported in the literature.

Role of axillary sentinel lymph node biopsy in patients with pure ductal carcinoma in situ of the breast.

BACKGROUND: Sentinel lymph node (SLN) biopsy is an effective tool for axillary staging in patients with invasive breast cancer. This procedure has been recently proposed as part of the treatment for patients with ductal carcinoma in situ (DCIS), because cases of undetected invasive foci and nodal metastases occasionally occur. However, the indications for SLN biopsy in DCIS patients are controversial. The aim of the present study was therefore to assess the incidence of SLN metastases in a series of patients with a diagnosis of pure DCIS. METHODS: A retrospective evaluation was made of a series of 102 patients who underwent SLN biopsy, and had a final histologic diagnosis of pure DCIS. Patients with microinvasion were excluded from the analysis. The patients were operated on in five Institutions between 1999 and 2004. Subdermal or subareolar injection of 30-50 MBq of 99 m-Tc colloidal albumin was used for SLN identification. All sentinel nodes were evaluated with serial sectioning, haematoxylin and eosin staining, and immunohistochemical analysis for cytocheratin. RESULTS: Only one patient (0.98%) was SLN positive. The primary tumour was a small micropapillary intermediate-grade DCIS and the SLN harboured a micrometastasis. At pathologic revision of the specimen, no detectable focus of microinvasion was found. CONCLUSION: Our findings indicate that SLN metastases in pure DCIS are a very rare occurrence. SLN biopsy should not therefore be routinely performed in patients who undergo resection for DCIS. SLN mapping can be performed, as a second operation, in cases in which an invasive component is identified in the specimen. Only DCIS patients who require a mastectomy should have SLN biopsy performed at the time of breast operation, since in these cases subsequent node mapping is not feasible.

[Medullary carcinoma of the thyroid: a clinical contribution]. / Il carcinoma midollare della tiroide: contributo clinico.

The authors report 20 cases of medullary thyroid carcinoma over the period from 1980 to 2000. Two patients turned out to be inoperable and 18 patients underwent total thyroidectomy, associated with dissection of the central lymphatic compartment in 5 patients and with dissection of the central and lateral lymphatic compartments in 10 patients with clinical or instrumental evidence of cervical lymphadenomegaly. Serum calcitonin levels proved to be a reliable marker for the diagnosis of persistence or recurrence of the disease. The follow-up, lasting from 1 to 208 months, demonstrated that in 7 cases in which serum levels of calcitonin underwent normalization there was no recurrence of disease. Among 11 cases with persistence of high calcitonin levels, 6 died and only 2 presented no evidence of metastases. On the basis of our analysis of the cases reported, total thyroidectomy associated with dissection of the central lymphatic compartment is an adequate treatment for patients in stages I and II. The authors regard routine dissection of the lateral lymphatic compartment as unadvisable.