Eosinophilic Airway Diseases: From Pathophysiological Mechanisms to Clinical Practice.

Eosinophils play a key role in airway inflammation in many diseases, such as allergic and non-allergic asthma, chronic rhinosinusitis with nasal polyps, and chronic obstructive pulmonary disease. In these chronic disabling conditions, eosinophils contribute to tissue damage, repair, remodeling, and disease persistence through the production a variety of mediators. With the introduction of biological drugs for the treatment of these respiratory diseases, the classification of patients based on clinical characteristics (phenotype) and pathobiological mechanisms (endotype) has become mandatory. This need is particularly evident in severe asthma, where, despite the great scientific efforts to understand the immunological pathways underlying clinical phenotypes, the identification of specific biomarkers defining endotypes or predicting pharmacological response remains unsatisfied. In addition, a significant heterogeneity also exists among patients with other airway diseases. In this review, we describe some of the immunological differences in eosinophilic airway inflammation associated with severe asthma and other airway diseases and how these factors might influence the clinical presentation, with the aim of clarifying when eosinophils play a key pathogenic role and, therefore, represent the preferred therapeutic target.

Role of frailty on cardiac rehabilitation in hospitalized older patients.

BACKGROUND: Cardiovascular diseases are the leading cause of mortality, morbidity, and disability in the world, especially in the older adults. A relevant proportion of patients admitted to Cardiac Rehabilitation (CR) may suffer from frailty, a complex geriatric syndrome with multifactorial aetiology. AIMS: The hypothesis underlying the study is that frailty complicates the management of older patients undergoing CR. The main objective is, therefore, to determine the relationship between frailty and CR outcomes in hospitalized older adults. METHODS: The participants have been recruited among patients aged ≥ 65 years admitted at the hospital for CR. A Comprehensive Geriatric Assessment (CGA)-based Frailty Index (FI) was created following a standard procedure. The outcome was measured as the ratio between 6-min walk test (6MWT) distance at the end of CR and normal predicted values for a healthy adult of same age and gender, according to reference equations. RESULTS: The study population consisted of 559 elderly patients, 387 males (69.2%), with age of 72 (69-76) years. The most frequent diagnosis at admission was ischaemic heart disease (231, 41.5%) and overall 6MWT ratio was 0.62 ± 0.21. At the multivariable regression analysis, gender, diagnosis and FI were significantly and independently associated with 6MWT ratio (p ≤ 0.0001, p ≤ 0.001 and p ≤ 0.0001, respectively), while no significant association emerged for age. CONCLUSION: FI resulted independently correlated to 6MWT ratio in a population of older patients undergoing in-hospital CR programs. Frailty is a multifactorial geriatric syndrome whose assessment is essential for prognostic evaluation of older patients, also in CR clinical setting.

Peripheral Neuropathy in Patients Recovering from Severe COVID-19: A Case Series.

Background and Objectives: Neurological manifestations have been reported in a significant proportion of coronavirus disease 2019 (COVID-19) patients. We aimed to evaluate the prevalence and severity of peripheral nervous system (PNS) involvement in a large group of convalescent COVID-19 patients undergoing in-hospital multidisciplinary rehabilitation. Materials and Methods: Convalescent COVID-19 patients admitted to a Pulmonary Rehabilitation Unit were consecutively screened for inclusion within 48 h of discharge from an acute care setting. All included patients underwent electrophysiological examinations. Results: Among 102 enrolled patients (mean age 62.0 years, 82.4% males), PNS electrophysiological alterations were detected in 42.2%. Mononeuropathies exclusively involving the peroneal nerve were observed in 8.8% (n = 9), while multiple mononeuropathies were similarly reported in nine patients (8.8%). A symmetric sensorimotor polyneuropathy was documented in 24.5% of participants (n = 25). A significant difference was found for exercise capacity and pulmonary function in post hoc comparisons between the three study groups. Conclusions: The risk of neuropathy in the convalescent phase of COVID-19 is relevant. This should be considered when planning multidisciplinary rehabilitation strategies.

Clinical assessment of endothelial function in heart failure with preserved ejection fraction: A meta-analysis with meta-regressions.

BACKGROUND: Endothelial dysfunction is a key mechanism in the development of cardiac remodelling and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Flow-mediated (FMD) and nitrate-mediated dilation (NMD) are noninvasive methods to assess endothelial function. We performed a meta-analysis evaluating the impact of HFpEF on FMD and NMD. METHODS: PubMed, Web of Science, Scopus and EMBASE databases were systematically searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences were expressed as mean difference (MD) with 95% confidence intervals (95%CI). The random effects method was used. RESULTS: A total of seven studies were included in the final analysis, 7 with data on FMD (326 HFpEF patients and 417 controls) and 3 on NMD (185 HFpEF patients and 271 controls). Compared to controls, HFpEF patients showed significantly lower FMD (MD: -1.929; 95%CI: -2.770, -1.088; P < .0001) and NMD values (MD: -2.795; 95%CI: -3.876, -1.715; P < .0001). Sensitivity analyses substantially confirmed results. Meta-regression models showed that increasing differences in E/A ratio (Z-score: -2.002; P = .045), E/E' ratio (Z-score: -2.181; P = .029) and left atrial diameter (Z-score: -1.951; P = .050) were linked to higher differences in FMD values between cases and controls. CONCLUSIONS: Impaired endothelial function can be documented in HFpEF, with the possibility of a direct association between the severity of diastolic and endothelial dysfunction. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option.

Diffuse Idiopathic Skeletal Hyperostosis (DISH) and a Possible Inflammatory Component.

PURPOSE OF REVIEW: Diffuse Idiopathic Skeletal Hyperostosis (DISH) is considered a metabolic condition, characterized by new bone formation affecting mainly at entheseal sites. Enthesitis and enthesopathies occur not only in the axial skeleton but also at some peripheral sites, and they resemble to some extent the enthesitis that is a cardinal feature in spondyloarthritis (SpA), which is an inflammatory disease. RECENT FINDINGS: We review the possible non-metabolic mechanism such as inflammation that may also be involved at some stage and help promote new bone formation in DISH. We discuss supporting pathogenic mechanisms for a local inflammation at sites typically affected by this disease, and that is also supported by imaging studies that report some similarities between DISH and SpA. Local inflammation, either primary or secondary to metabolic derangements, may contribute to new bone formation in DISH. This new hypothesis is expected to stimulate further research in both the metabolic and inflammatory pathways in order to better understand the mechanisms that lead to new bone formation. This may lead to development of measures that will help in earlier detection and effective management before damage occurs.

A Rapid Antigen Detection Test to Diagnose SARS-CoV-2 Infection Using Exhaled Breath Condensate by A Modified Inflammacheck® Device.

BACKGROUND: The standard test that identifies the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is based on reverse transcriptase-polymerase chain reaction (RT-PCR) from nasopharyngeal (NP) swab specimens. We compared the accuracy of a rapid antigen detection test using exhaled breath condensate by a modified Inflammacheck® device with the standard RT-PCR to diagnose SARS-CoV-2 infection. METHODS: We performed a manufacturer-independent, cross-sectional, diagnostic accuracy study involving two Italian hospitals. Sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), positive (PPV) and negative predictive value (NPV) and diagnostic accuracy with 95% confidence intervals (95% CI) of Inflammacheck® were calculated using the RT-PCR results as the standard. Further RT-PCR tests were conducted on NP specimens from test positive subjects to obtain the Ct (cycle threshold) values as indicative evidence of the viral load. RESULTS: A total of 105 individuals (41 females, 39.0%; 64 males, 61.0%; mean age: 58.4 years) were included in the final analysis, with the RT-PCR being positive in 13 (12.4%) and negative in 92 (87.6%). The agreement between the two methods was 98.1%, with a Cohen's κ score of 0.91 (95% CI: 0.79-1.00). The overall sensitivity and specificity of the Inflammacheck® were 92.3% (95% CI: 64.0%-99.8%) and 98.9% (95% CI: 94.1%-100%), respectively, with a PLR of 84.9 (95% CI: 12.0-600.3) and a NLR of 0.08 (95% CI: 0.01-0.51). Considering a 12.4% disease prevalence in the study cohort, the PPV was 92.3% (95% CI: 62.9%-98.8%) and the NPV was 98.9% (95% CI: 93.3%-99.8%), with an overall accuracy of 98.1% (95% CI: 93.3%-99.8%). The Fagan's nomogram substantially confirmed the clinical applicability of the test in a realistic scenario with a pre-test probability set at 4%. Ct values obtained for the positive test subjects by means of the RT-PCR were normally distributed between 26 and 38 cycles, corresponding to viral loads from light (38 cycles) to high (26 cycles). The single false negative record had a Ct value of 33, which was close to the mean of the cohort (32.5 cycles). CONCLUSIONS: The modified Inflammacheck® device may be a rapid, non-demanding and cost-effective method for SARS-CoV-2 detection. This device may be used for routine practice in different healthcare settings (community, hospital, rehabilitation).

COVID-19 and Venous Thromboembolism: A Meta-analysis of Literature Studies.

Coronavirus disease 2019 (COVID-19) may have a wide spectrum of clinical presentations, leading in some cases to a critical condition with poor long-term outcomes and residual disability requiring post-acute rehabilitation. A major concern in severe COVID-19 is represented by a concomitant prothrombotic state. However, contrasting data are available about the prevalence of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and/or pulmonary embolism (PE). A detailed search on the association of COVID-19 with thromboembolic complications was conducted in the main electronic databases (PubMed, Web of Science, and Scopus) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The weighted mean prevalence (WMP) with 95% confidence interval (95% CI) was calculated with the random-effects model. Twenty studies enrolling 1,988 COVID-19 patients were included. The WMP of VTE was 31.3% (95% CI: 24.3-39.2%). The WMP of DVT was 19.8% (95% CI: 10.5-34.0%), whereas the WMP of PE was 18.9% (95% CI: 14.4-24.3%). Similar results were obtained when specifically analyzing studies on patients admitted to intensive care units and those on patients under antithrombotic prophylaxis. Regression models showed that an increasing age was associated with a higher prevalence of VTE (Z-score: 3.11, p = 0.001), DVT (Z-score: 2.33, p = 0.002), and PE (Z-score: 3.03, p = 0.002), while an increasing body mass index was associated with an increasing prevalence of PE (Z-score = 2.01, p = 0.04). Male sex did not impact the evaluated outcomes. The rate of thromboembolic complications in COVID-19 patients is definitely high. Considering the risk of fatal and disabling complications, adequate screening procedures and antithrombotic strategies should be implemented.

Association of systemic lupus erythematosus with peripheral arterial disease: a meta-analysis of literature studies.

OBJECTIVE: SLE patients have an increased cardiovascular morbidity and mortality. Contrasting data are available about the association between peripheral arterial disease (PAD) and SLE. We aimed to perform a meta-analysis of studies evaluating the association between SLE and PAD. METHODS: Studies were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases according to preferred reporting items for systematic reviews and meta-analyses guidelines. RESULTS: Eight studies reporting on 263 258 SLE patients and 768 487 controls showed that the prevalence of PAD was 15.8% (95% CI: 10.5%, 23.2%) in SLE patients and 3.9% (95% CI: 1.8%, 7.9%) in controls with a corresponding odds ratio of 4.1 (95% CI: 1.5, 11.6; P <0.001). In addition, five studies reporting on ankle-brachial index showed significantly lower values in 280 SLE patients as compared with 201 controls (mean difference: -0.018; 95% CI: -0.034, -0.001; P =0.033). Meta-regression models showed that age, hypertension and diabetes were inversely associated with the difference in the prevalence of PAD between SLE patients and non-SLE controls, whereas no effect for all the other clinical and demographic variables on the evaluated outcome was found. CONCLUSION: SLE patients exhibit an increased prevalence of PAD and lower ankle-brachial index values as compared with non-SLE controls. This should be considered when planning prevention, interventional and rehabilitation strategies for these chronic patients with functional disability and poor long-term outcomes.

Clinical application of nasal nitric oxide measurement in allergic rhinitis: A systematic review and meta-analysis.

BACKGROUND: Nasal nitric oxide (nNO) is considered a biomarker of nasal inflammation. OBJECTIVE: To perform a systematic review with meta-analysis and meta-regressions on the association between nNO levels and allergic rhinitis (AR). METHODS: PubMed, Web of Science, Scopus, and EMBASE databases were systematically searched. Differences between cases and controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). RESULTS: Overall, 39 articles were included: 30 containing data on nNO measured by nasal aspiration (1881 patients with AR and 1337 controls) and 12 assessing nNO by nasal exhalation (525 patients with AR and 350 controls). Compared with controls, AR presented significantly higher nNO values both during nasal aspiration (SMD, 1.309; 95% CI, 0.841-1.777; P < .001) and nasal exhalation (SMD, 0.708; 95% CI, 0.303-1.114; P = .001). Sensitivity and subgroup analyses confirmed that the results for the evaluated outcomes were not affected by the presence of clinical confounding factors (asthma, nasal polyps, inhaled corticosteroids, smoking history), this being valid for both perennial and seasonal diseases during exposure to allergens. For the aspiration method, meta-regressions indicated that older age and a better pulmonary function were associated with a lower difference in nNO levels between patients with AR and controls, whereas an increasing aspiration flow was associated with a high effect size. CONCLUSION: nNO levels are higher in AR, particularly when using high aspiration flows and in younger patients, who often perceive this condition as a source of disability. Further studies are needed to evaluate the usefulness of this biomarker for monitoring airway disorders and optimizing strategies in different settings (community, hospital, rehabilitation).

Assessment of Hemophilic Arthropathy by Ultrasound: Where Do We Stand?

Joint hemorrhages represent the most common type of bleeding episode in persons with hemophilia, and recurrent hemarthrosis triggers chronic arthropathy, which is the most frequent chronic complication in these patients. In recent years, in the frame of a comprehensive care approach, a growing attention has been given to the periodic assessment of the joint status in hemophilia patients with the aim to identify early arthropathic changes and to prevent the development of a clinically overt arthropathy. Besides clinical examination, X-ray and magnetic resonance imaging (MRI) are currently used to evaluate joint status and to monitor the disease progression in hemophilia. Considering the limitations of X-ray and MRI, growing interest has been given to ultrasound (US) as a possible tool to assess joint status and identify early arthropathic changes in hemophilia patients. In the present review, we summarize major literature evidence on the use of joint US for the evaluation of markers of disease activity (joint effusion and synovial hypertrophy) and of degenerative damages (osteochondral changes) in patients with hemophilia. On the whole, being able to identify the presence of intra- or extra-articular fluid, US examination is the fastest and most reliable technique to identify acute conditions, such as hemarthrosis. In addition, the information on joint involvement provided by US in the patient follow-up may influence treatment decisions on a personalized basis. The use of US as part of a routine clinical examination by hemophilia experts may optimize the diagnostic workflow, avoiding additional costs and long waiting lists for patients referred to imaging departments. In the frame of a comprehensive care approach, US might represent a strategy to early detect and monitor synovial hypertrophy and osteochondral changes in hemophilia, thus extending the clinical examination and helping identify joints to be studied with a second-level examination such as MRI.

The risk of osteoporosis in patients with liver cirrhosis: a meta-analysis of literature studies.

OBJECTIVE: Data about the association between cirrhosis and osteoporosis are contrasting. Thus, we have performed a meta-analysis of literature studies on this topic. DESIGN: MEDLINE, Cochrane library, EMBASE, Scopus and Web of Science databases have been searched to retrieve all articles of interest. Data on prevalence of osteoporosis, bone mineral density (BMD) and bone turnover laboratory parameters were compared among cirrhotic patients and control subjects without cirrhosis. PATIENTS: Studies on patients with liver cirrhosis screened for the presence of osteoporosis were included. RESULTS: Six case-control studies (372 cirrhotic patients and 1579 controls) were included. The prevalence of osteoporosis was higher in cirrhotic patients than in controls (34·7% vs 12·8%, OR: 2·52, 95%CI: 1·11, 5·69; P = 0·03, I(2) = 81%; P = 0·005). Accordingly, a reduced lumbar spine BMD (MD: -0·13, 95%CI: -0·24, -0·02; P = 0·02, I(2) = 93%; P < 0·00001) and z-score (MD: -1·06, 95%CI: -1·79, -0·34; P = 0·004, I(2) = 95%; P < 0·00001) were found in cirrhotic patients as compared with controls. In contrast, no significant differences were reported in femoral neck BMD and z-score. Interestingly, bone turnover laboratory parameters widely confirmed these results showing higher levels of ALP and D-Pyr, accompanied by reduced levels of IGF-1, PTH and 25-OH-D in cirrhotic patients as compared with controls. CONCLUSIONS: Despite the high heterogeneity among studies, data showed an increased prevalence of osteoporosis in patients with cirrhosis. This information suggests the need of an accurate screening of bone mineral density in patients with liver cirrhosis to plan an adequate osteoporosis management.

Exploring novel perspectives on eosinophilic inflammation in severe asthma.

Two recent articles by the same research group documented that patients with severe eosinophilic asthma exhibit an increased proportion of a subtype of eosinophils, namely CD62Llow inflammatory eosinophils (iEos) and identified an intriguing correlation between such iEos and asthma control scores. Moreover, CD62Llow iEos were reduced after treatment with the anti-IL-5 monoclonal antibody mepolizumab. In the future, we believe that eosinophil subtypes could represent a useful biomarker in severe eosinophilic asthma, helping clinicians characterize patient endotypes and monitoring the response to biological drugs.

Autoimmunity against Nucleus Ambiguous Is Putatively Possible in Both Long-COVID-19 and Vaccinated Subjects: Scientific Evidence and Working Hypothesis.

As reported by the World Health Organization (WHO), about 10-20% of people have experienced mid- to long-term effects following SARS-CoV-2 infection, collectively referred to as post-COVID-19 condition or long-COVID, including some neurovegetative symptoms. Numerous findings have suggested that the onset of these neurovegetative symptoms upon viral infection may be caused by the production of autoantibodies through molecular mimicry phenomena. Accordingly, we had previously demonstrated that 22 of the human proteins sharing putatively immunogenic peptides with SARS-CoV-2 proteins are expressed in the dorsal motor nucleus and nucleus ambiguous. Therefore, if molecular mimicry occurs following severe forms of COVID-19, there could be transitory or permanent damage in some vagal structures, resulting in a lower vagal tone and all the related clinical signs. We investigated the presence of autoantibodies against two proteins of vagal nuclei sharing a peptide with SARS-CoV-2 spike glycoprotein using an immunoassay test on blood obtained from patients with cardiorespiratory symptoms in patients affected by ongoing symptomatic COVID-19 (long-COVID), subjects vaccinated without a history of SARS-CoV-2 infection, and subjects not vaccinated without a history of SARS-CoV-2 infection. Interestingly, putative autoantibodies were present in both long-COVID-19 and vaccinated groups, opening interesting questions about pathogenic mechanisms of the disease.

Visual vertical neglect in acquired brain injury: a systematic review.

Vertical neglect represents a visuospatial deficit occurring as a possible consequence of acquired brain injury (ABI). Differently from unilateral spatial neglect on horizontal space, vertical neglect is poorly studied in the literature and rarely assessed in clinical practice. In the available studies, the terms "radial," "vertical," and "altitudinal" neglect are often used interchangeably, although they do not describe the same spatial dimension. "Altitudinal" and "vertical" refer to the sagittal plane, whereas "radial" refers to the transverse plane. The term "vertical" is sometimes used interchangeably with respect to both axes. The aim of this systematic review was to identify the main characteristics of vertical neglect after ABI, the diagnostic tools used, and the treatment options. We also proposed a clarification of the manifestations and characteristics of vertical and radial neglect. The 23 articles reviewed, showed that the vertical neglect occurred more frequently on the lower space than on the upper space, that its presence was associated with horizontal neglect, and that it could also occur with compromise of the radial space, with the near radial being more common. The most frequent etiology associated with vertical neglect is vascular, particularly ischaemic. The lesions side are very heterogeneous and include both cortical and subcortical areas and all lobes, although the temporal lobe is most affected. With regard to the assessment tools, paper and pencil tasks are the most commonly used diagnostic tools to identify vertical neglect, although in recent years the use of computer-based tasks increased. Taken together, our results suggest that vertical neglect may be underestimated in patients with right hemisphere lesions and should always be assessed, especially in cases where the patient shows signs of horizontal neglect. The clinical assessment of vertical neglect is very important since it can lead to important functional limitations in everyday life, such as poor wheelchair handling, stumbling over unnoticed obstacles located below (or above), walking down stairs, taking off shoes.

The Beneficial Impact of Pulmonary Rehabilitation in Idiopathic Pulmonary Fibrosis: A Review of the Current Literature.

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible fibrotic disease whose natural history is characterised by a progressive worsening of the pulmonary function, exertional dyspnoea, exercise intolerance, reduced physical activity, and health-related quality of life (HRQOL) impairment. Pulmonary rehabilitation (PR) is a comprehensive, multi-disciplinary programme that uses a combination of strength training, teaching, counselling, and behaviour modification techniques to reduce symptoms and optimise functional capacity in patients with chronic lung disease. Based on the well-documented effectiveness of PR in chronic obstructive pulmonary disease (COPD), over the years supportive evidence of its benefits for other respiratory diseases has been emerging. Although the latest rehabilitation guidelines recognised PR's efficacy for interstitial lung disease (ILD) and IPF in particular, this comprehensive approach remains underused and under-resourced. In this review, we will discuss the advantages and beneficial effects of PR on IPF, analysing its impact on exercise capacity, disease-related symptoms, cardiovascular outcomes, body composition, and HRQOL.

Novel Strategies in Diagnosing Heart Failure with Preserved Ejection Fraction: A Comprehensive Literature Review.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a prevalent global condition affecting approximately 50% of the HF population. With the aging of the worldwide population, its incidence and prevalence are expected to rise even further. Unfortunately, until recently, no effective medications were available to reduce the high mortality and hospitalization rates associated with HFpEF, making it a significant unmet need in cardiovascular medicine. Although HFpEF is commonly defined as HF with normal ejection fraction and elevated left ventricular filling pressure, performing invasive hemodynamic assessments on every individual suspected of having HFpEF is neither feasible nor practical. Consequently, several clinical criteria and diagnostic tools have been proposed to aid in diagnosing HFpEF. Overall, these criteria and tools are designed to assist healthcare professionals in identifying and evaluating patients who may have HFpEF based on a combination of signs, symptoms, biomarkers, and non-invasive imaging findings. By employing these non-invasive diagnostic approaches, clinicians can make informed decisions regarding the best pharmacological and rehabilitation strategies for individuals with suspected HFpEF. This literature review aims to provide an overview of all currently available methods for diagnosing and monitoring this disabling condition.

Arthropathy in patients with moderate hemophilia a: a systematic review of the literature.

Chronic arthropathy is a major complication in severe hemophilia A (Factor [F] VIII < 1%). Almost all adults with severe hemophilia, who have not received prophylaxis with FVIII since their early childhood, suffer from chronic arthropathy. Patients with moderate hemophilia (FVIII activity 1-5%) usually experience fewer joint bleeds than those with severe hemophilia and are thought to rarely develop a significant degree of chronic arthropathy. However, some patients with moderate hemophilia behave like those with the severe form of the disorder, reporting several joint bleeds per year and significant joint impairment. Currently, only little data are available about the prevalence of arthropathy, the degree of quality of life impairment, and the need for orthopedic care/aids in patients with moderate hemophilia. In this systematic review of literature, the prevalence of overt arthropathy ranges between 15 and 77% in patients with moderate hemophilia and prophylactic replacement treatment is prescribed in approximately 30% of these patients, usually after diagnosis of clinically overt arthropathy. Moreover, because of the lack of imaging studies (magnetic resonance and/or ultrasound), the prevalence of subclinical arthropathy cannot be determined. These data confirm that severity of hemophilia should not be defined only according to FVIII levels and that a relevant proportion of patients with nonsevere hemophilia might benefit from a "tailored early prophylaxis."