Exhaled Nitric Oxide as Biomarker of Type 2 Diseases.

Nitric oxide (NO) is a short-lived gas molecule which has been studied for its role as a signaling molecule in the vasculature and later, in a broader view, as a cellular messenger in many other biological processes such as immunity and inflammation, cell survival, apoptosis, and aging. Fractional exhaled nitric oxide (FeNO) is a convenient, easy-to-obtain, and non-invasive method for assessing active, mainly Th2-driven, airway inflammation, which is sensitive to treatment with standard anti-inflammatory therapy. Consequently, FeNO serves as a valued tool to aid the diagnosis and monitoring of several asthma phenotypes. More recently, FeNO has been evaluated in several other respiratory and/or immunological conditions, including allergic rhinitis, chronic rhinosinusitis with/without nasal polyps, atopic dermatitis, eosinophilic esophagitis, and food allergy. In this review, we aim to provide an extensive overview of the current state of knowledge about FeNO as a biomarker in type 2 inflammation, outlining past and recent data on the application of its measurement in patients affected by a broad variety of atopic/allergic disorders.

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.

Fractional Exhaled Nitric Oxide (FeNO) in Patients with Stable Chronic Obstructive Pulmonary Disease: Short-Term Variability and Potential Clinical Implications.

BACKGROUND: The use of fractional exhaled nitric oxide (FeNO) has been proposed for identifying and monitoring eosinophilic airway inflammation in chronic obstructive pulmonary disease (COPD). To explore the clinical utility of FeNO in COPD, we aimed to assess its short-term variability in a clinically stable COPD cohort. METHODS: Consecutive COPD patients, formerly smokers, underwent FeNO assessment at the baseline and six time-points through serial sampling spaced 3 days apart. RESULTS: A total of 41 patients (mean age 72.9, 87.8% males) showed a median baseline value of FeNO of 11.7 (8.0-16.8) ppb. A weak linear relationship was documented between baseline FeNO values and both eosinophil counts (r = 0.341, p = 0.029) and the percentage of eosinophils (r = 0.331, p = 0.034), confirmed in multiple linear regressions after adjusting for steroid use. The overall individual variability of FeNO between time-points was 3.90 (2.53-7.29) ppb, with no significant difference in the distribution of FeNO values measured at different time-points (p = 0.204). A total of 28 (68.3%) patients exhibited FeNO always below the 25 ppb cut-off at all determinations, while the remining 13 (31.7%) had at least one value above the established limit. Interestingly, none of these 13 participants had FeNO stably above 25 ppb, all showing at least one normal value during serial sampling. Compared to these patients with more fluctuating values, the 28 with stably normal FeNO only exhibited a significantly higher body weight (80.0 ± 18.2 kg vs. 69.0 ± 8.8 kg, p = 0.013) and body mass index (29.7 ± 6.5 kg/m2 vs. 25.9 ± 3.7 kg/m2, p = 0.026), confirmed in multiple logistic regressions after adjusting for major potential confounders. CONCLUSIONS: A certain degree of FeNO variability, apparently unrelated to eosinophil counts but somehow influenced by body weight, must be considered in COPD patients. Further studies are needed to clarify whether this biomarker may be effectively used to plan more personalized pharmacological and rehabilitation strategies in this clinical setting.

Bronchodilator Response as a Possible Predictor of Lung Function Improvement After Pulmonary Rehabilitation in Post-COVID-19 Patients

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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.

Cognitive Impairment in Convalescent COVID-19 Patients Undergoing Multidisciplinary Rehabilitation: The Association with the Clinical and Functional Status.

BACKGROUND: Cognitive impairment has been reported in the aftermath of severe acute respiratory syndrome due to coronavirus 2 (SARS-CoV-2) infection. We investigated the possible association between cognitive impairment and the main clinical and functional status variables in a cohort of convalescent COVID-19 patients without premorbid diseases potentially affecting cognition. METHODS: We consecutively screened for inclusion of convalescent COVID-19 patients referring to a post-acute care facility for pulmonary rehabilitation. All the enrolled patients were assessed for cognitive functions. We also investigated features of psychological distress (anxiety, depression, symptoms of posttraumatic stress disorder and quality of life) and cardiac and pulmonary functional status. RESULTS: The 63 enrolled patients (mean age 59.82 ± 10.78, male gender = 47) showed a high frequency of depressive symptoms (76.2%) and anxiety (55.5%), and a high prevalence of symptoms of posttraumatic stress disorder (PTSD, 44.4%). About half of the total sample showed reduced cognitive efficiency (RCE, 44.4%) in the domains of spatial and verbal long-term memory and executive functions. Patients with RCE more frequently showed alteration of blood pressure (BP) circadian rhythm (p = 0.01), higher levels of D-Dimer (p = 0.03), had experienced a severe illness (p = 0.02), had longer disease duration (p = 0.04), more clinically relevant symptoms of PTSD (p = 0.02), more frequent cognitive complaints (p = 0.002), higher anxiety scores (p = 0.01) and lower quality of life (p = 0.02) than patients with normal cognitive efficiency. CONCLUSIONS: Our findings indicated a possible association between the RCE after COVID-19 and some cardiological variables, including some indirect measures of a residual autonomic disorder, such as the presence of an altered BP circadian rhythm. Future research studies with large samples are needed to provide valid conclusions.

Identification of biomarkers in COPD by metabolomics of exhaled breath condensate and serum/plasma.

Chronic obstructive pulmonary disease (COPD) is the third cause of death worldwide, presenting poor long-term outcomes and chronic disability. COPD is a condition with a wide spectrum of clinical presentations because its pathophysiological determinants relate to tobacco smoke, genetic factors, alteration of several metabolic pathways, and oxidative stress. Consequently, patients present different phenotypes even with comparable degrees of airflow limitation. Because of the increasing social and economic costs of COPD, a growing attention is currently paid to "omics" techniques for more personalized treatments and patient-tailored rehabilitation programs. In this regard, the systematic investigation of the metabolome (i.e., the whole set of endogenous molecules) in biomatrices, namely metabolomics, has become indispensable for phenotyping respiratory diseases. The metabolomic profiling of biological samples contains the small molecules produced during biological processes and their identification and quantification help in the diagnosis, comprehension of disease outcome and treatment response. Exhaled breath condensate (EBC), plasma and serum are biofluids readily available, with negligible invasiveness, and, therefore, suitable for metabolomics investigations. In this paper, we describe the latest advances on metabolomic profiling of EBC, plasma and serum in COPD patients.

Can FeNO be a biomarker in the post-COVID-19 patients monitoring?

The nature of the inflammatory and fibrotic processes found in patients with post-COVID-19 syndrome makes it possible to speculate that in such patients fractional exhaled nitric oxide (FeNO) may be a useful biomarker. Consequently, we set out to verify the consistency of this hypothesis. We consecutively enrolled 68 post-COVID patients after being hospitalized for persistent clinical manifestations within 2 months from disease onset and 29 healthy volunteers as control group. None of post-COVID patients had bronchial asthma or were being treated with a corticosteroid. Only 19 out of 68 post-COVID-19 patients reported a FeNO value > 25 ppb. The mean FeNO value in post-COVID-19 patients was 18.55 ppb (95% CI: 15.50 to 21.58), while in healthy subjects it was 17.46 ppb (95% CI: 15.75 to 19.17). The mean difference was not statistically significant (P = 0.053). However, the mean FeNO value of post-COVID-19 patients was higher in men than in women (20.97 ppb; 95% CI: 16.61 to 25.33 vs 14.36 ppb; 95% CI: 11.11 to 17.61) with a difference between the two sexes that was statistically significant (P = 0.016). Mean FeNO was 14.89 ppb (95% CI: 10.90 to 18.89) in patients who had been treated with systemic corticosteroids because of their COVID-19, and 20.80 ppb (95% CI: 16.56 to 25.04) in those who had not taken them, with a difference that was statistically significant (P = 0.043). The data generated in this study suggest that measurement of FeNO is not useful as a biomarker in post-COVID-19 patient. However, this hypothesis needs solid validation with additional specifically designed studies.

Metabolomics of COPD Pulmonary Rehabilitation Outcomes via Exhaled Breath Condensate.

Chronic obstructive pulmonary disease (COPD) is characterized by different phenotypes and clinical presentations. Therefore, a single strategy of pulmonary rehabilitation (PR) does not always yield the expected clinical outcomes as some individuals respond excellently, others discreetly, or do not respond at all. Fifty consecutive COPD patients were enrolled. Of them, 35 starting a 5-week PR program were sampled at admission (T0), after 2 (T2W) and 5 (T5W) weeks, while 15 controls not yet on PR were tested at T0 and T5W. Nuclear magnetic resonance (NMR) profiling of exhaled breath condensate (EBC) and multivariate statistical analysis were applied to investigate the relationship between biomarkers and clinical parameters. The model including the three classes correctly located T2W between T0 and T5W, but 38.71% of samples partially overlapped with T0 and 32.26% with T5W, suggesting that for some patients PR is already beneficial at T2W (32.26% overlapping with T5W), while for others (38.71% overlapping with T0) more time is required. Rehabilitated patients presented several altered biomarkers. In particular, methanol from T0 to T5W decreased in parallel with dyspnea and fatigue, while the walk distance increased. Methanol could be ascribed to lung inflammation. We demonstrated that the metabolic COPD phenotype clearly evolves during PR, with a strict relationship between clinical and molecular parameters. Methanol, correlating with clinical parameters, represents a useful biomarker for monitoring personalized outcomes and establishing more targeted protocols.

Metabolomic Profiling of Exhaled Breath Condensate and Plasma/ Serum in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is an increasing cause of global morbidity and mortality, with poor long-term outcomes and chronic disability. COPD is a condition with a wide spectrum of clinical presentations, with different phenotypes being identified even among patients with comparable degrees of airflow limitation. Considering the burden of COPD in terms of social and economic costs, in recent years growing attention has been given to the need for more personalized approaches and patienttailored rehabilitation programs. In this regard, the systematic analysis of metabolites in biological matrices, namely metabolomics, may become an essential tool in phenotyping diseases. Through the identification and quantification of the small molecules produced during biological processes, metabolomic profiling of biological samples has thus been proposed as an opportunity to identify novel biomarkers of disease outcome and treatment response. Exhaled breath condensate (EBC) and plasma/serum are fluid pools, which can be easily extracted and analyzed. In this review, we discuss the potential clinical applications of the metabolomic profiling of EBC and plasma/serum in COPD.

Performance of fractional exhaled nitric oxide in predicting response to inhaled corticosteroids in chronic cough: a meta-analysis.

Background. Chronic cough is a disabling condition with a high proportion of diagnostic and therapeutic failures. Fractional exhaled nitric oxide (FeNO) has been considered a useful biomarker for predicting inhaled corticosteroids (ICS) response. We evaluated the relationship between FeNO and ICS response in chronic cough by performing a systematic review with meta-analysis.Methods. PubMed, Web of Science, Scopus and EMBASE databases were systematically searched. Differences were expressed as Odds Ratio (OR) with 95% confidence intervals (95%CI). Pooled sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), and area under the hierarchical summary receiver operating characteristic curve (HSROCAUC) were estimated.Results. Nine articles on 740 chronic-cough patients showed that the response rate to ICS was 87.4% (95%CI: 83.8-91.0) in 317 patients with a high FeNO and 46.3% (95%CI: 41.6-51.0) in 423 controls, with an attributable proportion of 47.0% and a diagnostic OR of 9.1 (95%CI: 3.7-22.4, p < .001). The pooled estimate of diagnostic indexes resulted in a sensitivity of 68.5% (95%CI: 46.7-84.4) and specificity of 81.9% (95%CI: 63.0-92.3), with a HSROCAUC of 0.82 (95%CI: 0.64-0.90). In a realistic scenario with a pre-test probability set at 30%, based on a pooled PLR of 3.79 (95%CI: 1.24-7.47) and NLR of 0.38 (95%CI: 0.22-0.66), the post-test probability was 62% with a high FeNO and 14% if the test was negative. Subgroup analyses confirmed a better performance for the recommended FeNO cut-off greater than 25 ppb. Meta-regression and sensitivity analyses showed no impact of major demographic and clinic variables on results.Conclusions. A high FeNO before starting ICS therapy may help identify chronic-cough patients responding to treatment, with a better performance ofhigher cut-off values. Further studies are needed to evaluate the real usefulness of this biomarker to guide cough therapy and optimise strategies in different healthcare settings (community, hospital, rehabilitation).Key messagesChronic cough is a disabling condition with a high proportion of diagnostic and therapeutic failures.Fractional exhaled nitric oxide (FeNO) may be a useful biomarker for identifying chronic cough patients who respond to steroid treatment.A FeNO cut-off lower than 25 ppb should be considered irrelevant for this clinical application.

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).

Preexisting cardiorespiratory comorbidity does not preclude the success of multidisciplinary rehabilitation in post-COVID-19 patients.

Patients recovering from coronavirus disease 2019 (COVID-19) may not return to a pre-COVID functional status and baseline levels of healthcare needs after discharge from acute care hospitals. Since the long-term outcomes of COVID-19 can be more severe in patients with underlying cardiorespiratory diseases, we aimed at verifying the impact of a preexisting cardiorespiratory comorbidity on multidisciplinary rehabilitation in post-COVID-19 patients. We enrolled 95 consecutive patients referring to the Pulmonary Rehabilitation Unit of Istituti Clinici Scientifici Maugeri Spa SB, IRCCS of Telese Terme, Benevento, Italy after being discharged from the COVID-19 acute care ward and after recovering from acute COVID-19 pneumonia. Forty-nine of them were not suffering from underlying comorbidities, while 46 had a preexisting cardiorespiratory disease. Rehabilitation induced statistically significant improvements in respiratory function, blood gases and the ability to exercise both in patients without any preexisting comorbidities and in those with an underlying cardiorespiratory disease. Response to the rehabilitation cycle tended to be greater in those without preexisting comorbidities, but DLco%-predicted was the only parameter that showed a significant greater improvement when compared to the response in the group of patients with underlying cardiorespiratory comorbidity. This study suggests that multidisciplinary rehabilitation may be useful in post-COVID-19 patients regardless of the presence of preexisting cardiorespiratory comorbidities.

Pulmonary rehabilitation in patients with interstitial lung diseases: Correlates of success.

BACKGROUND AND AIM: Benefits of pulmonary rehabilitation in Interstitial Lung Diseases (ILD) have been reported. The aim of this large multicenter study was to identify the success predictors of pulmonary rehabilitation in a real-life setting. METHODS: Data of 240 in-patients (110 idiopathic pulmonary fibrosis (IPF), 106 ILD other than IPF and 24 undetermined ILD) undergoing pulmonary rehabilitation in a 10-year period were retrospectively evaluated. Six minute walking distance (6MWT), body weight-walking distance product tests, dyspnoea and arterial blood gases were assessed at admission and discharge. Differences in post rehabilitation changes in outcome measures as function of baseline characteristics were evaluated. RESULTS: After rehabilitation, patients showed improvements in all outcome measures (p < 0.05), regardless of the underlying diagnosis or disease severity. Patients needing oxygen therapy at rest showed reduced benefits. Baseline 6MWD inversely correlated with its changes at discharge. Non-significant greater benefits after rehabilitation were found in IPF patients under antifibrotic therapy. In a subset of 50 patients assessed on average 10.3 ± 3.5 months after discharge, the benefits in 6MWD were not maintained (312.9 ± 139.4, 369.7 ± 122.5 and 310.8 ± 139.6 m at admission, discharge and follow up respectively: p < 0.0001). CONCLUSION: Pulmonary rehabilitation may improve dyspnoea, exercise capacity and fatigue in patients with ILD of different aethiologies and level of severity. The long-term effects need to be established.

Bronchodilator reversibility testing in post-COVID-19 patients undergoing pulmonary rehabilitation.

BACKGROUND: The usefulness of bronchodilators in coronavirus diseases 2019 (COVID-19) survivors is still uncertain, especially for patients with a concomitant obstructive lung disease. We aimed at verifying the level of bronchodilator reversibility in COVID-19 patients undergoing multidisciplinary pulmonary rehabilitation after the acute phase. METHODS: We enrolled 105 consecutive patients referring to the Pulmonary Rehabilitation Unit of Istituti Clinici Scientifici Maugeri Spa SB, IRCCS of Telese Terme, Benevento, Italy after being discharged from the COVID-19 acute care ward and after recovering from acute COVID-19 pneumonia. All subjects performed a spirometry before and after inhalation of salbutamol 400 µg to determine the bronchodilation response within 48 h of admission to the unit. RESULTS: All patients had suffered from a moderate to severe COVID-19, classified 3 or 4 according to the WHO classification, Seventeen patients had concomitant obstructive lung disease (14 suffering from COPD and 3 from asthma). FEV1 after salbutamol improved on average by 41.7 mL in the entire examined sample, by 29.4 mL in subjects without concomitant obstructive lung diseases, by 59.3 mL in COPD patients and by 320.0 mL in asthma patients. Mean FVC after salbutamol improved by 65.7 mL in the entire examined sample, by 52.5 mL in subjects without concomitant obstructive lung diseases, by 120.0 mL in COPD patients, and by 200.0 mL in asthma patients. CONCLUSIONS: This study suggests that a treatment with bronchodilators must always be taken into consideration in post-COVID-19 patients because it can induce a functional improvement that, even if small, can facilitate the breathing of these patients.

Subject Preferences and Psychological Implications of Portable Oxygen Concentrator Versus Compressed Oxygen Cylinder in Chronic Lung Disease.

BACKGROUND: Oxygen therapy represents the elective therapy to improve the quality of life for patients with chronic respiratory diseases like COPD and interstitial lung disease. Lightweight portable oxygen concentrators (POCs) are a valid alternative to traditional systems such as portable compressed oxygen cylinders. However, patient preference and the possible psychological implications related to the use of both devices have been poorly assessed. We sought to evaluate patient preference between the ambulatory oxygen systems (ie, a POC or a small cylinder) for patients with COPD and interstitial lung disease experiencing exertional desaturation in a rehabilitation setting. Furthermore, the use of one device in comparison with the other was related to specific mechanical characteristics and related to perceived quality of life, anxiety, and depressive symptoms. METHODS: 30 subjects with COPD and interstitial lung disease, who demonstrated exertional desaturation on room air during 6-min walk test (6MWT), were recruited. Each subject performed 2 6MWTs, in random order: one breathing oxygen via a POC and one with a portable compressed oxygen cylinder. Both devices were set up to ensure oxyhemoglobin saturation between 92% and 95% during the 6MWTs. All subjects completed a questionnaire assessing anxiety, depression, and quality of life. Each device was randomly assigned to each subject for 1 week, and then replaced with the other in the following week. At the end of the trial period, all subjects completed a questionnaire evaluating several aspects of the oxygen therapy devices. RESULTS: There were no significant differences in oxygen saturation or the mean distances achieved during the 6MWTs between the 2 portable oxygen devices. The subjects expressed greater preference for the POC (73.3%), basing their choice mainly on ease of transport and lower weight. Subjects' age also correlated with preferences: younger subjects were more negatively focused on the weight of the portable compressed oxygen cylinder, whereas older subjects considered the POC easier to manage. No significant differences in preferences were present between COPD and interstitial lung disease. CONCLUSIONS: The POC and the portable compressed oxygen cylinder performed in a comparable manner during 6MWT for subjects with COPD and interstitial lung disease and exertional desaturation. Subjects preferred the POC because it was associated with better mobility.