Long COVID in Children: A Multidisciplinary Review.

Long COVID syndrome has emerged as a long-lasting consequence of acute SARS-CoV-2 infection in adults. In addition, children may be affected by Long COVID, with potential clinical issues in different fields, including problems in school performance and daily activities. Yet, the pathophysiologic bases of Long COVID in children are largely unknown, and it is difficult to predict who will develop the syndrome. In this multidisciplinary clinical review, we summarise the latest scientific data regarding Long COVID and its impact on children. Special attention is given to diagnostic tests, in order to help the physicians to find potential disease markers and quantify impairment. Specifically, we assess the respiratory, upper airways, cardiac, neurologic and motor and psychological aspects. Finally, we also propose a multidisciplinary clinical approach.

Role of hyperpnea in the relaxant effect of inspired CO2 on methacholine-induced bronchoconstriction.

Inhaling carbon dioxide (CO2) in humans is known to cause inconsistent effects on airway function. These could be due to direct effects of CO2 on airway smooth muscle or to changes in minute ventilation (V̇e). To address this issue, we examined the responses of the respiratory system to inhaled methacholine in healthy subjects and subjects with mild asthma while breathing air or gas mixtures containing 2% or 4% CO2. Respiratory mechanics were measured by a forced oscillation technique at 5 Hz during tidal breathing. At baseline, respiratory resistance (R5) was significantly higher in subjects with asthma (2.53 ± 0.38 cmH2O·L-1·s) than healthy subjects (2.11 ± 0.42 cmH2O·L-1·s) (P = 0.008) with room air. Similar values were observed with CO2 2% or 4% in the two groups. V̇e, tidal volume (VT), and breathing frequency (BF) significantly increased with CO2-containing mixtures (P < 0.001) with insignificant differences between groups. After methacholine, the increase in R5 and the decrease in respiratory reactance (X5) were significantly attenuated up to about 50% with CO2-containing mixtures instead of room air in both asthmatic (P < 0.001) and controls (P < 0.001). Mediation analysis showed that the attenuation of methacholine-induced changes in respiratory mechanics by CO2 was due to the increase in V̇e (P = 0.006 for R5 and P = 0.014 for X5) independently of the increase in VT or BF, rather than a direct effect of CO2. These findings suggest that the increased stretching of airway smooth muscle by the CO2-induced increase in V̇e is a mechanism through which hypercapnia can attenuate bronchoconstrictor responses in healthy subjects and subjects with mild asthma.NEW & NOTEWORTHY The main results of the present study are as follows: 1) breathing gas mixtures containing 2% or 4% CO2 significantly attenuated bronchoconstrictor responses to methacholine, not differently in healthy subjects and subjects with mild asthma, and 2) the causal inhibitory effect of CO2 was significantly mediated via an indirect effect of the increment of V̇e in response to intrapulmonary hypercapnia.

Effects of Air Stacking on Dyspnea and Lung Function in Neuromuscular Diseases.

OBJECTIVE: To investigate whether the decrease in dyspnea in neuromuscular diseases after air stacking (AS) occurs mostly in patients with decreased inspiratory muscle force and ensuing chest wall restriction or heterogeneous ventilation across the lungs. DESIGN: Interventional, before-after study. SETTING: A neurorehabilitation inpatient and outpatient center. PARTICIPANTS: Fifteen consecutive adult patients affected by neuromuscular diseases (N=15). INTERVENTIONS: AS treatment. MAIN OUTCOME MEASURES: Patients had vital capacity (VC) and sniff nasal inspiratory pressure (SNIP) measured. We measured Borg score, oxygen saturation, and ventilation heterogeneity across the lung as estimated from the difference between respiratory resistance at 5 and 19 Hz (R5-19) with the forced oscillation technique before and 5, 30, 60, and 120 minutes after applying AS. RESULTS: Before AS, Borg score was significantly related to R5-19 (r2 0.46, P<.05) but not to VC % predicted, SNIP % predicted, and time since symptom onset. After AS, average Borg score gradually decreased (P=.005), whereas inspiratory flow resistance at 5 Hz, R5-19, and inspiratory reactance at 5 Hz tended to improve, despite not reaching statistical significance. The decrease in dyspnea at 60 and 120 minutes after AS significantly correlated with baseline R5-19 (r2 0.49, P<.01 and r2 0.29, P<.05, respectively), but not with VC % predicted, SNIP % predicted, time since symptom onset, and clinical severity score for patients affected by amyotrophic lateral sclerosis. CONCLUSIONS: These findings suggest that dyspnea in neuromuscular diseases is related to heterogeneous ventilation rather than inspiratory muscle force and/or lung volumes decrease. Restoring ventilation distribution across the lungs with AS appears to improve dyspnea.

Measuring vital capacity in amyotrophic lateral sclerosis: Effects of interfaces and reproducibility.

BACKGROUND: Deterioration of vital capacity (VC) in amyotrophic lateral sclerosis (ALS) signifies disease progression and indicates need for non-invasive ventilation. Weak facial muscles consequent to ALS, with resulting poor mouth seal, may interfere with the accuracy of VC measurements. OBJECTIVES: To determine whether different interfaces affect VC measurements in ALS patients and whether the interface yielding the largest VC produces an even higher VC when re-measured after one week (learning effect). To explore the relationship between optimal interface VC and sniff nasal pressure (SNIP), a measurement of global inspiratory muscle strength. METHODS: Thirty-five patients (17 bulbar and 18 spinal ALS) were studied. Three interfaces (rigid-cylindrical, flanged, oronasal mask) were tested. One week after the first visit, VC was recorded using the optimal interface. SNIP recordings were also obtained. RESULTS: In the bulbar ALS group, median (interquartile range) VC with the flanged mouthpiece was 8.4% (3.9-15.5) larger than with the cylindrical mouthpiece (p < 0.001). VC values with oronasal mask were intermediate to VC with the other two interfaces. In spinal ALS, flanged mouthpiece VC was 4.6% (2.3-7.5) larger than with oronasal mask (p < 0.0006). The latter was 4.5% (0.6-5.2) smaller than with the cylindrical mouthpiece (p = 0.002). In both groups, VC during the second visit was greater than during the first visit (p < 0.025). SNIPs were logarithmically related to VC values recorded with the flanged mouthpiece. CONCLUSION: A flanged mouthpiece yields the largest values of VC in patients with bulbar and spinal ALS.

Inpatient Care during the COVID-19 Pandemic: A Survey of Italian Physicians.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a potentially fatal disease that is of great global public health concern. OBJECTIVE: We explored the clinical management of inpatients with COVID-19 in Italy. METHODS: A self-administered survey was sent by email to Italian physicians caring for adult patients with COVID-19. A panel of experts was selected according to their clinical curricula and their responses were analyzed. RESULTS: A total of 1,215 physicians completed the survey questionnaire (17.4% response rate). Of these, 188 (15.5%) were COVID-19 experts. Chest computed tomography was the most used method to detect and monitor COVID-19 pneumonia. Most of the experts managed acute respiratory failure with CPAP (56.4%), high flow nasal cannula (18.6%), and non-invasive mechanical ventilation (8%), while an intensivist referral for early intubation was requested in 17% of the cases. Hydroxychloroquine was prescribed as an antiviral in 90% of cases, both as monotherapy (11.7%), and combined with protease inhibitors (43.6%) or azithromycin (36.2%). The experts unanimously prescribed low-molecular-weight heparin to patients with severe COVID-19 pneumonia, and half of them (51.6%) used a dose higher than standard. The respiratory burden in patients who survived the acute phase was estimated as relevant in 28.2% of the cases, modest in 39.4%, and negligible in 9%. CONCLUSIONS: In our survey some major topics, such as the role of non-invasive respiratory support and drug treatments, show disagreement between experts, likely reflecting the absence of high-quality evidence studies. Considering the significant respiratory sequelae reported following COVID-19, proper respiratory and physical therapy programs should be promptly made available.

DNA Fragmentation in Viable and Non-Viable Spermatozoa Discriminates Fertile and Subfertile Subjects with Similar Accuracy.

Sperm DNA fragmentation (sDF) negatively affects reproduction and is traditionally detected in total sperm population including viable and non-viable spermatozoa. Here, we aimed at exploring the ability of DNA fragmentation to discriminate fertile and subfertile men when detected in viable (viable sDF), non-viable (non-viable sDF), and total spermatozoa (total sDF). We revealed sDF in 91 male partners of infertile couples and 71 fertile men (max 1 year from natural conception) with LiveTUNEL coupled to flow cytometry, able to reveal simultaneously DNA fragmentation and cell viability. We found that the three sDF parameters discriminated fertile and subfertile men with similar accuracy and independently from age and basal semen parameters: AUCs (area under the curves) (95% CI) were: 0.696 (0.615-0.776), p < 0.001 for total sDF; 0.718 (0.640-0.797), p < 0.001 for viable sDF; 0.760 (0.685-0.835), p < 0.001 for non-viable sDF. We also found that total and non-viable but not viable sDF significantly correlated to age and semen quality. In conclusion, the three sDF parameters similarly discriminated fertile and subfertile men. Viable spermatozoa with DNA fragmentation are likely cells able to fertilize the oocyte but failing to properly support subsequent embryo development. Non-viable sDF could be a sign of a subtler damage extended beyond the non-viable cells.

Clinical Use and Barriers of Thoracic Ultrasound: A Survey of Italian Pulmonologists.

INTRODUCTION: Thoracic ultrasound is accurate in the diagnosis of a wide range of respiratory diseases. Yet the extent of its use is unknown. Through a national survey, we aimed to explore the clinical use of thoracic ultrasound and the barriers to the diffusion of the technique in Italy. METHODS: Accademia di Ecografia Toracica (AdET) developed a self-administered survey which was sent by email to Italian pulmonologists via national scientific societies and networks. RESULTS: Of the 2010 physicians invited, 514 completed the survey (26% response rate). According to 99% of responders, thoracic ultrasound had a relevant clinical role. Seventy-nine percent of the responders used thoracic ultrasound at least once a month. The main settings were: 53% pulmonology ward, 15% outpatient clinic, 15% interventional pulmonology room, 10% internal medicine ward, 4% respiratory intensive care units, and 9% other. Thoracic ultrasound was primarily used: (1) with both diagnostic and interventional aims (72%), (2) as diagnostic imaging (17%), and (3) as guidance for interventional procedures (11%). The main clinical applications were: (1) diagnosis and management of pleural effusion, (2) pneumothorax, (3) pneumonia, (4) cardiac failure, and (5) acute dyspnea. Twenty-one percent of the responders do not use thoracic ultrasound. The main reported bar-riers were: (1) availability of an ultrasound system (52%), (2) lack of protected time and training (22%), and (3) use of the technique by other specialists (15%). CONCLUSION: Thoracic ultrasound is widely used by Italian pulmonologists and considered a clinically relevant tool. The availability of dedicated ultrasound systems seems to be a major limit of the use of the technique.

Management of Chronic Respiratory Failure in Interstitial Lung Diseases: Overview and Clinical Insights.

Interstitial lung diseases (ILDs) may be complicated by chronic respiratory failure (CRF), especially in the advanced stages. Aim of this narrative review is to evaluate the current evidence in management of CRF in ILDs. Many physiological mechanisms underlie CRF in ILDs, including lung restriction, ventilation/perfusion mismatch, impaired diffusion capacity and pulmonary vascular damage. Intermittent exertional hypoxemia is often the initial sign of CRF, evolving, as ILD progresses, into continuous hypoxemia. In the majority of the cases, the development of CRF is secondary to the worsening of the underlying disease; however, associated comorbidities may also play a role. When managing CRF in ILDs, the need for pulmonary rehabilitation, the referral to lung transplant centers and palliative care should be assessed and, if necessary, promptly offered. Long-term oxygen therapy is commonly prescribed in case of resting or exertional hypoxemia with the purpose to decrease dyspnea and improve exercise tolerance. High-Flow Nasal Cannula oxygen therapy may be used as an alternative to conventional oxygen therapy for ILD patients with severe hypoxemia requiring both high flows and high oxygen concentrations. Non-Invasive Ventilation may be used in the chronic setting for palliation of end-stage ILD patients, although the evidence to support this application is very limited.

ERS statement on chest imaging in acute respiratory failure.

Chest imaging in patients with acute respiratory failure plays an important role in diagnosing, monitoring and assessing the underlying disease. The available modalities range from plain chest X-ray to computed tomography, lung ultrasound, electrical impedance tomography and positron emission tomography. Surprisingly, there are presently no clear-cut recommendations for critical care physicians regarding indications for and limitations of these different techniques.The purpose of the present European Respiratory Society (ERS) statement is to provide physicians with a comprehensive clinical review of chest imaging techniques for the assessment of patients with acute respiratory failure, based on the scientific evidence as identified by systematic searches. For each of these imaging techniques, the panel evaluated the following items: possible indications, technical aspects, qualitative and quantitative analysis of lung morphology and the potential interplay with mechanical ventilation. A systematic search of the literature was performed from inception to September 2018. A first search provided 1833 references. After evaluating the full text and discussion among the committee, 135 references were used to prepare the current statement.These chest imaging techniques allow a better assessment and understanding of the pathogenesis and pathophysiology of patients with acute respiratory failure, but have different indications and can provide additional information to each other.

Management of acute respiratory failure in interstitial lung diseases: overview and clinical insights.

BACKGROUND: Interstitial lung diseases (ILDs) are a heterogeneous group of diseases characterized by widespread fibrotic and inflammatory abnormalities of the lung. Respiratory failure is a common complication in advanced stages or following acute worsening of the underlying disease. Aim of this review is to evaluate the current evidence in determining the best management of acute respiratory failure (ARF) in ILDs. METHODS: A literature search was performed in the Medline/PubMed and EMBASE databases to identify studies that investigated the management of ARF in ILDs (the last search was conducted on November 2017). RESULTS: In managing ARF, it is important to establish an adequate diagnostic and therapeutic management depending on whether the patient has an underlying known chronic ILD or ARF is presenting in an unknown or de novo ILD. In the first case both primary causes, such as acute exacerbations of the disease, and secondary causes, including concomitant pulmonary infections, fluid overload and pulmonary embolism need to be investigated. In the second case, a diagnostic work-up that includes investigations in regards to ILD etiology, such as autoimmune screening and bronchoalveolar lavage, should be performed, and possible concomitant causes of ARF have to be ruled out. Oxygen supplementation and ventilatory support need to be titrated according to the severity of ARF and patients' therapeutic options. High-Flow Nasal oxygen might potentially be an alternative to conventional oxygen therapy in patients requiring both high flows and high oxygen concentrations to correct hypoxemia and control dyspnea, however the evidence is still scarce. Neither Non-Invasive Ventilation (NIV) nor Invasive Mechanical Ventilation (IMV) seem to change the poor outcomes associated to advanced stages of ILDs. However, in selected patients, such as those with less severe ARF, a NIV trial might help in the early recognition of NIV-responder patients, who may present a better short-term prognosis. More invasive techniques, including IMV and Extracorporeal Membrane Oxygenation, should be limited to patients listed for lung transplant or with reversible causes of ARF. CONCLUSIONS: Despite the overall poor prognosis of ARF in ILDs, a personalized approach may positively influence patients' management, possibly leading to improved outcomes. However, further studies are warranted.

Respiratory muscle testing in amyotrophic lateral sclerosis: a practical approach.

In amyotrophic lateral sclerosis (ALS), respiratory muscle weakness leads to respiratory failure and death. Non-invasive positive pressure ventilation (NIPPV) appears to reduce lung function decline, thus improving survival and quality-of-life of patients affected by the disease. Unfortunately, clinical features and timing to start NIPPV are not well defined. Starting from recent findings, we examine established and novel tests of respiratory muscle function that could help clinicians decide whether and when to start NIPPV in ALS. Non-invasive tests estimate the function of inspiratory, expiratory, and bulbar muscles, whereas clinical examination allows to assess the overall neurologic and respiratory symptoms and general conditions. Most of the studies recommend that together with a thorough clinical evaluation of the patient according to current guidelines, vital capacity, maximal static and sniff nasal inspiratory pressures, maximal static expiratory pressures and peak cough expiratory flow, and nocturnal pulse oximetry be measured. A sound understanding of physiology can guide the physician also through the current armamentarium for additional supportive treatments for ALS, such as symptomatic drugs and new treatments to manage sialorrhea and thickened saliva, cough assistance, air stacking, and physiotherapy. In conclusion, careful clinical and functional evaluation of respiratory function and patient's preference are key determinants to decide "when" and "to whom" respiratory treatments can be provided.

Point-of-Care Lung Sonography: An Audit of 1150 Examinations.

OBJECTIVES: Point-of-care lung sonography has theoretical usefulness in numerous diseases; however clinical indications and the impact of this technique have not been fully investigated. We aimed to describe the current use of point-of-care lung sonography. METHODS: A 2-year prospective observational study was performed by pulmonologists in an Italian university hospital. Techniques, indications, consequences of lung sonography, and barriers to the examination were analyzed. RESULTS: A total of 1150 lung sonographic examinations were performed on 951 patients. The most common indications were diagnosis and follow-up of pleural effusion in 361 cases (31%), evaluation of lung consolidation (322 [28%]), acute heart failure (195 [17%]), guide to pleural procedures (117 [10%]), pneumothorax (54 [5%]) and acute exacerbations of chronic obstructive pulmonary disease (30 [3%]). The mean duration of the examination ± SD was 6 ± 4 minutes. The transducers most frequently used were convex (746 [65%]) and linear (161 [14%]), whereas in 205 examinations (18%), both transducers were used. According to the judgment of the caring clinician, 51% of the examinations were clinically relevant. CONCLUSIONS: Point-of-care lung sonography performed by pulmonologists is quick and feasible and could be widely used for different clinical indications with a potentially high clinical impact. The widespread use of this technique may have a relevant clinical impact in several indications.

A Review of the Ultrasound Assessment of Diaphragmatic Function in Clinical Practice.

Ultrasonography is the only non-invasive, non-ionizing imaging technique widely available to directly assess diaphragmatic function. Two different sonographic approaches permit the assessment of muscle thickening in the zone of apposition and excursion of the dome of the diaphragm. Thanks to the new hand-held ultrasound instruments, the morphology and function of the diaphragm can be assessed in different settings, such as outpatient clinic, pulmonary function test laboratory, hospital department and intensive care unit, and under different conditions. Despite the existence of different acoustic views and several codified approaches, a comprehensive sonographic examination has never been standardized for clinical use. In this review, we summarize the clinical indications, methods and perspectives of the technique in adults.