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Dyspnea is a common yet poorly understood symptom of long COVID, affecting many patients. This brief report examines the role of dysfunctional breathing in persistent dyspnea among patients with mild post-COVID-19 using hyperventilation provocation tests (HVPT). In this case series, six patients with unexplained dyspnea and normal cardiopulmonary function underwent HVPT. Despite normal exercise testing results, all patients exhibited delayed PETCO2 recovery, indicative of a hyperventilation pattern consistent with chronic hyperventilation syndrome, without typical symptomatic manifestations. These findings suggest underlying post-COVID respiratory dysregulation, emphasizing the importance of targeted diagnostic and therapeutic approaches for persistent respiratory symptoms in long COVID patients.
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BACKGROUND: Bronchial thermoplasty (BT) is a bronchoscopic procedure for patients with severe uncontrolled asthma, but randomized controlled studies of its efficacy in severe asthma with frequent exacerbations are lacking. The current aim was to assess BT efficacy in this patient population. METHODS: Thirty patients with asthma (GINA 5) who had experienced at least four severe exacerbations in the preceding year were randomized to BT (n = 15) or control groups (n = 15). All patients had four follow-up visits over the following 15 months, corresponding to 3, 6, 9, and 12 months after the last procedure for the BT group. The primary outcome was number of exacerbations at 15 months after inclusion (i.e. 12 months after bronchial thermoplasty). RESULTS: All but three patients had received an asthma biologic without receiving benefit. In the year preceding enrollment, patients in the BT group had an average of five exacerbations, compared with six among controls. For patients in the BT group, oral steroid intake was 9.3 mg/d, compared with 11.0 mg/d among controls. The BT group had 1.58 fewer severe exacerbations (mean, 6.09) compared with controls (mean, 8.28) in the 12-month period after the therapy (p = 0.047). Oral steroid intake during follow-up after BT was significantly lower in the BT group (ratio vs controls: 0.61; p = 0.0002). Quality-of-life measures between inclusion and the last visit were significantly improved in the BT group, but not among controls. Few mild to moderate adverse events were reported, and all were controlled within days. CONCLUSION: In patients with severe asthma and frequent severe exacerbations, BT significantly decreased the rate of severe exacerbations and oral steroid intake and led to improved quality of life during the 15 months after inclusion. BT appears to offer a therapeutic option for severe asthma with frequent exacerbations.
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Background: The French RAMSES study is an observational prospective multicentre real-life cohort including severe asthmatic subjects. The objective of the study was to compare the characteristics of patients, in terms of phenotype and asthma care trajectories, between those managed by tertiary referral centres (TRCs) or secondary care centres (SCCs). Methods: Patients were prospectively recruited and enrolled for a 5-year follow-up. Patients' characteristics were analysed at inclusion and compared between TRCs and SCCs. Results: 52 centres (24 TRCs and 28 SCCs) included 2046 patients: 1502 (73.4%) were included by a TRC and 544 (26.6%) by a SCC. Patients were mainly women (62%), 53±15â years old, 67% with Asthma Control Test <20; at inclusion, 14% received oral corticosteroids (OCS) and 66% biologics. Compared with the SCC group, the TRC group had more frequent comorbidities and lower blood eosinophil counts (262 versus 340â mm-3; p=0.0036). OCS and biologics use did not differ between groups, but patients in the TRC group benefited more frequently from an educational programme (26% versus 18%; p=0.0008) and received more frequently two or more sequential lines of biologics (33% versus 24%; p=0.0105). In-depth investigations were more frequently performed in the TRC group (allergy tests: 74% versus 62%; p<0.0001; exhaled nitric oxide fraction: 56% versus 21%; p<0.0001; induced sputum: 6% versus 3%; p=0.0390). Conclusions: Phenotypes and care trajectories differed in the RAMSES cohort between SCCs and TRCs, probably related to different levels of asthma severity and differences in medical resources and practices among centres. This highlights the need for standardisation of severe asthma care.
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BACKGROUND: Numerous children present with early wheeze symptoms, yet solely a subgroup develops childhood asthma. Early identification of children at risk is key for clinical monitoring, timely patient-tailored treatment, and preventing chronic, severe sequelae. For early prediction of childhood asthma, we aimed to define an integrated risk score combining established risk factors with genome-wide molecular markers at birth, complemented by subsequent clinical symptoms/diagnoses (wheezing, atopic dermatitis, food allergy). METHODS: Three longitudinal birth cohorts (PAULINA/PAULCHEN, n = 190 + 93 = 283, PASTURE, n = 1133) were used to predict childhood asthma (age 5-11) including epidemiological characteristics and molecular markers: genotype, DNA methylation and mRNA expression (RNASeq/NanoString). Apparent (ap) and optimism-corrected (oc) performance (AUC/R2) was assessed leveraging evidence from independent studies (Naïve-Bayes approach) combined with high-dimensional logistic regression models (LASSO). RESULTS: Asthma prediction with epidemiological characteristics at birth (maternal asthma, sex, farm environment) yielded an ocAUC = 0.65. Inclusion of molecular markers as predictors resulted in an improvement in apparent prediction performance, however, for optimism-corrected performance only a moderate increase was observed (upto ocAUC = 0.68). The greatest discriminate power was reached by adding the first symptoms/diagnosis (up to ocAUC = 0.76; increase of 0.08, p = .002). Longitudinal analysis of selected mRNA expression in PASTURE (cord blood, 1, 4.5, 6 years) showed that expression at age six had the strongest association with asthma and correlation of genes getting larger over time (r = .59, p < .001, 4.5-6 years). CONCLUSION: Applying epidemiological predictors alone showed moderate predictive abilities. Molecular markers from birth modestly improved prediction. Allergic symptoms/diagnoses enhanced the power of prediction, which is important for clinical practice and for the design of future studies with molecular markers.
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Asma , Humanos , Asma/epidemiología , Asma/genética , Asma/diagnóstico , Femenino , Masculino , Niño , Preescolar , Factores de Riesgo , Estudios Longitudinales , Metilación de ADN , Biomarcadores , Cohorte de NacimientoAsunto(s)
Antiasmáticos , Anticuerpos Monoclonales Humanizados , Asma , Interleucina-5 , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antiasmáticos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/tratamiento farmacológico , Eosinofilia/tratamiento farmacológico , Interleucina-5/antagonistas & inhibidores , Receptores de Interleucina-5 , Índice de Severidad de la EnfermedadRESUMEN
PURPOSE: This review aimed to summarise evidence about the impact of pharmacological and non-pharmacological interventions on survival in COPD patients. METHODS: We performed a narrative literature review on the effect of pharmacological and non-pharmacological interventions on survival in COPD patients. RESULTS: Inhaled therapies are central to reduce symptoms in COPD. In particular, inhaled steroids seem to have the greatest effect on mortality. Despite the anti-inflammatory effects attributed to statins, their benefit in COPD has been shown only in cases of combined cardiovascular diseases. The use of beta-blockers in COPD has not been associated with increased COPD-related mortality and a beneficial effect on all-cause mortality has even been shown in COPD patients with cardiovascular diseases. Influenza and pneumococcal vaccination reduced the occurrence of exacerbations and mortality due to COPD. In addition, long-term oxygen therapy (LTOT) (≥15h/day) in COPD patients with severe hypoxemia had a positive effect on survival. Regarding non-pharmacological interventions, it has been demonstrated that smoking cessation, treatment compliance and nutritional supplementation for underweight patients also have a positive effect on survival. Non-invasive ventilation results were dependent on patient PaCO2 levels. In patients with advanced COPD, further prospective studies are needed to know the effect of bronchoscopic lung volume reduction and lung transplant on COPD survival. Regarding lung transplant, a survival benefit in patients with a pre-transplant BODE score of ≥7 has been shown in retrospective studies. CONCLUSION: Most of the studies did not evaluate survival as the main criteria and further long-term studies on the global management of COPD are required.
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Enfermedades Cardiovasculares , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Estudios Retrospectivos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/terapia , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Terapia por Inhalación de Oxígeno , Esteroides/uso terapéuticoRESUMEN
BACKGROUND: Cardiopulmonary exercise testing (CPET) is an important clinical tool that provides a global assessment of the respiratory, circulatory and metabolic responses to exercise which are not adequately reflected through the measurement of individual organ system function at rest. In the context of critical COVID-19, CPET is an ideal approach for assessing long term sequelae. METHODS: In this prospective single-center study, we performed CPET 12 months after symptom onset in 60 patients that had required intensive care unit treatment for a severe COVID-19 infection. Lung function at rest and chest computed tomography (CT) scan were also performed. RESULTS: Twelve months after severe COVID-19 pneumonia, dyspnea was the most frequently reported symptom although only a minority of patients had impaired respiratory function at rest. Mild ground-glass opacities, reticulations and bronchiectasis were the most common CT scan abnormalities. The majority of the patients (80%) had a peak O2 uptake (V'O2) considered within normal limits (median peak predicted O2 uptake (V'O2) of 98% [87.2-106.3]). Length of ICU stay remained an independent predictor of V'O2. More than half of the patients with a normal peak predicted V'O2 showed ventilatory inefficiency during exercise with an abnormal increase of physiological dead space ventilation (VD/Vt) (median VD/VT of 0.27 [0.21-0.32] at anaerobic threshold (AT) and 0.29 [0.25-0.34] at peak) and a widened median peak alveolar-arterial gradient for O2 (35.2 mmHg [31.2-44.8]. Peak PetCO2 was significantly lower in subjects with an abnormal increase of VD/Vt (p = 0.001). Impairments were more pronounced in patients with dyspnea. Peak VD/Vt values were positively correlated with peak D-Dimer plasma concentrations from blood samples collected during ICU stay (r2 = 0.12; p = 0.02) and to predicted diffusion capacity of the lung for carbon monoxide (DLCO) (r2 = - 0.15; p = 0.01). CONCLUSIONS: Twelve months after severe COVID-19 pneumonia, most of the patients had a peak V'O2 considered within normal limits but showed ventilatory inefficiency during exercise with increased dead space ventilation that was more pronounced in patients with persistent dyspnea. TRIAL REGISTRATION: NCT04519320 (19/08/2020).
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COVID-19 , Prueba de Esfuerzo , Humanos , Progresión de la Enfermedad , Disnea , Prueba de Esfuerzo/métodos , Tolerancia al Ejercicio , Hospitalización , Estudios ProspectivosRESUMEN
BACKGROUND: Although children can frequently experience a cough that affects their quality of life, few epidemiological studies have explored cough without a cold during childhood. OBJECTIVES: The objective of the study was to describe the latent class trajectories of cough from one to 10 years old and analyse their association with wheezing, atopy and allergic diseases. METHODS: Questions about cough, wheeze and allergic diseases were asked at 1, 1.5, 2, 3, 4, 5, 6 and 10 years of age in the European prospective cohort of Protection against Allergy: STUdy in Rural Environment (PASTURE). Specific IgE assays were performed at 10 years of age. Questions regarding a cough without a cold were used to build a latent class model of cough over time. RESULTS: Among the 961 children included in the study, apart from the never/infrequent trajectory (59.9%), eight trajectories of cough without a cold were identified: five grouped acute transient classes (24.1%), moderate transient (6.8%), late persistent (4.8%) and early persistent (4.4%). Compared with the never/infrequent trajectory, the other trajectories were significantly associated with wheezing, asthma and allergic rhinitis. For asthma, the strongest association was with the early persistent trajectory (ORa = 31.00 [14.03-68.51]), which was inversely associated with farm environment (ORa = 0.39 [0.19-0.77]) and had a high prevalence of cough triggers and unremitting wheeze. Late and early persistent trajectories were also associated with food allergy. Atopic sensitization was only associated with the late persistent trajectory. CONCLUSION: Late and early persistent coughs without a cold are positively associated with atopic respiratory diseases and food allergy. Children having recurrent cough without a cold with night cough and triggers would benefit from an asthma and allergy assessment. Growing up on a farm is associated with reduced early persistent cough.
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Asma , Hipersensibilidad a los Alimentos , Hipersensibilidad Inmediata , Niño , Preescolar , Humanos , Lactante , Tos/epidemiología , Tos/etiología , Estudios Prospectivos , Ruidos Respiratorios/etiología , Calidad de Vida , Asma/epidemiología , Asma/etiología , Hipersensibilidad a los Alimentos/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND: An important window of opportunity for early-life exposures has been proposed for the development of atopic eczema and asthma. OBJECTIVE: However, it is unknown whether hay fever with a peak incidence around late school age to adolescence is similarly determined very early in life. METHODS: In the Protection against Allergy-Study in Rural Environments (PASTURE) birth cohort potentially relevant exposures such as farm milk consumption and exposure to animal sheds were assessed at multiple time points from infancy to age 10.5 years and classified by repeated measure latent class analyses (n = 769). Fecal samples at ages 2 and 12 months were sequenced by 16S rRNA. Hay fever was defined by parent-reported symptoms and/or physician's diagnosis of hay fever in the last 12 months using questionnaires at 10.5 years. RESULTS: Farm children had half the risk of hay fever at 10.5 years (adjusted odds ratio [aOR] 0.50; 95% CI 0.31-0.79) than that of nonfarm children. Whereas early life events such as gut microbiome richness at 12 months (aOR 0.66; 95% CI 0.46-0.96) and exposure to animal sheds in the first 3 years of life (aOR 0.26; 95% CI 0.06-1.15) were determinants of hay fever, the continuous consumption of farm milk from infancy up to school age was necessary to exert the protective effect (aOR 0.35; 95% CI 0.17-0.72). CONCLUSIONS: While early life events determine the risk of subsequent hay fever, continuous exposure is necessary to achieve protection. These findings argue against the notion that only early life exposures set long-lasting trajectories.
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Rinitis Alérgica Estacional , Animales , Humanos , Rinitis Alérgica Estacional/epidemiología , Granjas , ARN Ribosómico 16S , Agricultura , Alérgenos , Encuestas y CuestionariosRESUMEN
Background: Sleep apnea (SA) was reported as possibly exacerbating symptoms of COVID-19, a disease induced by SARS-CoV-2 virus. The same comorbidities are common with both pathologies. This study aimed to estimate the prevalence, characteristics of SA and variation in AHI three months after severe COVID-19 requiring intensive care unit (ICU) admission. Methods: A prospective cohort of patients admitted to ICU for severe COVID-19 underwent an overnight home polygraphy 3 months after onset of symptoms, as part of a comprehensive follow-up program (pulmonary function tests, 6-minute walk tests and chest CT-scan). Patients with an apnea hypopnea index (AHI) ≥5 were considered as having SA. We performed a comparative descriptive analysis of 2 subgroups according to the existence, severity of SA and indication for effective SA treatment: patients with absent or mild SA (AHI <15) vs patients with moderate to severe SA (AHI ≥15). Results: Among 68 patients included, 62 (91%) had known comorbidities (34 hypertension, 21 obesity, 20 dyslipidemia, 16 type 2 diabetes). It has been observed a preexisting SA for 13 patients (19.1%). At 3 months, 62 patients (91%) had SA with 85.5% of obstructive events. Twenty-four patients had no or a mild SA (AHI <15) and 44 had moderate to severe SA (AHI ≥15). Ischemic heart disease exclusively affected the moderate to severe SA group. Except for thoracic CT-scan which revealed less honeycomb lesions, COVID-19 symptoms were more severe in the group with moderate to severe SA, requiring a longer curarization, more prone position sessions and more frequent tracheotomy. Conclusion: SA involved 91% of patients in our population at 3 months of severe COVID-19 and was mainly obstructive type. Although SA might be a risk factor as well as consequences of ICU care in severe COVID-19 infection, our results underline the importance of sleep explorations after an ICU stay for this disease.
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Skeletal muscle ischemia reperfusion is very frequent in humans and results not only in muscle destruction but also in multi-organ failure and death via systemic effects related to inflammation and oxidative stress. In addition to overabundance of pro-inflammatory stimuli, excessive and uncontrolled inflammation can also result from defects in resolution signaling. Importantly, the resolution of inflammation is an active process also based on specific lipid mediators including lipoxins, resolvins and maresins that orchestrate the potential return to tissue homeostasis. Thus, lipid mediators have received growing attention since they dampen deleterious effects related to ischemia-reperfusion. For instance, the treatment of skeletal muscles with resolvins prior to ischemia decreases polymorphonuclear leukocyte (PMN) infiltration. Additionally, remote alterations in lungs or kidneys are reduced when enhancing lipid mediators' functions. Accordingly, lipoxins prevented oxidative-stress-mediated tissue injuries, macrophage polarization was modified and in mice lacking DRV2 receptors, ischemia/reperfusion resulted in excessive leukocyte accumulation. In this review, we first aimed to describe the inflammatory response during ischemia and reperfusion in skeletal muscle and then discuss recent discoveries in resolution pathways. We focused on the role of specialized pro-resolving mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) and their potential therapeutic applications.
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INTRODUCTION: Survivors of viral ARDS are at risk of long-term physical, functional and neuropsychological complications resulting from the lung injury itself, but also from potential multiorgan dysfunction, and the long stay in the intensive care unit (ICU). Recovery profiles after severe SARS-CoV-2 pneumonia in intensive care unit survivors have yet to be clearly defined. MATERIAL AND METHODS: The goal of this single-center, prospective, observational study was to systematically evaluate pulmonary and extrapulmonary function at 12 months after a stay in the ICU, in a prospectively identified cohort of patients who survived SARS-CoV-2 pneumonia. Eligible patients were assessed at 3, 6 and 12 months after onset of SARS-CoV-2. Patients underwent physical examination, pulmonary function testing, chest computed tomography (CT) scan, a standardized six-minute walk test with continuous oximetry, overnight home respiratory polygraphy and have completed quality of life questionnaire. The primary endpoint was alteration of the alveolar-capillary barrier compared to reference values as measured by DLCO, at 12 months after onset of SARS-CoV-2 symptoms. RESULTS: In total, 85 patients (median age 68.4 years, (interquartile range [IQR] = 60.1-72.9 years), 78.8% male) participated in the trial. The median length of hospital stay was 44 days (IQR: 20-60) including 17 days in ICU (IQR: 11-26). Pulmonary function tests were completed at 3 months (n = 85), 6 months (n = 80), and 12 months (n = 73) after onset of symptoms. Most patients showed an improvement in DLCO at each timepoint (3, 6, and 12 months). All patients who normalized their DLCO did not subsequently deteriorate, except one. Chest CT scans were abnormal in 77 patients (96.3%) at 3 months and although the proportion was the same at 12 months, but patterns have changed. CONCLUSION: We report the results of a comprehensive evaluation of 85 patients admitted to the ICU for SARS-CoV-2, at one-year follow-up after symptom onset. We show that most patients had an improvement in DLCO at each timepoint. TRIAL REGISTRATION: Clinical trial registration number: NCT04519320.
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Lipoxinas , Alérgenos , Eosinófilos , Humanos , Inflamación , Células Asesinas Naturales , Mucosa Nasal , Pruebas de Provocación NasalRESUMEN
Cardiovascular diseases (CVDs) are devastating disorders and the leading cause of mortality worldwide. The pathophysiology of cardiovascular diseases is complex and multifactorial and, in the past years, mitochondrial dysfunction and excessive production of reactive oxygen species (ROS) have gained growing attention. Indeed, CVDs can be considered as a systemic alteration, and understanding the eventual implication of circulating blood cells peripheral blood mononuclear cells (PBMCs) and or platelets, and particularly their mitochondrial function, ROS production, and mitochondrial DNA (mtDNA) releases in patients with cardiac impairments, appears worthwhile. Interestingly, reports consistently demonstrate a reduced mitochondrial respiratory chain oxidative capacity related to the degree of CVD severity and to an increased ROS production by PBMCs. Further, circulating mtDNA level was generally modified in such patients. These data are critical steps in term of cardiac disease comprehension and further studies are warranted to challenge the possible adjunct of PBMCs' and platelets' mitochondrial dysfunction, oxidative stress, and circulating mtDNA as biomarkers of CVD diagnosis and prognosis. This new approach might also allow further interesting therapeutic developments.
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Formerly considered as a passive process, the resolution of acute inflammation is now recognized as an active host response, with a cascade of coordinated cellular and molecular events that promotes termination of the inflammatory response and initiates tissue repair and healing. In a state of immune fitness, the resolution of inflammation is contained in time and space enabling the restoration of tissue homeostasis. There is increasing evidence that poor and/or inappropriate resolution of inflammation participates in the pathogenesis of chronic inflammatory diseases, extending in time the actions of pro-inflammatory mechanisms, and responsible in the long run for excessive tissue damage and pathology. In this review, we will focus on how resolution can be the target for therapy in "Th1/Th17 cell-driven" immune diseases and "Th2 cell-driven" immune diseases, with inflammatory bowel diseases (IBD) and asthma, as relevant examples. We describe the main cells and mediators stimulating the resolution of inflammation and discuss how pharmacological and dietary interventions but also life style factors, physical and psychological conditions, might influence the resolution phase. A better understanding of the impact of endogenous and exogenous factors on the resolution of inflammation might open a whole area in the development of personalized therapies in non-resolving chronic inflammatory diseases.
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Asma/inmunología , Homeostasis/inmunología , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Animales , Enfermedad Crónica , Humanos , Mediadores de Inflamación/inmunologíaRESUMEN
Smoking cessation remains a major issue for asthmatic smokers. Respiratory rehabilitation and respiratory physiotherapy have shown a benefit in controlling symptoms, preventing exacerbations and improving the quality of life. The control of the environment is crucial and must be approached in a global way. Management of obesity and psychological disorders should be systematically proposed. Allergen immunotherapy may be discussed in allergic persistent asthma to house dust mites. Certain dietary interventions or alternative medicines have not proved their worth.
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Asma/terapia , Humanos , Terapia Respiratoria , Fumar/terapiaRESUMEN
Here we extensively describe a FACS-based protocol for isolating intact non-stained human eosinophils from peripheral blood; a stop forward from our recently published initial study. This method of purification could be accomplished in <3â¯h with only small volumes of whole blood necessary, even in healthy subjects generally exhibiting low levels of circulating eosinophils. Eosinophil activation during the isolation steps appeared to be minimal and this purification procedure yielded high quality RNA. Moreover, these FACS-isolated eosinophils had prolonged viability in culture and were suitable for further activation assays.
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Eosinófilos/citología , Eosinófilos/metabolismo , Citometría de Flujo/métodos , ARN/aislamiento & purificación , Técnicas de Cultivo de Célula , Supervivencia Celular , Femenino , Humanos , Masculino , ARN/metabolismoRESUMEN
RATIONALE: Acute respiratory distress syndrome (ARDS) is a devastating illness with limited therapeutic options. A better understanding of early biochemical and immunological events in ARDS could inform the development of new preventive and treatment strategies. OBJECTIVES: To determine select peripheral blood lipid mediator and leukocyte responses in patients at risk for ARDS. METHODS: Patients at risk for ARDS were randomized as part of a multicenter, double-blind clinical trial of aspirin versus placebo (the LIPS-A [Lung Injury Prevention Study with Aspirin] trial; NCT01504867). Plasma thromboxane B2 (TXB2), aspirin-triggered lipoxin A4 (15-epi-LXA4, ATL), and peripheral blood leukocyte number and activation were determined on enrollment and after treatment with either aspirin or placebo. MEASUREMENTS AND MAIN RESULTS: Thirty-three of 367 subjects (9.0%) developed ARDS after randomization. Baseline ATL levels, total monocyte counts, intermediate monocyte counts, and monocyte-platelet aggregates were associated with the development of ARDS. Peripheral blood neutrophil count and monocyte-platelet aggregates significantly decreased over time. Of note, nine subjects developed ARDS after randomization yet before study drug initiation, including seven subjects assigned to aspirin treatment. Subjects without ARDS at the time of first dose demonstrated a lower incidence of ARDS with aspirin treatment. Compared with placebo, aspirin significantly decreased TXB2 and increased the ATL/TXB2 ratio. CONCLUSIONS: Biomarkers of intravascular monocyte activation in at-risk patients were associated with development of ARDS. The potential clinical benefit of early aspirin for prevention of ARDS remains uncertain. Together, results of the biochemical and immunological analyses provide a window into the early pathogenesis of human ARDS and represent potential vascular biomarkers of ARDS risk. Clinical trial registered with www.clinicaltrials.gov (NCT01504867).