RÉSUMÉ
Background: Patients with alpha-1 antitrypsin deficiency (AATD) exhibit dysregulated inflammatory responses and a predilection for autoimmunity. While the adverse event (AE) profiles of COVID-19 vaccines in several chronic inflammatory conditions are now available, safety and tolerability data for patients with severe AATD have yet to be described. The feasibility of coadministering vaccines against COVID-19 and influenza in this population is similarly unclear. Methods: We conducted a prospective study of 170 patients with Pi*ZZ genotype AATD receiving their initial vaccination series with ChAdOx1 nCoV-19 (AstraZeneca). Patients were monitored clinically for AEs over the week that followed their first and second doses. In parallel, we conducted the same assessments in patients with Pi*MM genotype chronic obstructive pulmonary disease (COPD) (n=160) and Pi*MM individuals without lung disease (n=150). The Pi*ZZ cohort was subsequently followed through 2 consecutive mRNA-based booster vaccines (monovalent and bivalent BNT162b2, Pfizer/BioNTech). To assess the safety of combined vaccination against COVID-19 and influenza, the quadrivalent influenza vaccine was administered to participants attending for their second COVID-19 booster vaccination, either on the same day or following a 1-week interval. Results: Pi*ZZ AATD participants did not display increased AEs compared to Pi*MM COPD or Pi*MM non-lung disease controls. Although unexpected and serious vaccine-associated AEs did occur, the majority of AEs experienced across the 3 groups were mild and self-limiting. The AATD demographic at highest risk for AEs (especially systemic and prolonged AEs) was young females. No increase in AE risk was observed in patients with established emphysema, sonographic evidence of liver disease, or in those receiving intravenous augmentation therapy. AE incidence declined sharply following the initial vaccine series. Same-day coadministration of the COVID-19 mRNA bivalent booster vaccine and the annual influenza vaccine did not result in increased AEs compared to sequential vaccines 1 week apart. Conclusions: Despite their pro-inflammatory state, patients with severe AATD are not at increased risk of AEs or serious AEs compared to patients with nonhereditary COPD and patients without lung disease. Same-day coadministration of COVID-19 booster vaccines with the annual influenza vaccine is feasible, safe, and well-tolerated in this population.
RÉSUMÉ
Patients with severe alpha-1 antitrypsin deficiency (AATD) are at increased risk for the development of chronic obstructive pulmonary disease (COPD), particularly if they smoke. This, coupled with their predilection for dysregulated inflammation and autoimmunity, makes affected individuals priority candidates for vaccination against coronavirus disease 2019 (COVID-19). To promote vaccine uptake effectively, an understanding of the factors motivating people to proceed with vaccination is essential. The attitudes of patients with AATD towards COVID-19 vaccination have yet to be described. We prospectively studied 170 Pi*ZZ genotype AATD patients, 150 patients with nonhereditary (Pi*MM genotype) COPD and 140 Pi*MM genotype individuals without lung disease receiving first-dose vaccination with ChAdOx1 nCoV-19 (AstraZeneca). Patient attitudes towards vaccination and motivations for getting vaccinated were assessed at the time of the vaccine being offered. Following completion of the 2-dose vaccine series, Pi*ZZ patients were then re-assessed regarding their attitudes towards booster vaccination. The most common primary motivation for accepting vaccination in Pi*ZZ participants ≥50 years old was a fear of illness or death from COVID-19. In contrast, Pi*ZZ patients <50 years most often cited a desire to socialize. The motivation pattern of younger Pi*ZZ AATD patients was similar to that of non-deficient individuals of comparable age, whereas older Pi*ZZ individuals were more closely aligned with Pi*MM COPD and differed from age-matched controls without lung disease. When considering booster vaccination, Pi*ZZ patients were increasingly motivated by a desire to reacquire social freedoms. A desire to reduce the risk of transmission was not a prominent consideration in any of the groups studied. The most commonly cited reason for booster hesitancy was a lack of incentive, given that no additional social freedoms were available to triple-vaccinated individuals compared to those who were double-vaccinated at the time. Taken together, these data may inform policymakers attempting to promote vaccine uptake among patients with AATD.
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False negatives from nasopharyngeal swabs (NPS) using reverse transcriptase PCR (RT-PCR) in SARS-CoV-2 are high. Exhaled breath condensate (EBC) contains lower respiratory droplets that may improve detection. We performed EBC RT-PCR for SARS-CoV-2 genes (E, S, N, ORF1ab) on NPS-positive (n=16) and NPS-negative/clinically positive COVID-19 patients (n=15) using two commercial assays. EBC detected SARS-CoV-2 in 93.5% (29/31) using the four genes. Pre-SARS-CoV-2 era controls (n=14) were negative. EBC was positive in NPS negative/clinically positive patients in 66.6% (10/15) using the identical E and S (E/S) gene assay used for NPS, 73.3% (11/15) using the N/ORF1ab assay and 14/15 (93.3%) combined.
Sujet(s)
Tests d'analyse de l'haleine/méthodes , Dépistage de la COVID-19/méthodes , COVID-19/diagnostic , Expiration , ARN viral/analyse , SARS-CoV-2/génétique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , COVID-19/épidémiologie , Femelle , Humains , Mâle , Adulte d'âge moyen , Études prospectives , Reproductibilité des résultatsRÉSUMÉ
Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1ß, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1ß, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1ß, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.
Sujet(s)
Réaction inflammatoire aigüe/immunologie , Protéines de transport/métabolisme , Infections à coronavirus/immunologie , Infections à coronavirus/métabolisme , Cytokines/immunologie , Sous-unité alpha du facteur-1 induit par l'hypoxie/métabolisme , Acide lactique/métabolisme , Protéines membranaires/métabolisme , Pneumopathie virale/immunologie , Pneumopathie virale/métabolisme , Hormones thyroïdiennes/métabolisme , alpha-1-Antitrypsine/immunologie , Réaction inflammatoire aigüe/métabolisme , Adulte , Sujet âgé , Betacoronavirus , Technique de Western , COVID-19 , Études cas-témoins , Infections communautaires/immunologie , Infections communautaires/métabolisme , Infections à coronavirus/mortalité , Infections à coronavirus/physiopathologie , Maladie grave , Électrophorèse sur gel de polyacrylamide , Test ELISA , Femelle , Hospitalisation , Humains , Unités de soins intensifs , Interleukine-10/immunologie , Interleukine-1 bêta/immunologie , Interleukine-6/immunologie , Interleukine-8/immunologie , Durée du séjour , Mâle , Adulte d'âge moyen , Granulocytes neutrophiles/immunologie , Granulocytes neutrophiles/métabolisme , Pandémies , Phosphorylation , Pneumopathie infectieuse/immunologie , Pneumopathie infectieuse/métabolisme , Pneumopathie virale/mortalité , Pneumopathie virale/physiopathologie , Récepteur au facteur de nécrose tumorale de type I/immunologie , SARS-CoV-2 , Indice de gravité de la maladie , alpha-1-Antitrypsine/métabolisme ,RÉSUMÉ
The Metabolic Dietetic Team in the National Centre for Inherited Metabolic Disorders (NCIMD) in Ireland deals with approximately 120 weekly phenylalanine (Phe) levels for both adults and children. A review of 500 Phe levels highlighted that 52% of the results were within the target range. Collaboration between information and communication technologies (ICT) departments, metabolic laboratory, and metabolic dietitians enabled the development of the PKU texting system. Following a successful pilot study, the system was then offered to all PKU patients aged over 2 years. The Phe is analysed and authorised on the laboratory system. The demographics are matched with the patient mobile phone number. Text messages are then validated and sent by the dietitian via a web portal using the Defero SMS texting service. Approximately 290 patients/families currently use the texting system. In order to assess the effectiveness of this quality improvement initiative, a patient survey was carried out in 2017. This showed 87% rated the system as either very good or excellent. 94% agreed it was time saving. 84% felt there was no influence on dietary compliance. Analysis of financial implications on dietetic time over 21 months revealed savings of 3,275 and 580 hours of dietetic time. There is no evidence, two years after implementation, that the system has had an effect on either the Phe levels in terms of recommended range or frequency of sampling.
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BACKGROUND: SSc-ILD and IPF demonstrate significant morbidity and mortality. Predicting disease progression is challenging in both diseases. OBJECTIVES: We sought a serum biomarker that could identify patients with SSc-ILD or IPF and prospectively predict short-term decline in lung function in these patients. METHODS: 10 healthy controls, 5 SSc w/o ILD, 6 SSc-ILD and 13 IPF patients underwent venesection. An array of cytokines including KL-6, SP-D and MMP7 were measured. PFTs were obtained at baseline and six months. Cytokine measurements were correlated with PFTs. RESULTS: KL-6 in IPF patients (633 ng/ml, IQR 492-1675) was significantly elevated compared to controls (198 ng/ml, IQR 52-360, p<0.01) and SSc w/o ILD patients (192 ng/ml, IQR 0-524, p<0.05); KL-6 in SSc-ILD patients (836 ng/ml, IQR 431-1303) was significantly higher than in controls (p<0.05). SP-D was significantly higher in IPF patients (542 ng/ml, IQR 305-577) compared to controls (137 ng/ml, IQR 97-284, p<0.01) or to SSc w/o ILD patients (169 ng/ml, IQR 137-219, p<0.05). In comparison with controls (0.0 ng/ml, IQR 0.0-0.6), MMP7 was significantly higher in both IPF patients (2.85 ng/ml, IQR 1.5-3.6, p<0.05) and SSc-ILD patients (5.41 ng/ml, IQR 2.6-7.2, p<0.001). Using a cut-off level of 459ng/ml for KL-6 and of 1.28 ng/ml for MMP7, 18 out of 19 patients with ILD had a serum value of either KL-6 or MMP7 above these thresholds. For all ILD patients, baseline serum SP-D correlated with ΔFVC %pred over six months (r=-0.63, p=0.005, 95% CI -0.85 to -0.24). CONCLUSIONS: Combining KL-6 with MMP7 may be a useful screening tool for patients at risk of ILD. SP-D may predict short-term decline in lung function.
Sujet(s)
Fibrose pulmonaire idiopathique/sang , Pneumopathies interstitielles/sang , Poumon/physiopathologie , Matrix metalloproteinase 7/sang , Mucine-1/sang , Sclérodermie systémique/sang , Sujet âgé , Sujet âgé de 80 ans ou plus , Marqueurs biologiques/sang , Études cas-témoins , Diagnostic différentiel , Femelle , Humains , Fibrose pulmonaire idiopathique/diagnostic , Fibrose pulmonaire idiopathique/physiopathologie , Poumon/imagerie diagnostique , Pneumopathies interstitielles/diagnostic , Pneumopathies interstitielles/physiopathologie , Mâle , Adulte d'âge moyen , Valeur prédictive des tests , Pronostic , Études prospectives , Tests de la fonction respiratoire , Sclérodermie systémique/diagnostic , Sclérodermie systémique/physiopathologie , Facteurs temps , TomodensitométrieRÉSUMÉ
OBJECTIVE: To determine if sputum colonization with Aspergillus species in patients with cystic fibrosis (PWCF) correlates with radiological abnormalities and/or a reduction in pulmonary function (FEV1). METHODS: We prospectively evaluated 32 PWCF utilizing high resolution computed tomography (HRCT) of the thorax and pulmonary function testing (PFT). The cohort was assessed as two groups: Aspergillus positive (n=16) and Aspergillus negative (n=16) based on sputum culture for Aspergillus species. A modified Bhalla scoring system was applied to each HRCT scan by two blinded radiologists. RESULTS: Aspergillus positive patients had more severe and significant bronchiectasis compared to those Aspergillus negative (p<0.05). This was most marked in the right upper and lower lobes (RUL, RLL). Total Bhalla score was clinically significant in both groups and approached statistical significance between groups (p=0.063). No difference in pulmonary function between the groups was detected. CONCLUSION: PWCF colonized by Aspergillus species have greater radiological abnormalities undetectable by PFTs. Early radiological evaluation of Aspergillus colonized PWCF is therefore warranted.
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Aspergillose/imagerie diagnostique , Aspergillose/physiopathologie , Dilatation des bronches/imagerie diagnostique , Dilatation des bronches/physiopathologie , Mucoviscidose/imagerie diagnostique , Mucoviscidose/physiopathologie , Tomodensitométrie/méthodes , Adolescent , Dilatation des bronches/microbiologie , Enfant , Humains , Études prospectives , Tests de la fonction respiratoire , Indice de gravité de la maladie , Expectoration/microbiologie , Statistique non paramétrique , Jeune adulteRÉSUMÉ
Despite comprehensive guidelines established by the European Global Initiative for Asthma and the U.S. National Asthma Education and Prevention Program on the diagnosis and management of asthma, its mortality in older adults continues to rise. Diagnostic and therapeutic problems contribute to older patients being inadequately treated. The diagnosis of asthma rests on the history and characteristic pulmonary function testing (PFT) with the demonstration of reversible airway obstruction, but there are unique problems in performing this test in older patients and in its interpretation. This review aims to address the difficulties in performing and interpreting PFT in older patients because of the effects of age-related changes in lung function on respiratory physiology. The concept of "airway remodeling" resulting in "fixed obstructive" PFT and the relevance of atopy in older people with asthma are assessed. There are certain therapeutic issues unique to older patients with asthma, including the increased probability of adverse effects in the setting of multiple comorbidities and issues surrounding effective drug delivery. The use of beta 2-agonist, anticholinergic, corticosteroid, and anti-immunoglobulin E treatments are discussed in the context of these therapeutic issues.
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Antiasthmatiques/usage thérapeutique , Asthme/diagnostic , Asthme/traitement médicamenteux , Sujet âgé , Antiasthmatiques/administration et posologie , Asthme/physiopathologie , Systèmes de délivrance de médicaments , Humains , Tests de la fonction respiratoireRÉSUMÉ
BACKGROUND: Toll-like receptors (TLRs) are pattern recognition receptors that act as a first-line of defence in the innate immune response by recognising and responding to conserved molecular patterns in microbial factors and endogenous danger signals. Cystic fibrosis (CF)-affected airways represent a milieu potentially rich in TLR agonists and the chronic inflammatory phenotype evident in CF airway epithelial cells is probably due in large part to activation of TLRs. OBJECTIVE/METHODS: To examine the prospects of developing novel therapies for CF by targeting TLRs. We outline the expression and function of TLRs and explore the therapeutic potential of naturally-occurring and synthetic TLR inhibitors for CF. RESULTS/CONCLUSION: Modulation of TLRs has therapeutic potential for the inflammatory lung manifestations of CF.
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Anti-inflammatoires non stéroïdiens/pharmacologie , Mucoviscidose/traitement médicamenteux , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Récepteurs de type Toll/antagonistes et inhibiteurs , Conception de médicament , Humains , Récepteurs de type Toll/génétique , Récepteurs de type Toll/métabolismeRÉSUMÉ
BACKGROUND: Patients with cystic fibrosis (CF) can become colonized by aspergillus, which can act as an allergen and cause allergic bronchopulmonary aspergillosis (ABPA). OBJECTIVE: To determine the rate of aspergillus colonization and ABPA in a population of Irish patients with CF. METHODS: In 50 consecutive patients with CF who presented with exacerbations, we looked for the presence of aspergillus in their sputum and signs and symptoms of ABPA. RESULTS: Fifteen patients (30%) grew aspergillus species in their sputum cultures. Six patients (12%) had ABPA. Matched for age, sex, genotype, and microbiology, there was no significant difference in forced expiratory volume in the first second (percent predicted, FEV(1)%) in subjects with aspergillus-positive sputum compared to those not colonized with aspergillus. Subjects with ABPA experienced sharp short-term deterioration in lung function (mean 6.7% predicted FEV(1)), which returned to baseline following at least 4 weeks of treatment. CONCLUSIONS: The prevalence of ABPA was 12%. Aspergillus-positive sputum of itself was not a poor prognostic sign in terms of lung function over the 5-year study course. ABPA produces short-term reversible declines in lung function and responds to treatment. The frequency of aspergillus isolates did not correlate with the occurrence of ABPA. A low threshold for the diagnosis of ABPA should be maintained in any patient with CF who does not improve with antibiotics.