RESUMEN
OBJECTIVES: In cystic fibrosis (CF), loss of CFTR-mediated bicarbonate secretion reduces the airway surface liquid (ASL) pH causing airway host defense defects. Aerosolized sodium bicarbonate can reverse these defects, but its effects are short-lived. Aerosolized tromethamine (THAM) also raises the ASL pH but its effects are much longer lasting. In this pilot study, we tested the hypothesis that nasally administered THAM would alter the nasal bacterial composition in adults with and without CF. METHODS: Subjects (n = 32 total) received intranasally administered normal saline or THAM followed by a wash out period prior to receiving the other treatment. Nasal bacterial cultures were obtained prior to and after each treatment period. RESULTS: At baseline, nasal swab bacterial counts were similar between non-CF and CF subjects, but CF subjects had reduced microbial diversity. Both nasal saline and THAM were well-tolerated. In non-CF subjects, nasal airway alkalinization decreased both the total bacterial density and the gram-positive bacterial species recovered. In both non-CF and CF subjects, THAM decreased the amount of Corynebacterium accolens detected, but increased the amount of Corynebacterium pseudodiphtheriticum recovered on nasal swabs. A reduction in Staphylococcus aureus nasal colonization was also found in subjects who grew C. pseudodiphtheriticum. CONCLUSIONS: This study shows that aerosolized THAM is safe and well-tolerated and that nasal airway alkalinization alters the composition of mucosal bacterial communities. CLINICAL TRIAL REGISTRATION: NCT00928135 (https://clinicaltrials.gov/ct2/show/NCT00928135).
Asunto(s)
Fibrosis Quística , Microbiota , Adulto , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Humanos , Concentración de Iones de Hidrógeno , Proyectos PilotoRESUMEN
Background: The most severe cases of Coronavirus-Disease-2019 (COVID-19) develop into Acute Respiratory Distress Syndrome (ARDS). It has been proposed that oxygenation may be inhibited by extracellular deoxyribonucleic acid (DNA) in the form of neutrophil extracellular traps (NETs). Dornase alfa (Pulmozyme, Genentech) is recombinant human deoxyribonuclease I that acts as a mucolytic by cleaving and degrading extracellular DNA. We performed a pilot study to evaluate the effects of dornase alfa in patients with ARDS secondary to COVID-19. Methods: We performed a pilot, non-randomized, case-controlled clinical trial of inhaled dornase for patients who developed ARDS secondary to COVID-19 pneumonia. Results: Improvement in arterial oxygen saturation to inhaled fraction of oxygen ratio (PaO2/FiO2) was noted in the treatment group compared to control at day 2 (95% CI, 2.96 to 95.66, P-value = 0.038), as well as in static lung compliance at days 3 through 5 (95% CI, 4.8 to 19.1 mL/cmH2O, 2.7 to 16.5 mL/cmH2O, and 5.3 to 19.2 mL/cmH2O, respectively). These effects were not sustained at 14 days. A reduction in bronchoalveolar lavage fluid (BALF) myeloperoxidase-DNA (DNA : MPO) complexes (95% CI, -14.7 to -1.32, P-value = 0.01) was observed after therapy with dornase alfa. Conclusion: Treatment with dornase alfa was associated with improved oxygenation and decreased DNA : MPO complexes in BALF. The positive effects, however, were limited to the time of drug delivery. These data suggest that degradation of extracellular DNA associated with NETs or other structures by inhaled dornase alfa can be beneficial. We propose a more extensive clinical trial is warranted. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT04402970.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Desoxirribonucleasa I/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , SARS-CoV-2/fisiología , Administración por Inhalación , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , ADN/metabolismo , Trampas Extracelulares/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Consumo de Oxígeno/efectos de los fármacos , Peroxidasa/metabolismo , Proyectos Piloto , Proteínas Recombinantes/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: The endemic human coronavirus NL63 strain (HCoV-NL63) employs angiotensin-converting enzyme 2 (ACE-2) receptors on cell surfaces to infect hosts in the same manner as SARS-CoV and the novel SARS-CoV-2. It has been proposed that patients on angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin receptor blockers (ARB) therapy infected with SARS-CoV-2 have a higher mortality rate due to over-expression of ACE-2 receptors. AIM: We sought to evaluate the impact of ACE-I/ARB on infectivity of various endemic coronavirus strains, hypothesizing that rates of ACE-I use among patients with HCoV-NL63 would be higher compared to other endemic coronavirus strains that do not utilize the ACE-2 receptor. DESIGN/METHODS: A retrospective cohort study was designed to evaluate a total 466 subjects with a positive respiratory pathogens panel for one of the endemic coronavirus strains. Rate of ACE-I/ARB use among each coronavirus strain and clinical outcomes from the 88 HCoV-NL63 positive subjects was collected. RESULTS: Analysis revealed a higher rate of ACE-I (p=0.006) use among the HCoV-NL63 positives compared to the other three endemic coronavirus strains. The rate of invasive mechanical ventilation (p=0.007) and 90-day mortality (p=0.045) among HCoV-NL63 positives on ACE-I therapy was higher compared to those HCoV-NL63 positives not on ACE-I therapy. CONCLUSION: Concurrent therapy with an ACE-I was associated with an increased rate and severity of infection with the HCoV-NL63. This association was not found in infected patients on concurrent ARB therapy. These findings support the importance of further evaluation in patients on these therapies who are infected with the novel coronavirus SARS-CoV-2.