American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Mar 2022
Observational StudyClinical Effectiveness of Elexacaftor/Tezacftor/Ivacaftor in People with Cystic Fibrosis.
Rationale: The cystic fibrosis (CF) modulator drug, elexacaftor/tezacaftor/ivacaftor (ETI), proved highly effective in controlled clinical trials for individuals with at least one F508del allele, which occurs in at least 85% of people with CF. Objectives: PROMISE is a postapproval study to understand the broad effects of ETI through 30 months' clinical use in a more diverse U. S. patient population with planned analyses after 6 months. ⋯ Conclusions: ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naive to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV1 in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).
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The term "advanced sarcoidosis" is used for forms of sarcoidosis with a significant risk of loss of organ function or death. Advanced sarcoidosis often involves the lung and is described as "advanced pulmonary sarcoidosis" (APS), which includes advanced pulmonary fibrosis, associated complications such as bronchiectasis and infections, and pulmonary hypertension. Although APS affects a small proportion of patients with sarcoidosis, it is the leading cause of poor outcomes, including death. Here we review the major patterns of APS with a focus on the current management as well as potential approaches for improved outcomes for this most serious sarcoidosis phenotype.
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Am. J. Respir. Crit. Care Med. · Mar 2022
Candidate Role for Toll-like Receptor 3 L412F Polymorphism and Infection in Acute Exacerbation of Idiopathic Pulmonary Fibrosis.
Rationale: The Toll-like receptor 3 Leu412Phe (TLR3 L412F) polymorphism attenuates cellular antiviral responses and is associated with accelerated disease progression in idiopathic pulmonary fibrosis (IPF). The role of TLR3 L412F in bacterial infection in IPF or in acute exacerbations (AE) has not been reported. Objectives: To characterize the association between TLR3 L412F and AE-related death in IPF. ⋯ Using 16S ribosomal RNA sequencing, we demonstrated that 412F-heterozygous patients with IPF have a dysregulated lung microbiome with increased frequencies of Streptococcus and Staphylococcus spp. Conclusions: This study reveals that TLR3 L412F dysregulates the IPF lung microbiome and reduces the responses of IPF lung fibroblasts to bacterial TLR agonists and live bacterial infection. These findings identify a candidate role for TLR3 L412F in viral- and bacterial-mediated AE death.
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Am. J. Respir. Crit. Care Med. · Mar 2022
Multicenter Study Observational StudyEffects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on CFTR Function in Patients with Cystic Fibrosis and One or Two F508del Alleles.
Rationale: The CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to improve clinical outcomes and sweat chloride concentration in patients with cystic fibrosis (CF) and one or two F508del alleles. However, the effect of ELX/TEZ/IVA on CFTR function in the airways and intestine has not been studied. Objectives: To assess the effect of ELX/TEZ/IVA on CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles aged 12 years and older. ⋯ In F508del homozygous patients, ELX/TEZ/IVA exceeded improvement of CFTR function observed with TEZ/IVA and increased CFTR-mediated Cl- secretion to a level of 47.4% of normal (IQR, 19.3-69.2; P < 0.001) in nasal and 45.9% (IQR, 19.7-66.6; P < 0.001) in intestinal epithelia. Conclusions: Treatment with ELX/TEZ/IVA results in effective improvement of CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).
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Am. J. Respir. Crit. Care Med. · Mar 2022
Association of Intensive Care Unit Admission and Outcomes in Sepsis and Acute Respiratory Failure.
Rationale: Many decisions to admit patients to the ICU are not grounded in evidence regarding who benefits from such triage, straining ICU capacity and limiting its cost-effectiveness. Objectives: To measure the benefits of ICU admission for patients with sepsis or acute respiratory failure. Methods: At 27 United States hospitals across two health systems from 2013 to 2018, we performed a retrospective cohort study using two-stage instrumental variable quantile regression with a strong instrument (hospital capacity strain) governing ICU versus ward admission among high-acuity patients (i.e., laboratory-based acute physiology score v2 ⩾ 100) with sepsis and/or acute respiratory failure who did not require mechanical ventilation or vasopressors in the emergency department. ⋯ In sensitivity analyses of length of stay, excluding, ignoring, or censoring death, results were similar in sepsis but not in respiratory failure. In subgroup analyses, harms of ICU admission for patients with sepsis were concentrated among older patients and those with fewer comorbidities, and the benefits of ICU admission for patients with respiratory failure were concentrated among older patients, highest-acuity patients, and those with more comorbidities. Conclusions: Among high-acuity patients with sepsis who did not require life support in the emergency department, initial admission to the ward, compared with the ICU, was associated with shorter length of stay and improved survival, whereas among patients with acute respiratory failure, triage to the ICU compared with the ward was associated with improved survival.