Assessment of Exercise Capacity of Individuals with Long COVID: A Cross-sectional Study.

BACKGROUND: Clinical investigations of long-term effects of coronavirus disease 2019 (COVID-19) are rarely translated to objective findings. OBJECTIVES: To assess the functional capacity of individuals reported on deconditioning that hampered their return to their pre-COVID routine. METHODS: Assessment included the 6-minute walk test (6MWT) and the 30-second sit-to-stand test (30-STST). We compared the expected and observed scores using the Wilcoxon signed-rank test. Predictors of test scores were identified using linear regression models. RESULTS: We included 49 individuals, of whom 38 (77.6%) were recovering from mild COVID-19. Twenty-seven (55.1%) individuals had a 6MWT score lower than 80% of expected. The average 6MWT scores were 129.5 ± 121.2 meters and 12.2 ± 5.0 repeats lower than expected scores, respectively (P < 0.001 for both). The 6MWT score was 107.3 meters lower for individuals with severe COVID-19 (P = 0.013) and rose by 2.7 meters per each 1% increase in the diffusing capacity of carbon monoxide (P = 0.007). The 30-STST score was 3.0 repeats lower for individuals who reported moderate to severe myalgia (P = 0.038). CONCLUSIONS: Individuals with long COVID who report on deconditioning exhibit significantly decreased physical capacity, even following mild acute illness. Risk factors include severe COVID-19 and impaired diffusing capacity or myalgia during recovery.

Risk Factors and Multidimensional Assessment of Long Coronavirus Disease Fatigue: A Nested Case-Control Study.

BACKGROUND: Fatigue is the most prevalent and debilitating long-COVID (coronavirus disease) symptom; however, risk factors and pathophysiology of this condition remain unknown. We assessed risk factors for long-COVID fatigue and explored its possible pathophysiology. METHODS: This was a nested case-control study in a COVID recovery clinic. Individuals with (cases) and without (controls) significant fatigue were included. We performed a multidimensional assessment evaluating various parameters, including pulmonary function tests and cardiopulmonary exercise testing, and implemented multivariable logistic regression to assess risk factors for significant long-COVID fatigue. RESULTS: A total of 141 individuals were included. The mean age was 47 (SD: 13) years; 115 (82%) were recovering from mild coronavirus disease 2019 (COVID-19). Mean time for evaluation was 8 months following COVID-19. Sixty-six (47%) individuals were classified with significant long-COVID fatigue. They had a significantly higher number of children, lower proportion of hypothyroidism, higher proportion of sore throat during acute illness, higher proportions of long-COVID symptoms, and of physical limitation in daily activities. Individuals with long-COVID fatigue also had poorer sleep quality and higher degree of depression. They had significantly lower heart rate [153.52 (22.64) vs 163.52 (18.53); P = .038] and oxygen consumption per kilogram [27.69 (7.52) vs 30.71 (7.52); P = .036] at peak exercise. The 2 independent risk factors for fatigue identified in multivariable analysis were peak exercise heart rate (OR: .79 per 10 beats/minute; 95% CI: .65-.96; P = .019) and long-COVID memory impairment (OR: 3.76; 95% CI: 1.57-9.01; P = .003). CONCLUSIONS: Long-COVID fatigue may be related to autonomic dysfunction, impaired cognition, and decreased mood. This may suggest a limbic-vagal pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04851561.

ESCMID rapid guidelines for assessment and management of long COVID.

SCOPE: The aim of these guidelines is to provide evidence-based recommendations for the assessment and management of individuals with persistent symptoms after acute COVID-19 infection and to provide a definition for this entity, termed 'long COVID'. METHODS: We performed a search of the literature on studies addressing epidemiology, symptoms, assessment, and treatment of long COVID. The recommendations were grouped by these headings and by organ systems for assessment and treatment. An expert opinion definition of long COVID is provided. Symptoms were reviewed by a search of the available literature. For assessment recommendations, we aimed to perform a diagnostic meta-analysis, but no studies provided relevant results. For treatment recommendations we performed a systematic review of the literature in accordance with the PRISMA statement. We aimed to evaluate patient-related outcomes, including quality of life, return to baseline physical activity, and return to work. Quality assessment of studies included in the systematic review is provided according to study design. RECOMMENDATIONS: Evidence was insufficient to provide any recommendation other than conditional guidance. The panel recommends considering routine blood tests, chest imaging, and pulmonary functions tests for patients with persistent respiratory symptoms at 3 months. Other tests should be performed mainly to exclude other conditions according to symptoms. For management, no evidence-based recommendations could be provided. Physical and respiratory rehabilitation should be considered. On the basis of limited evidence, the panel suggests designing high-quality prospective clinical studies/trials, including a control group, to further evaluate the assessment and management of individuals with persistent symptoms of COVID-19.

Cost Analysis of New Antibiotics to Treat Multidrug-Resistant Bacterial Infections: Mind the Gap.

INTRODUCTION: Guidelines for treatment of multidrug-resistant (MDR) bacteria rely on newly approved antibiotics, with limited evidence of their effectiveness for treating these infections. Data regarding cost of such an approach are lacking. We aimed to evaluate estimated cost of using newly approved antibiotic drugs compared to older antibiotics for the treatment of difficult-to-treat pathogens. METHODS: MDR bacteria of interest included those defined by the World Health Organization as critical or of high priority for research. Old and newly approved antibiotics for these bacteria, defined as approved before or after January 2010, respectively, were evaluated for treatment cost and for 14-day treatment course. Estimated annual costs were calculated based on the Centers for Disease Control and Prevention's' report on MDR bacteria prevalence in US hospitalized patients. Old and new drugs costs were compared. RESULTS: The cost of a 14-day treatment course for methicillin-resistant Staphylococcus aureus bacteremia with a newly approved drug was found to be 6 to 60 times higher than that of older drugs. Similarly, the cost of a 14-day course for carbapenem-resistant Enterobacterales or MDR Pseudomonas aeruginosa was doubled with new drugs; and for carbapenem-resistant Acinetobacter baumannii, ~ 20 times higher with newer drugs. Annual incremental costs of treating difficult-to-treat Gram-negative bacteria with new drugs ranged from 30 million to over 500 million USD. CONCLUSIONS: Using newly approved antibiotic drugs for MDR infections carries a large incremental cost. Additional data to support survival benefit of these drugs are required to justify the price differences. Subgroups of patients who would benefit most from treatment should be defined.

Assessment of Data Supporting the Efficacy of New Antibiotics for Treating Infections Caused by Multidrug-resistant Bacteria.

BACKGROUND: Infections caused by multidrug-resistant (MDR) bacteria are a major public health threat. We aimed to assess the data supporting US Food and Drug Administration (FDA) approval of new agents aimed to treat MDR bacterial infections and the data provided by postmarketing studies. METHODS: We identified all drugs with in vitro activity against MDR bacteria initially approved by the FDA between January 2010 and December 2018. Characteristics of trials supporting approval and regulatory pathways were collected from Drugs@FDA. Characteristics of postmarketing studies were extracted from drug labels and ClinicalTrials.gov entries effective 1 June 2019. RESULTS: Initial approval of 11 newly approved antibiotics with anti-MDR activity was supported by 20 trials, all with noninferiority design. All initially approved indications were for common infections, mostly acute bacterial skin and skin-structure infections, regardless of causative microorganism. The proportion of MDR bacteria in most trials was low (<10% for gram-negative infections, <1% for gram-positive pneumonia). Most trials (90%) excluded immunocompromised and critically ill patients. Of 16 additional postmarketing randomized controlled trials identified through ClinicalTrials.gov, only 2 exclusively included infections caused by MDR bacteria, comprising 116 patients. No drug was granted accelerated approval, which would mandate postmarketing efficacy studies. CONCLUSIONS: The approval of new drugs with potential clinical activity against MDR bacteria is supported by trials evaluating infections caused by non-MDR organisms, using noninferiority design and excluding the patients most likely to require these agents. Subsequent postmarketing efficacy data against these organisms are scarce. Healthcare professionals and regulators should demand more robust data to support clinical decision making.

Early detection of infectious complications during induction therapy for acute leukemia with serial C-reactive protein biomarker assessment.

Febrile neutropenia (FN) and blood stream infections (BSI) are major complications of induction treatment for acute leukemia. We assessed the predictive utility of C-reactive protein (CRP), an acute phase reactant, for FN and BSI during induction. CRP levels and dynamics were analyzed in 138 consecutive patients. FN and BSI occurred in 110 (80.3%) and 10 (7.5%) patients, respectively. Median peak CRP level in the 24-hours preceding FN was 7.5 mg/dl (0.2-38.1) vs. median peak CRP level of 5.11 mg/dl (0.2-23.1, p = .009) in patients without FN. CRP levels preceding BSI were 13.1 mg/dl (6.9-27.9) vs. 6.3 mg/dl (0.16-38.14, p = .011). CRP increase prior to event (ΔCRP) was higher among patients with BSI vs. patients without BSI (p = .013). CRP was predictive for FN (p = .009) and BSI (p = .01) on ROC curve analysis and was also independently associated with FN on multivariate analysis. In conclusion, CRP is a sensitive biomarker that precedes FN and BSI.

Assessment of frequency and reporting of design changes among clinical drug trials published in influential medical journals.

BACKGROUND: Modifications of primary outcome measures after trial initiation can undermine their scientific validity. We aimed to quantify these changes and to characterize potential predictors in clinical drug trials published in high impact factor general medicine journals. METHODS: The study cohort included all prospective, adult drug clinical trials published in the New England Journal of Medicine, JAMA and Lancet between June 2017 and May 2018. The matching ClinicalTrials.gov entries effective at trial initiation were compared with those effective on July 2018, thereby identifying amendments to primary outcome definitions and assessment timeframes and the planned sample size (defined as >10% change). The primary publications were reviewed for reporting of these amendments. Associations between identified changes and trial characteristics were explored using logistic regression. RESULTS: Of the 147 included trials, modifications to primary outcome measures were identified in 80 (54%). Primary outcome definitions, outcome assessment timeframes and the planned sample size were modified in 28 (19%), 12 (8%) and 65 (45%) of registry entries, respectively; of which 21 (75%), 11 (92%), and 33 (51%), respectively, were not reported in the related publications. There were no significant associations between modifications in registry entries and study characteristics. CONCLUSIONS: Approximately half of trials published in influential medical journals present changes to the design while patient accrual is ongoing, and two thirds of them are unreported. Justification for such modifications should be reported more clearly. Reviewers, editors and readers should consult ClinicalTrials.gov for a more comprehensive report of the evolution of key study methods.