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PubMed; 2022.
Preprint in English | PubMed | ID: ppcovidwho-338328


BACKGROUND: Mechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 "PASC" or "Long COVID") remain unclear. The purpose of this study was to elucidate the pathophysiology of cardiopulmonary PASC using multimodality cardiovascular imaging including cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring. METHODS: We performed CMR, CPET, and ambulatory rhythm monitoring among adults > 1 year after PCR-confirmed SARS-CoV-2 infection in the UCSF Long-Term Impact of Infection with Novel Coronavirus cohort (LIINC;NCT04362150 ) and correlated findings with previously measured biomarkers. We used logistic regression to estimate associations with PASC symptoms (dyspnea, chest pain, palpitations, and fatigue) adjusted for confounders and linear regression to estimate differences between those with and without symptoms adjusted for confounders. RESULTS: Out of 120 participants in the cohort, 46 participants (unselected for symptom status) had at least one advanced cardiac test performed at median 17 months following initial SARS-CoV-2 infection. Median age was 52 (IQR 42-61), 18 (39%) were female, and 6 (13%) were hospitalized for severe acute infection. On CMR (n=39), higher extracellular volume was associated with symptoms, but no evidence of late-gadolinium enhancement or differences in T1 or T2 mapping were demonstrated. We did not find arrhythmias on ambulatory monitoring. In contrast, on CPET (n=39), 13/23 (57%) with cardiopulmonary symptoms or fatigue had reduced exercise capacity (peak VO 2 <85% predicted) compared to 2/16 (13%) without symptoms (p=0.008). The adjusted difference in peak VO 2 was 5.9 ml/kg/min lower (-9.6 to -2.3;p=0.002) or -21% predicted (-35 to -7;p=0.006) among those with symptoms. Chronotropic incompetence was the primary abnormality among 9/15 (60%) with reduced peak VO 2 . Adjusted heart rate reserve <80% was associated with reduced exercise capacity (OR 15.6, 95%CI 1.30-187;p=0.03). Inflammatory markers (hsCRP, IL-6, TNF-alpha) and SARS-CoV-2 antibody levels measured early in PASC were negatively correlated with peak VO 2 more than 1 year later. CONCLUSIONS: Cardiopulmonary symptoms and elevated inflammatory markers present early in PASC are associated with objectively reduced exercise capacity measured on cardiopulmonary exercise testing more than 1 year following COVID-19. Chronotropic incompetence may explain reduced exercise capacity among some individuals with PASC. Clinical Perspective: What is New?Elevated inflammatory markers in early post-acute COVID-19 are associated with reduced exercise capacity more than 1 year later.Impaired chronotropic response to exercise is associated with reduced exercise capacity and cardiopulmonary symptoms more than 1 year after SARS-CoV-2 infection.Findings on ambulatory rhythm monitoring point to perturbed autonomic function, while cardiac MRI findings argue against myocardial dysfunction and myocarditis. Clinical Implications: Cardiopulmonary testing to identify etiologies of persistent symptoms in post-acute sequalae of COVID-19 or "Long COVID" should be performed in a manner that allows for assessment of heart rate response to exercise. Therapeutic trials of anti-inflammatory and exercise strategies in PASC are urgently needed and should include assessment of symptoms and objective testing with cardiopulmonary exercise testing.

Journal of the American College of Cardiology ; 79(9):2108-2108, 2022.
Article in English | Web of Science | ID: covidwho-1848575
Circulation ; 144:2, 2021.
Article in English | Web of Science | ID: covidwho-1711006
Circulation ; 144(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1638116


Introduction: Myocardial injury is associated with COVID-19 mortality, but the prognostic value of adverse right ventricular (RV) remodeling on transthoracic echocardiogram (TTE) is uncertain. Therefore we studied the association between RV dilation and in-hospital mortality in acute COVID19. Methods: We included all adults hospitalized with COVID-19 between March 2020 and February 2021 who had a clinical TTE performed during hospitalization at UCSF Health (Parnassus, Mission Bay, or Mount Zion) or Zuckerberg San Francisco General. Clinical and echo data were extracted from the electronic medical record. Biomarkers (BNP & troponin) were log transformed. The primary exposure was qualitative assessment of RV dilation on TTE and the primary outcome was inhospital mortality. We conducted analysis with STATA MP 16.1 using logistic regression models with adjustment for age and sex (Model 1) and age, sex, log(BNP), log(troponin), and mechanical ventilation (Model 2) and compared models with and without RV size with the likelihood ratio test. Results: There were 225 people hospitalized with COVID-19 who had a clinical TTE performed. The mean age was 62.9 years old, 77 (34%) were female, and 48 (21%) died. The majority of patients identified as Latinx (40%), and most patients received Medicaid (58%). Of 212 TTEs adequate to assess RV size, 47 (22%) had RV dilation of whom 16 (34%) died compared to 31 (19%) with normal RV size (RR 1.81, 95%CI 1.09-3.01, p=0.03). Of 185 TTEs adequate to assess RV function, 18 (10%) had RV dysfunction of whom 6 (33%) died compared to 12 (18%) with normal RV function (RR 1.86, 95%CI 0.89-3.84, p=0.12). There were no differences in tricuspid annulus plane systolic excursion or RV systolic excursion velocity. Adjusted for age and sex, RV dilation was associated with mortality (OR 2.16, 95%CI 1.02-4.58;p=0.045), with a larger effect among those with RV dilation and dysfunction (OR 3.40, 95% CI 0.93-12.4, p=0.063). This effect was attenuated after adjusting for BNP, troponin and mechanical ventilation at the time of TTE (OR 1.61, 95%CI 0.52-4.98, p=0.41). Conclusions: RV dilation on TTE is associated with mortality in acute COVID-19, although the effect is attenuated after accounting for mechanical ventilation and biomarkers.

Preprint in English | medRxiv | ID: ppmedrxiv-21265555


BackgroundRobust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness. MethodsWe conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients. FindingsWe show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression is associated with the presence of a high viral load. We further demonstrate that systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 severity. For clinical outcome prediction (e.g. respiratory failure), IFI27 expression displays a high positive (0.83) and negative (0.95) predictive value, outperforming all other known predictors of COVID-19 severity. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 swine influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients. InterpretationThese data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched the scientific literature using PubMed to identify studies that used the IFI27 biomarker to predict outcomes in COVID-19 patients. We used the search terms "IFI27", "COVID-19, "gene expression" and "outcome prediction". We did not identify any study that investigated the role of IFI27 biomarker in outcome prediction. Although ten studies were identified using the general terms of "gene expression" and "COVID-19", IFI27 was only mentioned in passing as one of the identified genes. All these studies addressed the broader question of the host response to COVID-19; none focused solely on using IFI27 to improve the risk stratification of infected patients in a pandemic. Added value of this studyHere, we present the findings of a multi-cohort study of the IFI27 biomarker in COVID-19 patients. Our findings show that the host response, as reflected by blood IFI27 gene expression, accurately predicts COVID-19 disease progression (positive and negative predictive values; 0.83 and 0.95, respectively), outperforming age, comorbidity, C-reactive protein and all other known risk factors. The strong association of IFI27 with disease severity occurs not only in SARS-CoV-2 infection, but also in other respiratory viruses with pandemic potential, such as the influenza virus. These findings suggest that host response biomarkers, such as IFI27, could help identify high-risk COVID-19 patients - those who are more likely to develop infection complications - and therefore may help improve patient triage in a pandemic. Implications of all the available evidenceThis is the first systemic study of the clinical role of IFI27 in the current COVID-19 pandemic and its possible future application in other respiratory virus pandemics. The findings not only could help improve the current management of COVID-19 patients but may also improve future pandemic preparedness.