Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America最新文献

{"title":"Trends over time in the risk of adverse outcomes among patients with SARS-CoV-2 infection","authors":"G. Ioannou, A. O’Hare, K. Berry, V. Fan, K. Crothers, M. Eastment, E. Locke, P. Green, Javeed A. Shah, J. Dominitz","doi":"10.1101/2021.03.08.21253090","DOIUrl":"https://doi.org/10.1101/2021.03.08.21253090","url":null,"abstract":"Objectives: We aimed to describe trends in the incidence of adverse outcomes among patients who tested positive for SARS-CoV-2 between February and September 2020 within a national healthcare system. Setting: US Veterans Affairs national healthcare system. Participants: Enrollees in the VA healthcare system who tested positive for SARS-CoV-2 between 2/28/2020 and 9/30/2020 (n=55,952). Outcomes: Death, hospitalization, intensive care unit (ICU) admission and mechanical ventilation within 30 days of testing positive. The incidence of these outcomes was examined among patients infected each month and trends were evaluated using an interrupted time-series analysis. Results: Between February and July 2020, during the first wave of the US pandemic, there were marked downward trends in the 30-day incidence of hospitalization (44.2% to 15.8%), ICU admission (20.3% to 5.3%), mechanical ventilation (12.7% to 2.2%), and death (12.5% to 4.4%), with subsequent stabilization between July and September 2020. These trends persisted after adjustment for sociodemographic characteristics, comorbid conditions, and documented symptoms and after additional adjustment for laboratory test results among hospitalized patients, including among subgroups admitted to the ICU and treated with mechanical ventilation. Among hospitalized patients, use of hydroxychloroquine (56.5% to 0%), azithromycin (48.3% to 16.6%) vasopressors (20.6% to 8.7%), and dialysis (11.6% to 3.8%) decreased while use of dexamethasone (3.4% to 53.1%), other corticosteroids (4.9% to 29.0%) and remdesivir (1.7% to 45.4%) increased from February to September. Conclusions: Among patients who tested positive for SARS-CoV-2 in a large national US healthcare system, risk for a range of adverse outcomes decreased markedly between February and July, with subsequent stabilization from July to September. These trends were not explained by changes in measured baseline patient characteristics.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77706455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population-based estimates of post-acute sequelae of SARS-CoV-2 infection (PASC) prevalence and characteristics","authors":"J. Hirschtick, Andrea R. Titus, Elizabeth Slocum, Laura E. Power, R. Hirschtick, M. Elliott, P. McKane, N. Fleischer","doi":"10.1101/2021.03.08.21252905","DOIUrl":"https://doi.org/10.1101/2021.03.08.21252905","url":null,"abstract":"Importance: Emerging evidence suggests many people have persistent symptoms after acute COVID-19 illness. Objective: To estimate the prevalence and correlates of persistent COVID-19 symptoms 30 and 60 days post onset using a population-based sample. Design & Setting: The Michigan COVID-19 Recovery Surveillance Study is a population-based cross-sectional survey of a probability sample of adults with confirmed COVID-19 in the Michigan Disease Surveillance System (MDSS). Respondents completed a survey online or via telephone in English, Spanish, or Arabic between June - December 2020. Participants: Living non-institutionalized adults (aged 18+) in MDSS with COVID-19 onset through mid-April 2020 were eligible for selection (n=28,000). Among 2,000 adults selected, 629 completed the survey. We excluded 79 cases during data collection due to ineligibility, 6 asymptomatic cases, 7 proxy reports, and 24 cases missing outcome data, resulting in a sample size of 593. The sample was predominantly female (56.1%), aged 45 and older (68.2%), and Non-Hispanic White (46.3%) or Black (34.8%). Exposures: Demographic (age, sex, race/ethnicity, and annual household income) and clinical factors (smoking status, body mass index, diagnosed comorbidities, and illness severity). Main outcomes and Measures: We defined post-acute sequelae of SARS-CoV-2 infection (PASC) as persistent symptoms 30+ days (30-day COVID-19) or 60+ days (60-day COVID-19) post COVID-19 onset. Results: 30- and 60-day COVID-19 were highly prevalent (52.5% and 35.0%), even among respondents reporting mild symptoms (29.2% and 24.5%) and non-hospitalized respondents (43.7% and 26.9%, respectively). Low income was statistically significantly associated with 30-day COVID-19 in adjusted models. Respondents reporting very severe (vs. mild) symptoms had 2.25 times higher prevalence of 30-day COVID-19 (Adjusted Prevalence Ratio [aPR] 2.25, 95% CI 1.46-3.46) and 1.71 times higher prevalence of 60-day COVID-19 (aPR 1.71, 95% 1.02-2.88). Hospitalized (vs. non-hospitalized) respondents had about 40% higher prevalence of both 30-day (aPR 1.37, 95% CI 1.12-1.69) and 60-day COVID-19 (aPR 1.40, 95% CI 1.02-1.93). Conclusions and Relevance: PASC is highly prevalent among cases with severe initial symptoms, and, to a lesser extent, cases with mild and moderate symptoms.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73971239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2 Sequence Characteristics of COVID-19 Persistence and Reinfection","authors":"M. Choudhary, Charles R. Crain, Xueting Qiu, W. Hanage, Jonathan Z. Li","doi":"10.1101/2021.03.02.21252750","DOIUrl":"https://doi.org/10.1101/2021.03.02.21252750","url":null,"abstract":"Background. Both SARS-CoV-2 reinfection and persistent infection have been described, but a systematic assessment of mutations is needed. We assessed sequences from published cases of COVID-19 reinfection and persistence, characterizing the hallmarks of reinfecting sequences and the rate of viral evolution in persistent infection. Methods. A systematic review of PubMed was conducted to identify cases of SARS-CoV-2 reinfection and persistent infection with available sequences. Amino acid changes in the reinfecting sequence were compared to both the initial and contemporaneous community variants. Time-measured phylogenetic reconstruction was performed to compare intra-host viral evolution in persistent COVID-19 to community-driven evolution. Results. Fourteen reinfection and five persistent infection cases were identified. Reports of reinfection cases spanned a broad distribution of ages, baseline health status, reinfection severity, and occurred as early as 1.5 months or >8 months after the initial infection. The reinfecting viral sequences had a median of 9 amino acid changes with enrichment of changes in the S, ORF8 and N genes. The number of amino acid changes did not differ by the severity of reinfection and reinfecting variants were similar to the contemporaneous sequences circulating in the community. Patients with persistent COVID-19 demonstrated more rapid accumulation of mutations than seen with community-driven evolution with continued viral changes during convalescent plasma or monoclonal antibody treatment. Conclusions. SARS-CoV-2 reinfection does not require an unusual set of circumstances in the host or virus, while persistent COVID-19 is largely described in immunosuppressed individuals and is associated with accelerated viral evolution as measured by clock rates.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84898090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Cytokine Signatures of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Influenza Infection Highlight Key Differences in Pathobiology","authors":"A. Karaba, Weiqiang Zhou, L. Hsieh, Alexis Figueroa, G. Massaccesi, R. Rothman, K. Fenstermacher, L. Sauer, Kathryn Shaw-Saliba, P. Blair, S. Leung, R. Wesson, N. Alachkar, R. El-Diwany, Hongkai Ji, A. Cox","doi":"10.1101/2021.01.29.21250317","DOIUrl":"https://doi.org/10.1101/2021.01.29.21250317","url":null,"abstract":"Background: Several inflammatory cytokines are upregulated in severe COVID-19. We compared cytokines in COVID-19 versus influenza in order to define differentiating features of the inflammatory response to these pathogens and their association with severe disease. Because elevated body mass index (BMI) is a known risk factor for severe COVID-19, we examined the relationship of BMI to cytokines associated with severe disease. Methods: Thirty-seven cytokines and chemokines were measured in plasma from 145 patients with COVID-19, 57 patients with influenza, and 30 healthy controls. Controlling for BMI, age, and sex, differences in cytokines between groups were determined by linear regression and random forest prediction was utilized to determine the cytokines most important in distinguishing severe COVID-19 and influenza. Mediation analysis was utilized to identify cytokines that mediate the effect of BMI on disease severity. Results: IL-18, IL-1{beta}, IL-6, and TNF- were significantly increased in COVID-19 versus influenza patients while GM-CSF, IFN-{gamma}, IFN-{lambda}1, IL-10, IL-15, and MCP-2 were significantly elevated in the influenza group. In subgroup analysis based on disease severity, IL-18, IL-6, and TNF- were elevated in severe COVID-19, but not severe influenza. Random forest analysis identified high IL-6 and low IFN-{lambda}1 levels as the most distinct between severe COVID-19 and severe influenza. Finally, IL-1RA was identified as a potential mediator of the effects of BMI on COVID-19 severity. Conclusions: These findings point to activation of fundamentally different innate immune pathways in SARS-CoV-2 and influenza infection, and emphasize drivers of severe COVID-19 to focus both mechanistic and therapeutic investigations.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87017312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Validation of a Novel T-cell Receptor Sequencing Assay for Identification of Recent or Prior SARS-CoV-2 Infection","authors":"S. Dalai, J. N. Dines, T. Snyder, R. Gittelman, Tera Eerkes, Pashmi Vaney, S. Howard, K. Akers, L. Skewis, Anthony Monteforte, P. Witte, C. Wolf, Hans P. Nesse, M. Herndon, Jia Qadeer, Sarah Duffy, E. Svejnoha, Caroline Taromino, I. Kaplan, J. Alsobrook, T. Manley, L. Baldo","doi":"10.1101/2021.01.06.21249345","DOIUrl":"https://doi.org/10.1101/2021.01.06.21249345","url":null,"abstract":"Background While diagnostic, therapeutic, and vaccine development in the COVID-19 pandemic has proceeded at unprecedented speed and scale, critical gaps remain in our understanding of the immune response to SARS-CoV-2. Current diagnostic strategies, including serology, have numerous limitations in addressing these gaps. Here we describe clinical performance of T-Detect COVID, the first reported assay to determine recent or prior SARS-CoV-2 infection based on T-cell receptor (TCR) sequencing and immune repertoire profiling from whole blood samples. Methods Methods for high-throughput immunosequencing of the TCR{beta} gene from blood specimens have been described1. We developed a statistical classifier showing high specificity for identifying prior SARS-CoV-2 infection2, utilizing >4,000 SARS-CoV-2-associated TCR sequences from 784 cases and 2,447 controls across 5 independent cohorts. The T-Detect COVID Assay comprises immunosequencing and classifier application to yield a qualitative positive or negative result. Several retrospective and prospective cohorts were enrolled to assess assay performance including primary and secondary Positive Percent Agreement (PPA; N=205, N=77); primary and secondary Negative Percent Agreement (NPA; N=87, N=79); PPA compared to serology (N=55); and pathogen cross-reactivity (N=38). Results T-Detect COVID demonstrated high PPA in subjects with prior PCR-confirmed SARS-CoV-2 infection (97.1% 15+ days from diagnosis; 94.5% 15+ days from symptom onset), high NPA (~100%) in presumed or confirmed SARS-CoV-2 negative cases, equivalent or higher PPA than two commercial EUA serology tests, and no evidence of pathogen cross-reactivity. Conclusion T-Detect COVID is a novel T-cell immunosequencing assay demonstrating high clinical performance to identify recent or prior SARS-CoV-2 infection from standard blood samples. This assay can provide critical insights on the SARS-CoV-2 immune response, with potential implications for clinical management, risk stratification, surveillance, assessing protective immunity, and understanding long-term sequelae.","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78563219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytokine Network and Sexual Human Immunodeficiency Virus Transmission in Men Who Have Sex With Men.","authors":"Christophe Vanpouille, Andrew Frick, Stephen A Rawlings, Martin Hoenigl, Andrea Lisco, Leonid Margolis, Sara Gianella","doi":"10.1093/cid/ciz1150","DOIUrl":"10.1093/cid/ciz1150","url":null,"abstract":"<p><strong>Background: </strong>Seminal human immunodeficiency virus (HIV) transmission from men to their partners remains the main driver of HIV epidemics worldwide. Semen is not merely a carrier of the virus, but also provides an immunological milieu that affects HIV transmission.</p><p><strong>Methods: </strong>We collected blood and semen from people with HIV whose epidemiologically linked sexual partners either did or did not acquire HIV. Viral transmission was confirmed by phylogenetic linkage (HIV pol). We measured the concentration of 34 cytokines/chemokines by Luminex in the blood and semen of 21 source partners who transmitted HIV (transmitters) and 22 who did not transmit HIV (nontransmitters) to their sexual partners. Differences between cytokine profiles in transmitters versus nontransmitters were analyzed using the multivariate statistical technique of partial least square discriminant analysis.</p><p><strong>Results: </strong>The cytokine profile in seminal fluid, but not in peripheral blood, was significantly different between men who have sex with men (MSM) who transmitted HIV and those who did not transmit HIV to their sexual partners (E = 19.77; P < .01). This difference persisted after excluding people with undetectable HIV RNA levels in nontransmitters.</p><p><strong>Conclusions: </strong>Seminal cytokine profiles correlated with transmission or nontransmission of HIV from the infected MSM to their partners, independently from seminal viral load. Seminal cytokine spectra might be a contributing determinant of sexual HIV transmission, thus providing new directions for the development of strategies aimed at preventing HIV transmission.</p>","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78177008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tuberculosis in Hospitalized Patients With Human Immunodeficiency Virus: Clinical Characteristics, Mortality, and Implications From the Rapid Urine-based Screening for Tuberculosis to Reduce AIDS Related Mortality in Hospitalized Patients in Africa.","authors":"Ankur Gupta-Wright, Katherine Fielding, Douglas Wilson, Joep J van Oosterhout, Daniel Grint, Henry C Mwandumba, Melanie Alufandika-Moyo, Jurgens A Peters, Lingstone Chiume, Stephen D Lawn, Elizabeth L Corbett","doi":"10.1093/cid/ciz1133","DOIUrl":"10.1093/cid/ciz1133","url":null,"abstract":"<p><strong>Background: </strong>Tuberculosis (TB) is the major killer of people living with human immunodeficiency virus (HIV) globally, with suboptimal diagnostics and management contributing to high case-fatality rates.</p><p><strong>Methods: </strong>A prospective cohort of patients with confirmed TB (Xpert MTB/RIF and/or Determine TB-LAM Ag positive) identified through screening HIV-positive inpatients with sputum and urine diagnostics in Malawi and South Africa (Rapid urine-based Screening for Tuberculosis to reduce AIDS Related Mortality in hospitalized Patients in Africa [STAMP] trial). Urine was tested prospectively (intervention) or retrospectively (standard of care arm). We defined baseline clinical phenotypes using hierarchical cluster analysis, and also used Cox regression analysis to identify associations with early mortality (≤56 days).</p><p><strong>Results: </strong>Of 322 patients with TB confirmed between October 2015 and September 2018, 78.0% had ≥1 positive urine test. Antiretroviral therapy (ART) coverage was 80.2% among those not newly diagnosed, but with median CD4 count 75 cells/µL and high HIV viral loads. Early mortality was 30.7% (99/322), despite near-universal prompt TB treatment. Older age, male sex, ART before admission, poor nutritional status, lower hemoglobin, and positive urine tests (TB-LAM and/or Xpert MTB/RIF) were associated with increased mortality in multivariate analyses. Cluster analysis (on baseline variables) defined 4 patient subgroups with early mortality ranging from 9.8% to 52.5%. Although unadjusted mortality was 9.3% lower in South Africa than Malawi, in adjusted models mortality was similar in both countries (hazard ratio, 0.9; P = .729).</p><p><strong>Conclusions: </strong>Mortality following prompt inpatient diagnosis of HIV-associated TB remained unacceptably high, even in South Africa. Intensified management strategies are urgently needed, for which prognostic indicators could potentially guide both development and subsequent use.</p>","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86365147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Efficacy of Fidaxomicin and Vancomycin in Children and Adolescents with Clostridioides (Clostridium) difficile Infection: A Phase 3, Multicenter, Randomized, Single-blind Clinical Trial (SUNSHINE).","authors":"Joshua Wolf, Krisztina Kalocsai, Claudia Fortuny, Stefan Lazar, Samantha Bosis, Bartosz Korczowski, Arnaud Petit, Daniel Bradford, Rodney Croos-Dabrera, Elodie Incera, Joost Melis, Rob van Maanen","doi":"10.1093/cid/ciz1149","DOIUrl":"10.1093/cid/ciz1149","url":null,"abstract":"<p><strong>Background: </strong>Fidaxomicin, a narrow-spectrum antibiotic approved for Clostridioides (Clostridium) difficile infection (CDI) in adults, is associated with lower rates of recurrence than vancomycin; however, pediatric data are limited. This multicenter, investigator-blind, phase 3, parallel-group trial assessed the safety and efficacy of fidaxomicin in children.</p><p><strong>Methods: </strong>Patients aged <18 years with confirmed CDI were randomized 2:1 to 10 days of treatment with fidaxomicin (suspension or tablets, twice daily) or vancomycin (suspension or tablets, 4 times daily). Safety assessments included treatment-emergent adverse events. The primary efficacy end point was confirmed clinical response (CCR), 2 days after the end of treatment (EOT). Secondary end points included global cure (GC; CCR without CDI recurrence) 30 days after EOT (end of study; EOS). Plasma and stool concentrations of fidaxomicin and its active metabolite OP-1118 were measured.</p><p><strong>Results: </strong>Of 148 patients randomized, 142 were treated (30 <2 years old). The proportion of participants with treatment-emergent adverse events was similar with fidaxomicin (73.5%) and vancomycin (75.0%). Of 3 deaths in the fidaxomicin arm during the study, none were CDI or treatment related. The rate of CCR at 2 days after EOT was 77.6% (76 of 98 patients) with fidaxomicin and 70.5% (31 of 44) with vancomycin, whereas the rate of GC at EOS was significantly higher in participants receiving fidaxomicin (68.4% vs 50.0%; adjusted treatment difference, 18.8%; 95% confidence interval, 1.5%-35.3%). Systemic absorption of fidaxomicin and OP-1118 was minimal, and stool concentrations were high.</p><p><strong>Conclusions: </strong>Compared with vancomycin, fidaxomicin was well tolerated and demonstrated significantly higher rates of GC in children and adolescents with CDI.</p><p><strong>Clinical trials registration: </strong>NCT02218372.</p>","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81994940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tuberculosis in Hospitalized Patients With Human Immunodeficiency Virus: Clinical Characteristics, Mortality, and Implications From the Rapid Urine-based Screening for Tuberculosis to Reduce AIDS Related Mortality in Hospitalized Patients in Africa.","authors":"Ankur Gupta-Wright, Katherine Fielding, Douglas Wilson, Joep J van Oosterhout, Daniel Grint, Henry C Mwandumba, Melanie Alufandika-Moyo, Jurgens A Peters, Lingstone Chiume, Stephen D Lawn, Elizabeth L Corbett","doi":"10.1093/cid/ciz1133","DOIUrl":"10.1093/cid/ciz1133","url":null,"abstract":"<p><strong>Background: </strong>Tuberculosis (TB) is the major killer of people living with human immunodeficiency virus (HIV) globally, with suboptimal diagnostics and management contributing to high case-fatality rates.</p><p><strong>Methods: </strong>A prospective cohort of patients with confirmed TB (Xpert MTB/RIF and/or Determine TB-LAM Ag positive) identified through screening HIV-positive inpatients with sputum and urine diagnostics in Malawi and South Africa (Rapid urine-based Screening for Tuberculosis to reduce AIDS Related Mortality in hospitalized Patients in Africa [STAMP] trial). Urine was tested prospectively (intervention) or retrospectively (standard of care arm). We defined baseline clinical phenotypes using hierarchical cluster analysis, and also used Cox regression analysis to identify associations with early mortality (≤56 days).</p><p><strong>Results: </strong>Of 322 patients with TB confirmed between October 2015 and September 2018, 78.0% had ≥1 positive urine test. Antiretroviral therapy (ART) coverage was 80.2% among those not newly diagnosed, but with median CD4 count 75 cells/µL and high HIV viral loads. Early mortality was 30.7% (99/322), despite near-universal prompt TB treatment. Older age, male sex, ART before admission, poor nutritional status, lower hemoglobin, and positive urine tests (TB-LAM and/or Xpert MTB/RIF) were associated with increased mortality in multivariate analyses. Cluster analysis (on baseline variables) defined 4 patient subgroups with early mortality ranging from 9.8% to 52.5%. Although unadjusted mortality was 9.3% lower in South Africa than Malawi, in adjusted models mortality was similar in both countries (hazard ratio, 0.9; P = .729).</p><p><strong>Conclusions: </strong>Mortality following prompt inpatient diagnosis of HIV-associated TB remained unacceptably high, even in South Africa. Intensified management strategies are urgently needed, for which prognostic indicators could potentially guide both development and subsequent use.</p>","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81851547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-Term Persistence of Spike Protein Antibody and Predictive Modeling of Antibody Dynamics After Infection With Severe Acute Respiratory Syndrome Coronavirus 2","authors":"L. Grandjean, Anja Saso, A. Ortiz, Tanya Lam, J. Hatcher, Rosie Thistlethwayte, M. Harris, T. Best, Marina Johnson, H. Wagstaffe, E. Ralph, Annabelle Mai, C. Colijn, J. Breuer, M. Buckland, K. Gilmour, D. Goldblatt","doi":"10.1101/2020.11.20.20235697","DOIUrl":"https://doi.org/10.1101/2020.11.20.20235697","url":null,"abstract":"Background: Antibodies to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) have been shown to neutralize the virus in-vitro. Similarly, animal challenge models suggest that neutralizing antibodies isolated from SARS-CoV-2 infected individuals prevent against disease upon re-exposure to the virus. Understanding the nature and duration of the antibody response following SARS-CoV-2 infection is therefore critically important. Methods: Between April and October 2020 we undertook a prospective cohort study of 3555 healthcare workers in order to elucidate the duration and dynamics of antibody responses following infection with SARS-CoV-2. After a formal performance evaluation against 169 PCR confirmed cases and negative controls, the Meso-Scale Discovery assay was used to quantify in parallel, antibody titers to the SARS-CoV-2 nucleoprotein (N), spike (S) protein and the receptor-binding-domain (RBD) of the S-protein. All seropositive participants were followed up monthly for a maximum of 7 months; those participants that were symptomatic, with known dates of symptom-onset, seropositive by the MSD assay and who provided 2 or more monthly samples were included in the analysis. Survival analysis was used to determine the proportion of sero-reversion (switching from positive to negative) from the raw data. In order to predict long-term antibody dynamics, two hierarchical longitudinal Gamma models were implemented to provide predictions for the lower bound (continuous antibody decay to zero, 'Gamma-decay') and upper bound (decay-to-plateau due to long lived plasma cells, 'Gamma-plateau') long-term antibody titers. Results: A total of 1163 samples were provided from 349 of 3555 recruited participants who were symptomatic, seropositive by the MSD assay, and were followed up with 2 or more monthly samples. At 200 days post symptom onset, 99% of participants had detectable S-antibody whereas only 75% of participants had detectable N-antibody. Even under our most pessimistic assumption of persistent negative exponential decay, the S-antibody was predicted to remain detectable in 95% of participants until 465 days [95% CI 370-575] after symptom onset. Under the Gamma-plateau model, the entire posterior distribution of S-antibody titers at plateau remained above the threshold for detection indefinitely. Surrogate neutralization assays demonstrated a strong positive correlation between antibody titers to the S-protein and blocking of the ACE-2 receptor in-vitro [R2=0.72, p<0.001]. By contrast, the N-antibody waned rapidly with a half-life of 60 days [95% CI 52-68]. Discussion: This study has demonstrated persistence of the spike antibody in 99% of participants at 200 days following SARS-CoV-2 symptoms and rapid decay of the nucleoprotein antibody. Diagnostic tests or studies that rely on the N-antibody as a measure of seroprevalence must be interpreted with caution. Our lowest bound prediction for duration of the spike antibody was 465 days and our upp","PeriodicalId":10421,"journal":{"name":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88374112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}