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Principal Investigator: Sameer Kadri
Organization: CLINICAL CENTER
Fiscal Year: 2024
Funding agency: NIH Clinical Center
Critical illness and sepsis (including critical disease from COVID-19) are associated with significant morbidity and mortality, especially in conditions where existing therapeutic strategies remain suboptimal. Our primary aim is to leverage large repositories of granular clinical data to better understand the clinical epidemiology of critical illness, sepsis and serious infections, including defining illness burden, risk factors and clinical impact.
The pathophysiology of organ dysfunction in streptococcal infection is attributed to inflammation mediated by exotoxin-mediated cytokine cascade. Clindamycin neutralizes exotoxin released by Group A Streptococcus. In a large propensity-matched cohort of patients we found that clindamycin added as an adjunct to beta lactam therapy was associated with improved survival in Group A streptococcal infection but also identified a trend toward harm when used in non-Group A, Group B streptococcal infections. These findings warrant confirmation in randomized trials.
Antibiotic overuse remains a significant problem in the critically ill and is associated with toxicity and development of antimicrobial resistance. Among critically ill patients with suspected or confirmed sepsis in a larger cohort of US hospitals, we found that use of procalcitonin significantly reduced duration of antibiotic use without worsening outcomes. We confirmed these findings in a meta-analysis of randomized controlled trials. We also described real world use patterns of this biomarker using large an enhanced administrative dataset and studied its performance characteristics in patients with suspected bloodstream infection.
Most estimates of sepsis incidence and mortality in existing literature are estimated using claims data. Unfortunately claims based data are subject to a variety of biases. We estimate 10-year trends in the incidence and outcome of septic shock using clinical indicators in a cohort of academic medical centers in the United States and compared it to estimates obtained using claims based data. We found that the prevalence of septic shock was rising and mortality declining over time, albeit, both less vigorously than suggested by claims based methods. In addition, we identified obesity as being associated with better outcomes in more than 50,000 patients with clinical indicators of sepsis at US hospitals. In collaboration with investigators at Harvard Medical School, we were able to study the differences in characteristics and outcomes of sepsis that originates in the community versus the hospital as well as studied variation in identifying sepsis and organ dysfunction using claims versus electronic health records. Along with the same group, we were able to assess how a severity score performs to identify patients with undifferentiated sepsis.
In collaboration with investigators at Harvard Department of Population Medicine, we found that models incorporating electronic health record data accurately predict hospital mortality for patients who meet an operational definition of sepsis based on clinical indicators and outperforms models using administrative data alone. This operational definition may enable more meaningful comparisons of hospital sepsis outcomes and provide an important window into quality of care. We also found that incorporating clinical data into risk adjustment substantially changes rankings of hospitals' sepsis mortality rates compared with using administrative data alone. Comprehensive risk adjustment using both administrative and clinical data is necessary before comparing hospitals by sepsis mortality rates. Our study on short stays for sepsis underscore the incomplete uptake of Sepsis-3 definitions, the breadth of illness severities encompassed by both traditional and new sepsis definitions, and the possibility that some patients with sepsis recover very rapidly. Our study on association between opioid use and sepsis highlight the disproportionately high mortality burden associated with younger opioid users developing sepsis. With this group, we also identified potential biases in time-to-antibiotic studies in sepsis.
As part of the ICU-CAR initiative, a research group of critical care and oncology providers, we participated in a study that surveyed clinicians from multiple ICUs in the US caring for patients with hematologic malignancies receiving T-cell directed therapy to understand prevailing practices around the management of cytokine release syndrome T Cell toxicities. Immune suppressed patients often develop invasive candidiasis. We used this entity as a proof of concept to show how machine learning can capture risk factors for infectious diseases of interest.
In collaboration with the CDC, we found that hospital surges are detrimental to survival for patients admitted with COVID-19. With the CDC group, we also found that risk of hospital-onset COVID-19 increases in the setting of high community transmission. In collaboration with a Canadian research group, we found that surges were particularly detrimental for non-COVID patients with conditions that tend to require the same healthcare resources as patients with COVID-19. With investigator from the same group, we found that vaccine booster doses were associated with improved outcomes in vaccinated patients with COVID-19 who were admitted to the ICU. We also found that the risk of COVID-19 reinfection remained low up to 9 months since index infection but our findings do not include the period where variants of concern were prevalent in the U.S. We found that hydroxychloroquine use fell sharply even before the emergency use authorization for this drug was revoked. We also found that corticosteroids were being used frequently in ventilated COVID-19 patients well before its benefit was publicly known from clinical trials. We found that inter hospital transport of patients with lower respiratory tract infections during the pandemic was just as safe as compared to during pre-pandemic times. We also found that the SOFA score, an acute severity score was a poor predictor of mortality in intubated patients with COVID-19, and yet most US States use it in their Crisis Standards of Care ventilator triage algorithms were heavily weighted by the SOFA score. We completed an investigation to test whether the modified 4 C score, a COVID-19 specific severity score performs adequately in a surge setting and over time, to test its candidacy for triage algorithms. We studied various strain metrics used during the pandemic and found that 37 unique metrics were used across 39 studies highlighting the heterogeneity in strain definitions and highlighting the need for a consensus metric. We also found that during widespread patient surges, there was overall decreased patient movement between hospitals and rural (vs urban) small hospitals encountered difficulty in expanding their transfer capabilities during the pandemic highlighting prevailing disparities in healthcare delivery in different parts of the country.
Terms: <Academic Medical Centers><Acute><Admission><Admission activity><Adrenal Cortex Hormones><Alberta><Alberta province><Algorithms><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antimicrobial Resistance><B.1.1.529><BMI><BMI percentile><BMI z-score><Bacterial Infections><Big Data><BigData><Biological Markers><Body mass index><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 crisis><COVID-19 death><COVID-19 epidemic><COVID-19 era><COVID-19 fatality><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infected patient><COVID-19 infection><COVID-19 mortality><COVID-19 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 related risk><COVID-19 risk><COVID-19 risk factor><COVID-19 virus infection><COVID-19 years><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 patient><COVID19 positive patient><COVID19 related death><COVID19 related fatality><COVID19 related mortality><CV-19><Canada><Candidiasis><Candidosis><Cardiac><Caring><Characteristics><Chlolincocin><Chlorlincocin><Circulatory Collapse><Clindamycin><Clinical><Clinical Data><Clinical Trials><Code><Coding System><Collaborations><Communicable Diseases><Communities><Consensus><Coronavirus Infectious Disease 2019><Corticoids><Corticosteroids><Country><Critical Care><Critical Illness><Critically Ill><Data><Data Set><Death Rate><Development><Disease><Disorder><Dose><Drugs><Dysfunction><Electronic Health Record><Epidemiological data><Epidemiology><Epidemiology data><Exotoxins><FDA EUA><FDA Emergency Use Authorization><Food and Drug Administration EUA><Food and Drug Administration Emergency Use Authorization><Frequencies><Functional disorder><Generations><Healthcare><Healthcare Delivery><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Heterogeneity><Hospital Admission><Hospital Mortality><Hospitalization><Hospitals><Hydroxychlorochin><Hydroxychloroquine><IGIV><IV Immunoglobulins><IVIG><Immune><Immune globulin IV><Immunes><In-house Mortalities><Incidence><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inhospital Mortality><Intravenous Antibodies><Intravenous IG><Intravenous Immune Globulin><Intravenous Immunoglobulins><Intubation><Investigation><Investigators><Literature><Lower Respiratory Tract Infection><Lower respiratory infection><Lung damage><Machine Learning><Malignant Hematologic Neoplasm><Measures><Mediating><Medication><Medicine><Meta-Analysis><Methods><Miscellaneous Antibiotic><Modeling><Moniliasis><Morbidity><Morbidity - disease rate><Mortality Decline><Movement><Necrotizing fasciitis><Obesity><Observation research><Observation study><Observational Study><Observational research><Omicron variant><Oncology><Oncology Cancer><Ontario><Opiate user><Opioid drug user><Organ><Outcome><Outcome Study><Oxychlorochin><Oxychloroquine><PWUO><Patient Admission><Patient Care><Patient Care Delivery><Patient Transfer><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pattern><Performance><Pharmaceutical Preparations><Physiopathology><Population><Prevalence><Provider><Publishing><QOC><Quality of Care><Quetelet index><Randomization trial><Randomized, Controlled Trials><Research><Research Personnel><Research Resources><Researchers><Resources><Risk><Risk Adjustment><Risk Factors><Rural><S agalactiae><S pyogenes><S. agalactiae><S. pyogenes><SARS-CoV-2 B.1.1.529><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 epidemic><SARS-CoV-2 fatality><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 omicron><SARS-CoV-2 omicron variant><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV2 infection><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Sepsis><Septic Shock><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severities><Severity of illness><Shock><Streptococcal Infections><Streptococcus Group A><Streptococcus Group B><Streptococcus agalactiae><Streptococcus infection><Streptococcus pyogenes><Survey Instrument><Surveys><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><Testing><Therapeutic><Time><Toxic effect><Toxicities><Triage><US State><Undifferentiated><United States><University Medical Centers><Vaccination><Vaccinee><Validation><Variant><Variation><Vasoactive Agonists><Vasoconstrictor Agents><Vasoconstrictor Drugs><Vasoconstrictors><Vasopressor Agents><Ventilator><adiposity><adoptive T cell transfer><adoptive T-cell therapy><anti-microbial resistant><bacteria infection><bacterial disease><beta lactam antibiotic><beta-Lactams><bio-markers><biologic marker><biomarker><blood infection><bloodstream infection><body movement><booster dose><booster shot><booster vaccine><burden of disease><burden of illness><calcitonin precursor polyprotein><care for patients><care of patients><caring for patients><circulatory shock><clinical epidemiology><cohort><community spread><community transmission><community-level spread><community-level transmission><coronavirus disease 2019><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 crisis><coronavirus disease 2019 death><coronavirus disease 2019 epidemic><coronavirus disease 2019 fatality><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 risk><coronavirus disease 2019 risk factor><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 mortality><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus infectious disease-19><coronavirus patient><corpulence><cost><cytokine><cytokine release syndrome><cytokine storm><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><death risk><depository><developmental><disease burden><disease severity><disparity in care><disparity in healthcare><drug repositioning><drug repurposing><drug/agent><electronic health care record><electronic health medical record><electronic health plan record><electronic health registry><electronic medical health record><emergency use authorization><epidemiologic><epidemiologic data><epidemiological><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><health and care delivery><health care><health care delivery><health care disparity><health care inequality><health care inequity><health delivery systems><health services delivery><healthcare disparity><healthcare inequality><healthcare inequity><improved><improved outcome><indexing><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><infection rate><interest><lung injury><machine based learning><medical college><medical schools><mortality><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><mortality rate><mortality ratio><mortality risk><omicron variant of COVID-19><omicron variant of SARS-CoV-2><opiate consumption><opiate drug use><opiate intake><opiate use><opioid consumption><opioid drug use><opioid intake><opioid use><opioid user><pandemic><pandemic disease><pathophysiology><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient oriented outcomes><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><people who use opioids><persons who use opioids><pre-pandemic><pro-calcitonin><procalcitonin><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><randomized control trial><randomized trial><rate of infection><repository><repurposing agent><repurposing medication><resistance to anti-microbial><resistant to antimicrobial><respiratory><risk associated with COVID-19><risk factor associated with COVID-19><risk factor related to COVID-19><risk related to COVID-19><school of medicine><severe acute respiratory syndrome coronavirus 2 B.1.1.529><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><shocks><smoke inhalation><systematic review><therapeutic T-cell platform><thymus derived lymphocyte><trend><uptake><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><vaccine boost><validations><variants of concern><vasopressor><ventilation><β lactam antibiotic><β-Lactams>