Browsing by Author "Steinbrink, Julie M"

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    Changing trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the pandemic.
    (American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2022-01) Heldman, Madeleine R; Kates, Olivia S; Safa, Kassem; Kotton, Camille N; Georgia, Sarah J; Steinbrink, Julie M; Alexander, Barbara D; Hemmersbach-Miller, Marion; Blumberg, Emily A; Multani, Ashrit; Haydel, Brandy; La Hoz, Ricardo M; Moni, Lisset; Condor, Yesabeli; Flores, Sandra; Munoz, Carlos G; Guitierrez, Juan; Diaz, Esther I; Diaz, Daniela; Vianna, Rodrigo; Guerra, Giselle; Loebe, Matthias; Rakita, Robert M; Malinis, Maricar; Azar, Marwan M; Hemmige, Vagish; McCort, Margaret E; Chaudhry, Zohra S; Singh, Pooja P; Hughes Kramer, Kailey; Velioglu, Arzu; Yabu, Julie M; Morillis, Jose A; Mehta, Sapna A; Tanna, Sajal D; Ison, Michael G; Derenge, Ariella C; van Duin, David; Maximin, Adrienne; Gilbert, Carlene; Goldman, Jason D; Lease, Erika D; Fisher, Cynthia E; Limaye, Ajit P; UW COVID-19 SOT Study Team
    Mortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020-June 19, 2020) and late 2020 (June 20, 2020-December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p < .001). Crude 28-day mortality decreased between the early and late periods (112/571 [19.6%] vs. 55/402 [13.7%]) and remained lower in the late period even after adjusting for baseline comorbidities (aOR 0.67, 95% CI 0.46-0.98, p = .016). Between the early and late periods, the use of corticosteroids (≥6 mg dexamethasone/day) and remdesivir increased (62/571 [10.9%] vs. 243/402 [61.5%], p < .001 and 50/571 [8.8%] vs. 213/402 [52.2%], p < .001, respectively), and the use of hydroxychloroquine and IL-6/IL-6 receptor inhibitor decreased (329/571 [60.0%] vs. 4/492 [1.0%], p < .001 and 73/571 [12.8%] vs. 5/402 [1.2%], p < .001, respectively). Mortality among SOTR hospitalized for COVID-19 declined between early and late 2020, consistent with trends reported in the general population. The mechanism(s) underlying improved survival require further study.
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    Delayed mortality among solid organ transplant recipients hospitalized for COVID-19.
    (Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2022-02) Heldman, Madeleine R; Kates, Olivia S; Safa, Kassem; Kotton, Camille N; Multani, Ashrit; Georgia, Sarah J; Steinbrink, Julie M; Alexander, Barbara D; Blumberg, Emily A; Haydel, Brandy; Hemmige, Vagish; Hemmersbach-Miller, Marion; La Hoz, Ricardo M; Moni, Lisset; Condor, Yesabeli; Flores, Sandra; Munoz, Carlos G; Guitierrez, Juan; Diaz, Esther I; Diaz, Daniela; Vianna, Rodrigo; Guerra, Giselle; Loebe, Matthias; Yabu, Julie M; Kramer, Kailey Hughes; Tanna, Sajal D; Ison, Michael G; Rakita, Robert M; Malinis, Maricar; Azar, Marwan M; McCort, Margaret E; Singh, Pooja P; Velioglu, Arzu; Mehta, Sapna A; van Duin, David; Goldman, Jason D; Lease, Erika D; Wald, Anna; Limaye, Ajit P; Fisher, Cynthia E; UW Covid-19 SOT Study Team

    Introduction

    Most studies of solid organ transplant (SOT) recipients with COVID-19 focus on outcomes within one month of illness onset. Delayed mortality in SOT recipients hospitalized for COVID-19 has not been fully examined.

    Methods

    We used data from a multicenter registry to calculate mortality by 90 days following initial SARS-CoV-2 detection in SOT recipients hospitalized for COVID-19 and developed multivariable Cox proportional-hazards models to compare risk factors for death by days 28 and 90.

    Results

    Vital status at day 90 was available for 936 of 1117 (84%) SOT recipients hospitalized for COVID-19: 190 of 936 (20%) died by 28 days and an additional 56 of 246 deaths (23%) occurred between days 29 and 90. Factors associated with mortality by day 90 included: age > 65 years [aHR 1.8 (1.3-2.4), p =<0.001], lung transplant (vs. non-lung transplant) [aHR 1.5 (1.0-2.3), p=0.05], heart failure [aHR 1.9 (1.2-2.9), p=0.006], chronic lung disease [aHR 2.3 (1.5-3.6), p<0.001] and body mass index ≥ 30 kg/m 2 [aHR 1.5 (1.1-2.0), p=0.02]. These associations were similar for mortality by day 28. Compared to diagnosis during early 2020 (March 1-June 19, 2020), diagnosis during late 2020 (June 20-December 31, 2020) was associated with lower mortality by day 28 [aHR 0.7 (0.5-1.0, p=0.04] but not by day 90 [aHR 0.9 (0.7-1.3), p=0.61].

    Conclusions

    In SOT recipients hospitalized for COVID-19, >20% of deaths occurred between 28 and 90 days following SARS-CoV-2 diagnosis. Future investigations should consider extending follow-up duration to 90 days for more complete mortality assessment.
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    Dysregulated transcriptional responses to SARS-CoV-2 in the periphery support novel diagnostic approaches.
    (medRxiv, 2020-07-26) McClain, Micah T; Constantine, Florica J; Henao, Ricardo; Liu, Yiling; Tsalik, Ephraim L; Burke, Thomas W; Steinbrink, Julie M; Petzold, Elizabeth; Nicholson, Bradly P; Rolfe, Robert; Kraft, Bryan D; Kelly, Matthew S; Sempowski, Gregory D; Denny, Thomas N; Ginsburg, Geoffrey S; Woods, Christopher W
    In order to elucidate novel aspects of the host response to SARS-CoV-2 we performed RNA sequencing on peripheral blood samples across 77 timepoints from 46 subjects with COVID-19 and compared them to subjects with seasonal coronavirus, influenza, bacterial pneumonia, and healthy controls. Early SARS-CoV-2 infection triggers a conserved transcriptomic response in peripheral blood that is heavily interferon-driven but also marked by indicators of early B-cell activation and antibody production. Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states. Heterogeneous activation of coagulation and fibrinolytic pathways are present in early COVID-19, as are IL1 and JAK/STAT signaling pathways, that persist into late disease. Classifiers based on differentially expressed genes accurately distinguished SARS-CoV-2 infection from other acute illnesses (auROC 0.95). The transcriptome in peripheral blood reveals unique aspects of the immune response in COVID-19 and provides for novel biomarker-based approaches to diagnosis.
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    Dysregulated transcriptional responses to SARS-CoV-2 in the periphery.
    (Nature communications, 2021-02-17) McClain, Micah T; Constantine, Florica J; Henao, Ricardo; Liu, Yiling; Tsalik, Ephraim L; Burke, Thomas W; Steinbrink, Julie M; Petzold, Elizabeth; Nicholson, Bradly P; Rolfe, Robert; Kraft, Bryan D; Kelly, Matthew S; Saban, Daniel R; Yu, Chen; Shen, Xiling; Ko, Emily M; Sempowski, Gregory D; Denny, Thomas N; Ginsburg, Geoffrey S; Woods, Christopher W
    SARS-CoV-2 infection has been shown to trigger a wide spectrum of immune responses and clinical manifestations in human hosts. Here, we sought to elucidate novel aspects of the host response to SARS-CoV-2 infection through RNA sequencing of peripheral blood samples from 46 subjects with COVID-19 and directly comparing them to subjects with seasonal coronavirus, influenza, bacterial pneumonia, and healthy controls. Early SARS-CoV-2 infection triggers a powerful transcriptomic response in peripheral blood with conserved components that are heavily interferon-driven but also marked by indicators of early B-cell activation and antibody production. Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states. Heterogeneous activation of coagulation and fibrinolytic pathways are present in early COVID-19, as are IL1 and JAK/STAT signaling pathways, which persist into late disease. Classifiers based on differentially expressed genes accurately distinguished SARS-CoV-2 infection from other acute illnesses (auROC 0.95 [95% CI 0.92-0.98]). The transcriptome in peripheral blood reveals both diverse and conserved components of the immune response in COVID-19 and provides for potential biomarker-based approaches to diagnosis.
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    The host transcriptional response to Candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approaches.
    (Genome medicine, 2021-07) Steinbrink, Julie M; Myers, Rachel A; Hua, Kaiyuan; Johnson, Melissa D; Seidelman, Jessica L; Tsalik, Ephraim L; Henao, Ricardo; Ginsburg, Geoffrey S; Woods, Christopher W; Alexander, Barbara D; McClain, Micah T

    Background

    Candidemia is one of the most common nosocomial bloodstream infections in the United States, causing significant morbidity and mortality in hospitalized patients, but the breadth of the host response to Candida infections in human patients remains poorly defined.

    Methods

    In order to better define the host response to Candida infection at the transcriptional level, we performed RNA sequencing on serial peripheral blood samples from 48 hospitalized patients with blood cultures positive for Candida species and compared them to patients with other acute viral, bacterial, and non-infectious illnesses. Regularized multinomial regression was utilized to develop pathogen class-specific gene expression classifiers.

    Results

    Candidemia triggers a unique, robust, and conserved transcriptomic response in human hosts with 1641 genes differentially upregulated compared to healthy controls. Many of these genes corresponded to components of the immune response to fungal infection, heavily weighted toward neutrophil activation, heme biosynthesis, and T cell signaling. We developed pathogen class-specific classifiers from these unique signals capable of identifying and differentiating candidemia, viral, or bacterial infection across a variety of hosts with a high degree of accuracy (auROC 0.98 for candidemia, 0.99 for viral and bacterial infection). This classifier was validated on two separate human cohorts (auROC 0.88 for viral infection and 0.87 for bacterial infection in one cohort; auROC 0.97 in another cohort) and an in vitro model (auROC 0.94 for fungal infection, 0.96 for bacterial, and 0.90 for viral infection).

    Conclusions

    Transcriptional analysis of circulating leukocytes in patients with acute Candida infections defines novel aspects of the breadth of the human immune response during candidemia and suggests promising diagnostic approaches for simultaneously differentiating multiple types of clinical illnesses in at-risk, acutely ill patients.
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    Validation of a Host Gene Expression Test for Bacterial/Viral Discrimination in Immunocompromised Hosts.
    (Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021-08) Mahle, Rachael E; Suchindran, Sunil; Henao, Ricardo; Steinbrink, Julie M; Burke, Thomas W; McClain, Micah T; Ginsburg, Geoffrey S; Woods, Christopher W; Tsalik, Ephraim L

    Background

    Host gene expression has emerged as a complementary strategy to pathogen detection tests for the discrimination of bacterial and viral infection. The impact of immunocompromise on host-response tests remains unknown. We evaluated a host-response test discriminating bacterial, viral, and noninfectious conditions in immunocompromised subjects.

    Methods

    An 81-gene signature was measured using real-time-polymerase chain reaction in subjects with immunocompromise (chemotherapy, solid-organ transplant, immunomodulatory agents, AIDS) with bacterial infection, viral infection, or noninfectious illness. A regularized logistic regression model trained in immunocompetent subjects was used to estimate the likelihood of each class in immunocompromised subjects.

    Results

    Accuracy in the 136-subject immunocompetent training cohort was 84.6% for bacterial versus nonbacterial discrimination and 80.8% for viral versus nonviral discrimination. Model validation in 134 immunocompromised subjects showed overall accuracy of 73.9% for bacterial infection (P = .04 relative to immunocompetent subjects) and 75.4% for viral infection (P = .30). A scheme reporting results by quartile improved test utility. The highest probability quartile ruled-in bacterial and viral infection with 91.4% and 84.0% specificity, respectively. The lowest probability quartile ruled-out infection with 90.1% and 96.4% sensitivity for bacterial and viral infection, respectively. Performance was independent of the type or number of immunocompromising conditions.

    Conclusions

    A host gene expression test discriminated bacterial, viral, and noninfectious etiologies at a lower overall accuracy in immunocompromised patients compared with immunocompetent patients, although this difference was only significant for bacterial infection classification. With modified interpretive criteria, a host-response strategy may offer clinically useful diagnostic information for patients with immunocompromise.