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  • 1
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    472. Corticosteroid Exposure as a Risk Factor for Pneumocystis jirovecii Pneumonia Mortality in HIV-Negative Patients: A Multicenter Retrospective Case-Control Study with a Global Research Network Validation
    Oxford University Press (OUP) ; 2022
    In:  Open Forum Infectious Diseases Vol. 9, No. Supplement_2 ( 2022-12-15)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 9, No. Supplement_2 ( 2022-12-15)
    Abstract: HIV-negative patients have higher mortality from PJP compared to patients with HIV, however, we lack data on predictors of PJP-associated mortality in HIV-negative patients. We aim to characterize the role of previous corticosteroid exposure in PJP-related mortality. Methods A multicenter retrospective case-control study was performed on HIV-negative patients tested for PJP within the UCHealth system from 2000 to 2021. Cox proportional-hazards model was used for survival analysis. We queried TrinetX, a global research network, to validate mortality risk differences among HIV-negative patients with PJP with prior corticosteroid exposure versus those without. We used propensity score matching to assess independent corticosteroid risk of 1-year mortality. Results We identified 105 cases of PJP and 71 controls without PJP. HIV-negative patients with steroid exposure in the previous 6 months were more likely to have a history of malignancy (26.5% vs 11.9%, p=0.026), solid organ transplant (14.8% vs 3.4%, p=0.023), inflammatory disease (27.6% vs 8.5%, p=0.03), or use of other immunosuppressive drugs (83.8% vs 13.6%, p & lt; 0.0001). The median prednisone equivalent dose was higher in patients who died at 7 weeks (33.7 vs. 21.5 mg/d) and 1 year (33.7 vs. 20 mg/d). Adjusted Cox proportional-hazard model found an increased rate of death at 10 weeks (HR: 3.8, CI: 1.6-9.26, p=0.003)(Figure 1) and 1 year (HR: 4.8, CI: 2.2-10.7, p & lt; 0.0001) among patients previously on steroids. A TrinetX-based propensity score matching of 2176 HIV-negative patients found a significantly increased 1-year mortality (OR: 1.9 CI: 1.6-2.2, p & lt; 0.0001) after PJP diagnoses in the group with corticosteroid exposure in the previous year compared to those with PJP without corticosteroid exposure. The mean β-d-glucan (203±154 vs. 82± 35.8 pg/mL, p=0.025) and ferritin levels (1591±5576 vs. 1041± 1300 mcg/L, p=0.02) were higher in those with prior steroid use. Figure 1.Adjusted 70-days mortality among HIV negative patients with PJP by corticosteroid exposure Conclusion HIV-negative patients with PJP and corticosteroid use preceding diagnosis have higher mortality than those without corticosteroid use. A higher fungal burden may influence corticosteroid mediated mortality. Disclosures All Authors: No reported disclosures.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofac492.530
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2757767-3
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  • 2
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    Clinical, hematologic, and immunologic effects of interleukin-10 in humans
    Springer Science and Business Media LLC ; 1996
    In:  Journal of Clinical Immunology Vol. 16, No. 5 ( 1996-09), p. 291-303
    Details
    In: Journal of Clinical Immunology, Springer Science and Business Media LLC, Vol. 16, No. 5 ( 1996-09), p. 291-303
    Type of Medium: Online Resource
    ISSN: 0271-9142 , 1573-2592
    URL: Article
    DOI: 10.1007/BF01541395
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1996
    detail.hit.zdb_id: 2016755-6
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  • 3
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    Previous corticosteroid exposure associates with an increased Pneumocystis jirovecii pneumonia mortality among HIV-negative patients: a global research network with a follow-up multicenter case-control study
    SAGE Publications ; 2023
    In:  Therapeutic Advances in Infectious Disease Vol. 10 ( 2023-01), p. 204993612311594-
    Details
    In: Therapeutic Advances in Infectious Disease, SAGE Publications, Vol. 10 ( 2023-01), p. 204993612311594-
    Abstract: HIV-negative patients have substantial mortality from Pneumocystis jirovecii pneumonia (PJP). We lack predictors of HIV-negative PJP-associated mortality. Objective: We aim to characterize the role of prior corticosteroid exposure in PJP-related mortality. Methods: We queried a global research network to identify adult HIV-negative patients with PJP with or without corticosteroid exposure in the preceding year before diagnosis ( n = 8,021). We performed a propensity score-matched analysis to adjust baseline patient characteristics and analyzed outcomes. We follow-up the results with a multicenter ten years retrospective case-control cohort of HIV-negative patients tested for PJP by PCP Direct Fluorescent Antigen. We used a Cox proportional hazards model for survival analysis. Results: 1822 HIV-negative propensity-scored matched patients with prior corticosteroid exposure had significantly increased 10 weeks (16% versus 9%, p  〈  0.0001) and one-year mortality after PJP diagnosis (23% versus 14%, p  〈  0.0001). (1→3)-β-D-glucan (197.6 ± 155.8 versus 63 ± 0 pg/ml, p = 0.014), ferritin levels (1227 ± 2486 versus 768 ± 1060 mcg/l, p = 0.047), lymphopenia (1.5 ± 1.5 versus 2.0 ± 1.6 10 3 cells/µl, p  〈  0.0001) and hypoxia (SatO 2 : 86.7% versus 91.6%, p  〈  0.0001) were higher or worse in those with prior steroid use. Patients who died were more likely to have previously received dexamethasone (35% versus 16%, p  〈  0.001) or prednisone (49% versus 29%, p  〈  0.001). Adjusted Cox proportional-hazard model validation showed an independently increased mortality at 10 weeks (HR: 3.7, CI: 1.5–9.2, p = 0.004) and 1 year (HR: 4.5, CI: 2.0–10.4, p  〈  0.0001) among HIV-negative patients with previous corticosteroid exposure. Conclusion: Preceding corticosteroids in HIV-negative patients with PJP are associated with higher mortality. A higher fungal burden may influence corticosteroid-mediated mortality. Assessment of PJP prophylaxis must become a standard clinical best practice when instituting corticosteroid therapy courses.
    Type of Medium: Online Resource
    ISSN: 2049-9361 , 2049-937X
    URL: Article
    DOI: 10.1177/20499361231159481
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2023
    detail.hit.zdb_id: 2728410-4
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  • 4
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    356. Risk Assessment of Pneumocystis jirovecii Pneumonia among Hospitalized Patients with Hypoxic Respiratory Failure - A Proposed Multivariable Calculator Based on Previous Prednisone Equivalent Dose
    Oxford University Press (OUP) ; 2022
    In:  Open Forum Infectious Diseases Vol. 9, No. Supplement_2 ( 2022-12-15)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 9, No. Supplement_2 ( 2022-12-15)
    Abstract: Corticosteroids increase the risk of Pneumocystis jirovecii pneumonia (PJP). It is unknown how much corticosteroid dose exposure would modify the risk of PJP in different populations. We aim to develop a PJP risk calculator based on the previous dose of corticosteroids and modulated by additional clinical factors. Methods A multicenter retrospective case-control study was performed on patients tested for PJP within the UCHealth system from 2000 to 2021. We developed a model for estimating PJP risk based on previous prednisone equivalent daily dose (PEDD) and adjustable for additional clinical variables. PJP was fit to a generalized additive model (GAM), with a spline for prednisone dose and additive covariates for demographics and risk factors. We used a multicenter federated network to calibrate the model to estimate the PJP prevalence among hospitalized patients with hypoxic respiratory failure. Results We had a complete sample of 199 patients, 104 cases with PJP, and 95 controls. Patients with HIV (OR: 19 CI: 6.3-60.8, p & lt; 0.0001), diabetes (OR: 4.1 CI: 1.2-14.8, p & lt; 0.0288), and autoimmune disease (OR: 5.2 CI: 1.4-19.2, p & lt; 0.0139) were more likely to have PJP. Patients with preexisting lung disease (OR: 0.3 CI: 0.1-0.6, p & lt; 0.0041) and on PJP prophylaxis (OR: 0.06 CI: 0.02-0.2, p & lt; 0.0001) were less likely to have PJP. 36.8% of controls and 49% of cases were on steroids with a mean PEDD of 15 mg/day and 20.4 mg/day, respectively. We found a prevalence of PJP of 0.126% among hospitalized patients with hypoxic respiratory failure. The developed model can estimate the PJP risk based on a previous PEDD in 32 different clinical combinations: e.g., a PEDD of 20 mg/day would give a calculated annual PJP risk of approximately 1.74% (95% CI: [0.39, 7.42]) if a patient has autoimmune disease only but 6.29% (95% CI: [1.34, 24.91] ) if a patient has HIV only (Figure 1). Figure 1.Predicted probability of PJP based on previous prednisone dose among hospitalized patients with hypoxic respiratory failure for three different clinical scenarios Conclusion Previous corticosteroid dose alone is inadequate to inform of an increased risk of PJP. A multivariable calculator incorporating the absence or presence of additional traditional risk factors could optimally stratify the PJP risk. Future directions include validating the findings in external cohorts and modeling PJP risk in the ambulatory setting to inform the need for PJP prophylaxis. Disclosures All Authors: No reported disclosures.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofac492.434
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2757767-3
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  • 5
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    Lower Mortality Associated With Adjuvant Corticosteroid Therapy in Non-HIV-Infected Patients With Pneumocystis jirovecii Pneumonia: A Single-Institution Retrospective US Cohort Study
    Oxford University Press (OUP) ; 2020
    In:  Open Forum Infectious Diseases Vol. 7, No. 9 ( 2020-09-01)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 7, No. 9 ( 2020-09-01)
    Abstract: Pneumocystis jirovecii pneumonia (PJP) remains a cause of mortality in HIV-negative patients. The clinical benefit of adjuvant corticosteroids in these patients is uncertain. This study aimed to determine if corticosteroids would reduce mortality in a cohort of HIV-negative PJP patients. Methods We examined a retrospective case series of patients diagnosed with PJP at the University of Colorado Hospital between 1995 and 2019. Data were collected in 71 PJP-infected patients. Twenty-eight patients were HIV-negative, and 43 were infected with HIV. We performed bivariate and forward, stepwise multivariable logistic regressions to identify mortality predictors. Results Common underlying conditions in HIV-negative patients were hematologic malignancies (28.6%), autoimmune disorders (25.9%), and solid organ transplantation (10.7%). HIV-negative patients had higher rates and durations of mechanical ventilation and intensive care unit stay. Survival was significantly increased in HIV-negative patients receiving adjuvant corticosteroids, with 100% mortality in patients not receiving corticosteroids vs 60% mortality in patients receiving corticosteroids (P = .034). In an adjusted multivariable model, no adjuvant corticosteroid use was associated with higher mortality (odds ratio, 13.5; 95% CI, 1.1–158.5; P = .039) regardless of HIV status. Conclusions We found substantial mortality among HIV-negative patients with PJP, and adjuvant corticosteroid use was associated with decreased mortality. Response to corticosteroids is best established in HIV-infected patients, but emerging reports suggest a similar beneficial response in PJP patients without HIV infection. Further prospective studies may establish a more definitive role of the addition of corticosteroids among HIV-negative patients with PJP.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofaa354
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 6
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    Patients with Nontuberculous Mycobacterial Lung Disease Exhibit Unique Body and Immune Phenotypes
    American Thoracic Society ; 2013
    In:  American Journal of Respiratory and Critical Care Medicine Vol. 187, No. 2 ( 2013-01-15), p. 197-205
    Details
    In: American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, Vol. 187, No. 2 ( 2013-01-15), p. 197-205
    Type of Medium: Online Resource
    ISSN: 1073-449X , 1535-4970
    URL: Article
    DOI: 10.1164/rccm.201206-1035OC
    RVK:
    XA 21200
    Language: English
    Publisher: American Thoracic Society
    Publication Date: 2013
    detail.hit.zdb_id: 1468352-0
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  • 7
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    α1-Antitrypsin Therapy Downregulates Toll-Like Receptor-Induced IL-1β Responses in Monocytes and Myeloid Dendritic Cells and May Improve Islet Function in Recently Diagnosed Patients With Type 1 Diabetes
    The Endocrine Society ; 2014
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 99, No. 8 ( 2014-08-01), p. E1418-E1426
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 99, No. 8 ( 2014-08-01), p. E1418-E1426
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2013-3864
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2014
    detail.hit.zdb_id: 2026217-6
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  • 8
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    419. Diagnostic Utility of a Ferritin to Procalcitonin Ratio to Differentiate Patients with COVID-19 from Those with Bacterial Pneumonia
    Oxford University Press (OUP) ; 2020
    In:  Open Forum Infectious Diseases Vol. 7, No. Supplement_1 ( 2020-12-31), p. S277-S277
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 7, No. Supplement_1 ( 2020-12-31), p. S277-S277
    Abstract: Accurate, rapid, inexpensive biomarkers are needed to differentiate COVID-19 from bacterial pneumonia, allowing effective treatment and antibiotic stewardship. We hypothesized that the ratio of ferritin to procalcitonin (F/P) reflects greater viral activity and host response with COVID-19 pneumonia, while bacterial pneumonia would be associated with less cytolysis (lower ferritin) and more inflammation (higher procalcitonin), thus a lower F/P ratio. Methods We conducted a retrospective study of adult patients admitted to a single University hospital in the US through May 2020, during the COVID-19 pandemic. We compared F/P ratio of patients diagnosed with COVID-19 or bacterial pneumonia, excluding patients with COVID-19 and bacterial co-infections. In a logistic regression, we controlled for age, sex, body mass index (BMI), diabetes (DM), and hypertension (HTN). We used a receiver operating characteristic analysis to calculate the sensitivity and specificity of F/P values for the diagnosis of COVID-19 versus bacterial pneumonia. Results Of 218 patients with COVID-19 and 17 with bacterial pneumonia, COVID-19 patients were younger (56 vs 66 years, p=0.04), male (66% vs 24%, p=0.009), had higher BMI (31 vs 27 kg/m2, p=0.03), and similar rates of HTN (59% vs 45%, p=0.3) and DM (32% vs 18%, p=0.2). The median F/P ratio was significantly higher in patients with COVID-19 (3195 vs 860, p=0.0003, Figure 1). An F/P ratio cut-off of ≥ 1250 generated a sensitivity of 78% and a specificity of 59% to correctly classify a COVID-19 case (Figure 2). When adjusted for age, gender, BMI, DM, and HTN, a ratio ≥ of 1250 was associated with significantly greater odds of COVID-19 versus bacterial pneumonia (OR: 4.9, CI: 1.5, 16.1, p=0.009). Figure 1. Ferritin to Procalcitonin Ratios of patients with COVID-19 and patients with Bacterial Pneumonia (controls). Figure 2. Receiver Operating Characteristic Analysis of Ferritin to Procalcitonin Ratio Cut-off Values Predicting COVID-19 Diagnosis. Conclusion We observed an elevated F/P ratio in patients with COVID-19 compared to those with bacterial pneumonia. A F/P ratio ≥ 1250 provides a clinically relevant increase in pre-test probability of COVID-19. Prospective studies evaluating the discriminatory characteristics of F/P ratio in larger cohorts is warranted. Disclosures All Authors: No reported disclosures
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofaa439.613
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2757767-3
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  • 9
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    Diagnostic Utility of a Ferritin-to-Procalcitonin Ratio to Differentiate Patients With COVID-19 From Those With Bacterial Pneumonia: A Multicenter Study
    Oxford University Press (OUP) ; 2021
    In:  Open Forum Infectious Diseases Vol. 8, No. 6 ( 2021-06-01)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 8, No. 6 ( 2021-06-01)
    Abstract: There is an urgent need for accurate, rapid, inexpensive biomarkers that can differentiate coronavirus disease 2019 (COVID-19) from bacterial pneumonia. We assess the role of the ferritin-to-procalcitonin (F/P) ratio to classify pneumonia cases into those due to COVID-19 vs those due to bacterial pathogens. Methods This multicenter case–control study compared patients with COVID-19 with those with bacterial pneumonia, admitted between March 1 and May 31, 2020. Patients with COVID-19 and bacterial pneumonia co-infection were excluded. The F/P in patients with COVID-19 vs with bacterial pneumonia were compared. Receiver operating characteristic curve analysis determined the sensitivity and specificity of various cutoff F/P values for COVID-19 vs bacterial pneumonia. Results A total of 242 COVID-19 pneumonia cases and 34 bacterial pneumonia controls were included. Patients with COVID-19 pneumonia had a lower mean age (57.1 vs 64.4 years; P = .02) and a higher body mass index (30.74 vs 27.15 kg/m2; P = .02) compared with patients with bacterial pneumonia. Cases and controls had a similar proportion of women (47% vs 53%; P = .5), and COVID-19 patients had a higher prevalence of diabetes mellitus (32.6% vs 12%; P = .01). The median F/P was significantly higher in patients with COVID-19 (4037.5) compared with the F/P in bacterial pneumonia (802; P  & lt; .001). An F/P ≥877, used to diagnose COVID-19, resulted in a sensitivity of 85% and a specificity of 56%, with a positive predictive value of 93.2% and a likelihood ratio of 1.92. In multivariable analyses, an F/P ≥877 was associated with greater odds of identifying a COVID-19 case (odds ratio, 11.27; 95% CI, 4–31.2; P  & lt; .001). Conclusions An F/P ≥877 increases the likelihood of COVID-19 pneumonia compared with bacterial pneumonia.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofab124
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2757767-3
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  • 10
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    α1-Antitrypsin monotherapy prolongs islet allograft survival in mice
    Proceedings of the National Academy of Sciences ; 2005
    In:  Proceedings of the National Academy of Sciences Vol. 102, No. 34 ( 2005-08-23), p. 12153-12158
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 34 ( 2005-08-23), p. 12153-12158
    Abstract: Islet transplantation for type 1 diabetic patients shows promising results with the use of nondiabetogenic immunosuppressive therapy. However, in addition to compromising the immune system of transplant recipients, long-term studies demonstrate that islet viability is impaired. Here, we demonstrate that, in the absence of immunosuppressive agents, monotherapy with clinical-grade human α1-antitrypsin (hAAT), the major serum serine-protease inhibitor, prolongs islet graft survival and normoglycemia in transplanted allogeneic diabetic mice, lasting until the development of anti-hAAT antibodies. Compared to untreated or albumin-control-treated graft recipients, which rejected islets at day 10, AAT-treated mice displayed diminished cellular infiltrates and intact intragraft insulin production throughout treatment. Using peritoneal infiltration models, we demonstrate that AAT decreases allogeneic fibroblast-elicited natural-killer-cell influx by 89%, CD3-positive cell influx by 44%, and thioglycolate-elicited neutrophil emigration by 66%. ATT also extended islet viability in mice after streptozotocin-induced beta cell toxicity. In vitro , several islet responses to IL-1β/IFNγ stimulation were examined. In the presence of AAT, islets displayed enhanced viability and inducible insulin secretion. Islets also released 36% less nitric oxide and 82% less macrophage inflammatory protein 1 α and expressed 63% fewer surface MHC class II molecules. TNFα release from IL-1β/IFNγ-stimulated islet cells was reduced by 99%, accompanied by an 8-fold increase in the accumulation of membrane TNFα on CD45-positive islet cells. In light of the established safety record and the nondiabetogenic potential of AAT, these data suggest that AAT may be beneficial as adjunctive therapy in patients undergoing islet transplantation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0505579102
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2005
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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