ICU-like Care of Nonhuman Primates with Ebola Virus Disease

Abstract Background Ebola virus disease (EVD) supportive care strategies are largely guided by retrospective observational research. This study investigated the effect of EVD supportive care algorithms on duration of survival in a controlled nonhuman primate (NHP) model. Methods Fourteen rhesus macaques were challenged intramuscularly (IM) with a target dose of 1000 PFU Zaire ebolavirus (Kikwit). NHPs were allocated to intensive care unit (ICU)-like algorithms (n=7), intravenous fluids (IVF) plus levofloxacin (n=2), or a control group (n=5). The primary outcome measure was duration of survival, and secondary outcomes included changes in clinical laboratory values. Results Duration of survival was not significantly different between the pooled ICU-like algorithm and control groups (8.2 vs 6.9 days of survival, hazard ratio 0.50, p = 0.25). Norepinephrine was effective in transiently maintaining baseline blood pressure. NHPs treated with ICU-like algorithms had delayed onset of liver and kidney injury. Conclusions While an obvious survival difference was not observed with ICU-like care, clinical observations from this model may aid in EVD supportive care NHP model refinement.

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The evolution of supportive care for Ebola virus disease

The Lancet ◽

10.1016/s0140-6736(19)30242-9 ◽

2019 ◽

Vol 393 (10172) ◽

pp. 620-621 ◽

Cited By ~ 9

Author(s):

François Lamontagne ◽

Christophe Clément ◽

Richard Kojan ◽

Mélanie Godin ◽

Patricia Kabuni ◽

...

Keyword(s):

Supportive Care ◽

Ebola Virus ◽

Virus Disease ◽

Ebola Virus Disease

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Peripheral Neuronopathy Associated With Ebola Virus Infection in Rhesus Macaques: A Possible Cause of Neurological Signs and Symptoms in Human Ebola Patients

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa304 ◽

2020 ◽

Vol 222 (10) ◽

pp. 1745-1755

Author(s):

David X Liu ◽

Donna L Perry ◽

Timothy K Cooper ◽

Louis M Huzella ◽

Randy J Hart ◽

...

Keyword(s):

Ebola Virus ◽

Neuronal Degeneration ◽

Virus Disease ◽

Rhesus Macaques ◽

Signs And Symptoms ◽

Ebola Virus Disease ◽

Target Cells ◽

Neurological Signs ◽

Enteric Ganglia ◽

Transmission Electron

Abstract Neurological signs and symptoms are the most common complications of Ebola virus disease. However, the mechanisms underlying the neurologic manifestations in Ebola patients are not known. In this study, peripheral ganglia were collected from 12 rhesus macaques that succumbed to Ebola virus (EBOV) disease from 5 to 8 days post exposure. Ganglionitis, characterized by neuronal degeneration, necrosis, and mononuclear leukocyte infiltrates, was observed in the dorsal root, autonomic, and enteric ganglia. By immunohistochemistry, RNAscope in situ hybridization, transmission electron microscopy, and confocal microscopy, we confirmed that CD68+ macrophages are the target cells for EBOV in affected ganglia. Further, we demonstrated that EBOV can induce satellite cell and neuronal apoptosis and microglial activation in infected ganglia. Our results demonstrate that EBOV can infect peripheral ganglia and results in ganglionopathy in rhesus macaques, which may contribute to the neurological signs and symptoms observed in acute and convalescent Ebola virus disease in human patients.

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411. Does an Early Cytokine Response During Ebola Virus Disease Improve the Duration of Survival in Rhesus Macaques?

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.484 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S208-S208

Author(s):

Paul W Blair ◽

Karen A O Martins ◽

Keshtkar-Jahromi Maryam ◽

Mark G Kortepeter ◽

Keebaugh Michael ◽

...

Keyword(s):

Ebola Virus ◽

Cox Regression ◽

Virus Disease ◽

Rhesus Macaques ◽

Early Death ◽

Ebola Virus Disease ◽

Cytokine Release ◽

Time To Death ◽

Post Exposure ◽

Increased Risk

Abstract Background Ebola virus disease results in a severe cytokine release resulting in organ failure and disseminated intravascular coagulation, often leading to death. An early post-exposure immune response may improve outcomes but that remains poorly characterized. Therefore, we evaluated select serum cytokine markers of immune activation in nonhuman primates (NHPs) for their association with duration of survival. Methods This was a post-hoc analysis of an interventional supportive care NHP study in which 13 rhesus macaques were inoculated intramuscularly with a target dose of 1000 PFU Zaire ebolavirus (Kikwit). We measured cytokines with a Luminex MAGPIX panel at baseline and daily starting day 3 post-exposure until euthanasia. Based on human clinical data, 10 cytokines and proteins were included in our analysis: IL-1ra, IL-6, IL-10, GM-CSF, MCP-1, MIP-1α, MIP-1β, IFN-γ, TNF-α, and C-reactive protein levels. After NHPs were divided into two groups by k-means clustering, we developed Kaplan–Meier curves for time to death (Figure 1). We visually explored Pearson’s correlation and kinetics of serum cytokines and log10viral load (Figure 1; Figure 2). We fitted cox regression models with each cytokine to evaluate the risk of early disease for each cytokine log10 level or log2-fold change. We performed a sensitivity analysis for MIP-1β centering the data at dpe 0. Results Among NHPs with temperature data, 83% (N = 10) developed fevers (>3 SD baseline) from dpe 3 to 4.The macrophage markerMIP-1β was associated with an increased risk of early death (per log10pg/mL increase, HR= 52.83 at dpe 3, adjusted P = 0.045). Surprisingly, this association was also observed at dpe 0 (HR= 36.88 at dpe 0, adjusted P = 0.044). Other cytokine levels or changes were not associated with an increased hazard of death. Conclusion Our findings did not support a role for early systemic cytokine release in improving survival. However, elevated baseline levels of the MIP-1β may predispose NHPs to early death from EVD. This finding could represent a target for therapeutic strategies and should be further researched. Disclosures All authors: No reported disclosures.

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A meta-analysis of clinical studies conducted during the West Africa Ebola virus disease outbreak confirms the need for randomized control groups

Science Translational Medicine ◽

10.1126/scitranslmed.aaw1049 ◽

2019 ◽

Vol 11 (520) ◽

pp. eaaw1049 ◽

Cited By ~ 9

Author(s):

Lori E. Dodd ◽

Dean Follmann ◽

Michael Proschan ◽

Jing Wang ◽

Denis Malvy ◽

...

Keyword(s):

West Africa ◽

Mortality Risk ◽

Clinical Studies ◽

Ebola Virus ◽

Virus Disease ◽

Disease Outbreaks ◽

Ebola Virus Disease ◽

Control Group ◽

Control Groups ◽

Randomized Control

Recent Ebola virus disease outbreaks affirm the dire need for treatments with proven efficacy. Randomized controlled clinical trials remain the gold standard but, during disease outbreaks, may be difficult to conduct due to ethical concerns and challenging field conditions. In the absence of a randomized control group, statistical modeling to create a control group could be a possibility. Such a model-based reference control would only be credible if it had the same mortality risk as that of the experimental group in the absence of treatment. One way to test this counterfactual assumption is to evaluate whether reasonable similarity exists across nonrandomized control groups from different clinical studies, which might suggest that a future control group would be similarly homogeneous. We evaluated similarity across six clinical studies conducted during the 2013–2016 West Africa outbreak of Ebola virus disease. These studies evaluated favipiravir, the biologic ZMapp, the antimalarial drug amodiaquine, or administration of convalescent plasma or convalescent whole blood. We compared the nonrandomized control groups of these six studies comprising 1147 individuals infected with Ebola virus. We found considerable heterogeneity, which did not disappear after statistical modeling to adjust for prognostic variables. Mortality risk varied widely (31 to 66%) across the nonrandomized control arms of these six studies. Models adjusting for baseline covariates (age, sex, and cycle threshold, a proxy for viral load) failed to sufficiently recalibrate these studies and showed that heterogeneity remained. Our findings highlight concerns about making invalid conclusions when comparing nonrandomized control groups to cohorts receiving experimental treatments.

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Correction to: Impact of intensive care unit supportive care on the physiology of Ebola virus disease in a universally lethal non-human primate model

Intensive Care Medicine Experimental ◽

10.1186/s40635-019-0283-9 ◽

2019 ◽

Vol 7 (1) ◽

Author(s):

Guillaume Poliquin ◽

Duane Funk ◽

Shane Jones ◽

Kaylie Tran ◽

Charlene Ranadheera ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Supportive Care ◽

Ebola Virus ◽

Virus Disease ◽

Ebola Virus Disease ◽

Primate Model ◽

Human Primate

Please note that four authors (Logan Banadyga, Alixandra Albietz, Brad Pickering, and Gary Wong) have been erroneously omitted from the author list in the published original article [1].

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Development of the PREDS Score to Predict In-Hospital Mortality of Patients With Ebola Virus Disease Under Advanced Supportive Care: Results From the EVISTA Cohort in the Democratic Republic of the Congo

SSRN Electronic Journal ◽

10.2139/ssrn.3986019 ◽

2021 ◽

Author(s):

Marie Jaspard ◽

Sabue Mulangu ◽

Sylvain Juchet ◽

Beatrice Serra ◽

Ibrahim Dicko ◽

...

Keyword(s):

Hospital Mortality ◽

Supportive Care ◽

Ebola Virus ◽

Democratic Republic ◽

Virus Disease ◽

Ebola Virus Disease ◽

Republic Of The Congo

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Clinical Laboratory Values in Human Ebola Virus Disease Support the Relevance of the Intramuscular Ebola-Kikwit Rhesus Model

Clinical Infectious Diseases ◽

10.1093/cid/cix1025 ◽

2017 ◽

Vol 66 (9) ◽

pp. 1479-1480 ◽

Cited By ~ 1

Author(s):

Ronald B Reisler ◽

Colleen S Kraft ◽

Sina Bavari ◽

Anthony P Cardile

Keyword(s):

Ebola Virus ◽

Clinical Laboratory ◽

Virus Disease ◽

Ebola Virus Disease ◽

Laboratory Values

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Barriers to supportive care during the Ebola virus disease outbreak in West Africa: Results of a qualitative study

PLoS ONE ◽

10.1371/journal.pone.0201091 ◽

2018 ◽

Vol 13 (9) ◽

pp. e0201091 ◽

Cited By ~ 6

Author(s):

Christine Loignon ◽

Elysée Nouvet ◽

François Couturier ◽

Lynda Benhadj ◽

Neill K. J. Adhikari ◽

...

Keyword(s):

Qualitative Study ◽

West Africa ◽

Supportive Care ◽

Ebola Virus ◽

Virus Disease ◽

Disease Outbreak ◽

Ebola Virus Disease

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The Cytokine Response Profile of Ebola Virus Disease in a Large Cohort of Rhesus Macaques Treated With Monoclonal Antibodies

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz046 ◽

2019 ◽

Vol 6 (3) ◽

Cited By ~ 2

Author(s):

Logan Banadyga ◽

Vinayakumar Siragam ◽

Wenjun Zhu ◽

Shihua He ◽

Keding Cheng ◽

...

Keyword(s):

Immune Response ◽

Ebola Virus ◽

Virus Disease ◽

Rhesus Macaques ◽

Hemorrhagic Fever ◽

Ebola Virus Disease ◽

Antibody Treatment ◽

Highly Pathogenic ◽

Cytokine Levels ◽

Response Profile

Abstract Ebola virus (EBOV) is a highly pathogenic filovirus that causes outbreaks of a severe hemorrhagic fever known as EBOV disease (EVD). Ebola virus disease is characterized in part by a dysregulated immune response and massive production of both pro- and anti-inflammatory cytokines. To better understand the immune response elicited by EVD in the context of treatment with experimental anti-EBOV antibody cocktails, we analyzed 29 cytokines in 42 EBOV-infected rhesus macaques. In comparison to the surviving treated animals, which exhibited minimal aberrations in only a few cytokine levels, nonsurviving animals exhibited a dramatically upregulated inflammatory response that was delayed by antibody treatment.

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