title: Natural History of Aerosol Exposure with Marburg Virus in Rhesus Macaques.
abstract: Marburg virus causes severe and often lethal viral disease in humans, and there are currently no Food and Drug Administration (FDA) approved medical countermeasures. The sporadic occurrence of Marburg outbreaks does not allow for evaluation of countermeasures in humans, so therapeutic and vaccine candidates can only be approved through the FDA animal rule-a mechanism requiring well-characterized animal models in which efficacy would be evaluated. Here, we describe a natural history study where rhesus macaques were surgically implanted with telemetry devices and central venous catheters prior to aerosol exposure with Marburg-Angola virus, enabling continuous physiologic monitoring and blood sampling without anesthesia. After a three to four day incubation period, all animals developed fever, viremia, and lymphopenia before developing tachycardia, tachypnea, elevated liver enzymes, decreased liver function, azotemia, elevated D-dimer levels and elevated pro-inflammatory cytokines suggesting a systemic inflammatory response with organ failure. The final, terminal period began with the onset of sustained hypotension, dehydration progressed with signs of major organ hypoperfusion (hyperlactatemia, acute kidney injury, hypothermia), and ended with euthanasia or death. The most significant pathologic findings were marked infection of the respiratory lymphoid tissue with destruction of the tracheobronchial and mediastinal lymph nodes, and severe diffuse infection in the liver, and splenitis.
authors.affiliation: Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA. evan.c.ewers.mil@mail.mil.
authors.forename: Evan C
authors.initials: EC
authors.lastname: Ewers
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA. william.d.pratt4.ctr@mail.mil.
authors.forename: William D
authors.initials: WD
authors.lastname: Pratt
authors.affiliation: Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA. nancy.a.twenhafel.mil@mail.mil.|US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA. nancy.a.twenhafel.mil@mail.mil.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Twenhafel
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA. joshua.d.shamblin1.civ@mail.mil.
authors.forename: Joshua
authors.initials: J
authors.lastname: Shamblin
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA. ginger.c.donnelly.ctr@mail.mil.
authors.forename: Ginger
authors.initials: G
authors.lastname: Donnelly
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA. heather.l.esham.civ@mail.mil.
authors.forename: Heather
authors.initials: H
authors.lastname: Esham
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA. carly.b.wlazlowski.ctr@mail.mil.
authors.forename: Carly
authors.initials: C
authors.lastname: Wlazlowski
authors.affiliation: Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA. joshua.johnson@nih.gov.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Johnson
authors.affiliation: US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA. miriam.a.botto.civ@mail.mil.
authors.forename: Miriam
authors.initials: M
authors.lastname: Botto
authors.affiliation: Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA. lisa.hensley@nih.gov.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Hensley
authors.affiliation: Department of Medicine, Tripler Army Medical Center, Honolulu, HI 96859, USA. arthur.j.goff.civ@mail.mil.|US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA. arthur.j.goff.civ@mail.mil.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Goff
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D001780:Blood Coagulation Tests; D016207:Cytokines / Q000097:blood; D005260:Female; D007677:Kidney Function Tests; D008111:Liver Function Tests; D008253:Macaca mulatta / Q000821:virology*; D008297:Male; D008379:Marburg Virus Disease / Q000175:diagnosis / Q000635:transmission* / Q000821:virology*; D029024:Marburgvirus / Q000502:physiology*; D014766:Viremia
chemical_list: D016207:Cytokines
keywords: Marburg virus; aerosol; animal model; filovirus; nonhuman primate; telemetry