Transcript ISARIC.WHO.EBOLA.ATOR.IRBES.[3] (download

ISARIC/WHO Teleconference
January 15, 2015
Treating the Host Response to Ebola Virus Disease
David S. Fedson, MD
[email protected]
The Challenge of Managing Patients with
Ebola Virus Disease in West Africa
• Almost 10,000 Ebola patients are known to have died
• The outbreak has been partially controlled in some regions, but
the end is not in sight
• Public health efforts will be essential for outbreak control
• Clinical management of individual Ebola patients has been
difficult (CFR 40-70%) and dangerous
• “Top down” interventions that target the virus (vaccines,
antivirals, antibody treatments) are experimental, in very short
supply, and will not have a major impact on the management of
individual patients in the foreseeable future
• A “bottom up” approach using safe and inexpensive generic
drugs to treat the host response of all patients with Ebola virus
disease is available in West Africa today and might save lives
Treating the Host Response to Ebola Virus Infection
in Sierra Leone: First Steps
• Op-Ed article in The New York Times on August 15th
David S. Fedson and Steve M. Opal
“Can Statins Help Treat Ebola”
• Letter in The Journal of Infectious Diseases published online on
August 25th (manuscript) and September 24th
Fedson D.S. A practical treatment for patients with Ebola virus disease.
J Infect Dis 2015; 211: 611-2.
• Dr. Ole Martin Rordam in Trondheim, Norway read the NYT Op-Ed
article, bought a supply of atorvastatin (40 mg, 4000 doses),
irbesartan (150 mg, 4000 doses) and clomiphene (50 mg, 50
doses), and sent it through a colleague to Sierra Leone
• Ebola patients (test-positive) have been treated by local
physicians in Freetown, Port Loko, Hastings and perhaps other sites
Atorvastatin and Irbesartan Treatment
in Sierra Leone - 1
34 Military Hospital in Freetown – early November
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22 test-positive patients treated with atorvastatin (40 mg/day) and
irbesartan (150 mg/day)
22 test-positive patients treated with irbesartan and clomiphene
(50 mg/day); only 50 doses of clomiphene had been supplied
Duration of treatment not known; all patients survived
One military physician was treated for 3 days and improved, but
treatment was changed to an antiviral and convalescent plasma
and he relapsed and died
On November 11th, following review of this experience by its
Expert Committee on Drug Safety, the Pharmacy Board of Sierra
Leone sought written guidance on further studies of treatment
(subsequent actions not known)
Report of 531 patients at the Hastings Ebola Treatment Centre
treated with IV fluids with 31% mortality; whether some patients
received atorvastatin and irbesartan is not known
Ansumana R et al. N Engl J Med 2014. Epub on December 24th.
Atorvastatin and Irbesartan Treatment
in Sierra Leone - 2
Port Loko Government Hospital – internal memorandum, 27/11/14
“Ten patients tested positive for EVD were commenced on the above
therapy while continuing the usual protocol for treatment on 16/11/14. They
showed remarkable improvement and five of them have been discharged
from the Maforkie Treatment. More patients are on the management and
we expect promising results.”
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Treatment records show 15 patients were treated orally with
atorvastatin (40 mg/day), irbesartan (150 mg/day) and clomiphene (50
mg/day) for three days, and then continued on atorvastatin and
irbesartan only for 3-4 more days
All 15 patients survived
One additional critically ill patient died after receiving only one or two
doses of treatment
At least ten additional patients at PLGH have been treated, but the
results are not known
Atorvastatin and Irbesartan Treatment
in Sierra Leone - 3
Limitations
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Patients apparently treated consecutively, not randomized
All patients received atorvastatin and irbesartan, only a few patients
received a short course of clomiphene
No additional details known (duration of illness before treatment
initiated, severity of initial signs and symptoms, other treatments,
rapidity of response to treatment)
No details known on the selection of patients for treatment and
characteristics of those not treated (duration of illness before
admission, clinical severity, outcome)
Are the clinical results significant?
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At least 100 patients have been treated with atorvastatin and
irbesartan, with two known deaths
To reduce mortality from 50% to 25% (with a significant 95% CI)
- RCT  210 subjects
- consecutive treatment  55 subjects
A matched set case-control study could establish the effectiveness of
treatment
On January 8, 2015, WHO initiated a review of the treatment
experience in Sierra Leone
Ebola Virus Disease and Sepsis in Patients:
Endothelial Dysfunction and Coagulopathy
• Clinical similarities
- pro-inflammatory cytokines/chemokines
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lymphocyte apoptosis
liver and renal abnormalities (MOF)
endothelial dysfunction and coagulopathy
high mortality
Henley LE, Geisbert TW. Thromb Haemost 2005; 94: 254-61.
McElroy AK et al. J Infect Dis 2014; 210: 558-66.
Opal SM, van der Poll T. J Intern Med 2015. To be published.
• Massive fluid losses internally (third spacing) and externally
(diarrhea, vomiting), severe electrolyte disturbances, not yet
documented in animal models
• In sepsis patients, RCT showed atorvastatin reduced the
development of MOF by 83%
Patel J et al. Crit Care 2012; 16: R231.
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Hamburg - Abdominal Ultrasound Exam of a Patient
with Ebola Virus Disease, Day 10
LIVER
normal aspect and size without local lesions, no
cholestasis, all liver vessels with orthograde flow
SPLEEN
normal aspect and size
KIDNEYS and
both kidneys of normal aspect and size, no obstruction
BLADDER
of the urinary tract
INTESTINAL
pronounced edema of the stomach, small intestine
TRACT
and large intestinal wall. Extremely distended intestinal
loops, with large amounts of intra-intestinal fluids and
complete absence of peristaltic movement
LYMPH NODES mesenteric lymph nodes enlarged
ABDOMINAL
complete collapse of the inferior vena cava
VESSELS
OTHER
No signs of pericardial effusion, pleural effusion or
ascites
Kreuls B et al. N Engl J Med 2014; 371: 2394-401.
Atlanta - Fluid Balance in Ebola Patient 2
Massive fluid deficits demonstrated over the course of the disease
Lyon GM et al. N Engl J Med 2014; 371: 2402-9.
Endothelial Barrier Dysfunction in Septic Shock
and Virus Infections
Opal SM et al. J Intern Med 2015. To be published.
Dalrymple NA et al. Curr Opin Virol 2014; 7: 134-40.
Ebola, Vascular Permeability, and its Treatment with
Statins and Angiotensin Receptor Blockers
In vitro mechanistic studies
• Atorvastatin inhibits Rho and
Rac GTPases, increases VEcadherin and preserves
endothelial junction integrity
Chen W et al. Am J Physiol Lung Cell
Mol Physiol 2008; 295: L575-L583.
Xiao H et al. PLoS One 2013; 8: e59233.
Non infectious Ebola virus shed
glycoprotein increases vascular
permeability
Escudero-Perez B et al. PLoS Pathog 2014; 10:
e1004509.
• Angiotensin II increases
endothelial permeability, and
this is blunted by angiotensin
receptor blockade
Bodor C et al. Am J Physiol Cell
Physiol 2012; 302: C267-C276.
Molecular Targets of Statins, ACE Inhibitors and ARBs
in Endothelial Cells
Combined treatment more effective than single agent treatment
Lee HY et al. Circ J 2014; 78: 281-7.
Ceriello A et al. Circulation 2005; 111: 2518-24.
Statins and ARBs: Possible Cell Signaling Effects in
Treating the Host Response to Ebola Virus Infection
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 TLR4, NF-kB and AP-1;  p38 MAPK and PI3/Akt (cytoprotective)
 pro-inflammatory TNF, IL-1b, IL-6, IL-8, MCP1, MIP1/, CCR5
 anti-inflammatory IL-10, TGF-
 pro-resolving mediators lipoxin A4, protectin D-1, resolvin D1
 HO-1   TLR signaling for PAMPs, alarmins (DAMPS)   cytokines
 cellular adhesion molecules (VCAM-1, ICAM-1, P-selectin)
 HMGB1/RAGE and late mediators of inflammation
 tissue factor,  thrombomodulin   pro-thrombotic coagulopathy
 iNOS,  eNOS  stabilize cardiovascular function
 adipokines (adiponectin) that decrease inflammation
 C5a-C5aR-related increase in vascular permeability
 pulmonary hypertension
modify macrophage function, caspase activation (inflammasomes) and
autophagy and apoptosis in different cells
 GSH,  NADPH oxidase (NOX)   ROS,  oxidative stress
stabilize endothelial cell actin cytoskeleton and EC adherens junctions  
endothelial barrier integrity,  vascular permeability
 AMPK/PGC-1   mitochondrial biogenesis,  ATP
Fedson DS. Antiviral Res 2013; 99: 417-35.
Candidates for Treating the Host Response in Ebola
Patients with Atorvastatin and Irbesartan
• Atorvastatin and irbesartan are known to be safe when given to
patients with acute critical illness
• Treat all patients with Ebola virus disease
- immediately treat all patients suspected of having EVD in
ETUs and those cared for at home
- continue treatment in those with laboratory-documented
infection
- discontinue treatment in those who are test-negative
when
they are not longer considered infected
• Prevent complications in those who might become infected
- health care workers in ETUs
- caregivers of Ebola patients treated at home
- community healthcare workers, surveillance staff and
burial
workers
- other close contacts of Ebola patients
Treating the Host Response to Ebola Virus Disease:
Summary
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Patients with Ebola virus disease in West Africa continue to
experience high mortality
The central pathophysiological lesion in Ebola patients is the loss
of endothelial barrier integrity, primarily in the GI tract
Drugs that treat the host response by restoring endothelial barrier
integrity could allow patients to live longer, develop their own
immune responses, and get rid of the virus
Atorvastatin and irbesartan (an angiotensin receptor blocker)
- restore endothelial barrier integrity
- are safe, inexpensive and widely available generic drugs
- dramatically reduced mortality in ~100 consecutively
treated patients in Sierra Leone
- these treatment results should be validated in a matched
set case-control study
If found to be effective, atorvastatin and irbesartan would radically
alter the management of Ebola virus disease in patients and their
close contacts
Treating the Host Response to Ebola Virus Disease
Thank you
Copies of additional slides, an unpublished essay and
additional articles are available on request
[email protected]