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Treating the Host Response to Ebola Virus Disease with
Generic Statins and Angiotensin Receptor Blockers
David S. Fedson, MD, Jeffrey R. Jacobson, MD, and Steve M. Opal, MD
------------------------------------The Ebola outbreak in West Africa is devastating Guinea, Liberia and Sierra Leone,
and the disease has recently spread to Mali. In many regions there are few
treatment units and in others healthcare systems have collapsed. Many Ebola
patients have no recourse but to rely on supportive care provided by family
members in their homes.
The clinical trials now being organized will be limited to testing antiviral agents,
specific antibody preparations and vaccines. If one of these treatments is shown to
be effective, it won’t be available for many months and supplies are likely to be
limited. Unless something else can be offered to all Ebola patients, the current high
case fatality rates (often 50-70%) will not change.
Two recent reports document the care given to three Ebola patients who were
evacuated from West Africa to Germany and the US [1, 2]. Each patient experienced
extraordinary internal (third spacing) and external (vomiting, diarrhea) fluid losses
that were accompanied by severe electrolyte disturbances. Two patients had
anasarca when first seen. Left untreated, these changes usually lead to profound
hypovolemia, multi-organ failure and death, but with careful fluid and electrolyte
management all three patients recovered. These findings suggest that endothelial
dysfunction and vascular barrier breakdown are central features of Ebola virus
disease.
These fluid and electrolyte abnormalities in Ebola patients might be reduced by
treating them with inexpensive generic drugs that have direct effects on the
response of endothelial cells to infection [3]. A recent study has shown that Ebola
virus glycoprotein (GP) shed from infected cells stimulates non infected dendritic
cells and macrophages to secrete pro- and anti-inflammatory cytokines, and this
leads to endothelial cell dysfunction, and increased vascular permeability [4]. Statins
[5], angiotensin receptor blockers (ARBs) [6] (and other drugs such as ACE inhibitors
and glitazones) preserve or restore endothelial barrier integrity. Sepsis is another
condition associated with endothelial dysfunction, and in some patients it can lead
to multi-organ failure. A randomized controlled trial in sepsis patients showed that
atorvastatin treatment reduced the occurrence of multi-organ failure by 83%
(discussed in [3]). Moreover, when statins and ARBs are given in combination to
patients with cardiovascular disease, they have additive or synergistic benefits in
counteracting endothelial dysfunction. The same benefits might be seen with
combination treatment of Ebola patients.
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Statins, ARBs and several other drugs that modify endothelial cell function are
produced as inexpensive generics in developing countries and are available in West
Africa [3]. They can be administered orally, and a course of treatment for an
individual patient would cost $1-2.00.
Healthcare workers in West Africa should test statin and ARB treatment of Ebola
patients in pragmatic clinical trials. Candidates for treatment include:
(1) Ebola patients cared for in hospitals and other facilities that are staffed by
trained healthcare workers;
(2) healthcare workers themselves to prevent severe illness in those who are
at high risk and might become infected while caring for Ebola patients; and
(3) Ebola patients and their family members, caregivers, burial workers and
other close contacts.
The primary goal of treatment would be to reduce patient mortality. Secondary goals
would be to reduce requirements for fluid and electrolyte replacement and prevent
severe disease in healthcare workers and others who become infected. These agents
could be used in combination with antivirals.
In all instances, these agents should be administered according to study protocols.
Treating all patients consecutively would be straightforward, and by comparing
results with those seen historically, the study might require few patients. The
disadvantages of this trial design are uncertainty about mortality rate in historical
“control” patients in settings where improvements in supportive care have already
reduced mortality rates, and difficulty in assessing treatment safety. If record
keeping in treatment units has been adequate, a matched set case-control study
could be considered.
A classical randomized controlled trial would also be straightforward, although it
would require a larger number of patients, and half of them would receive no active
treatment. Given the already high mortality rate of untreated patients, investigators
might understandably reject this study design. An adaptive clinical trial would be a
more efficient way to minimize the number of untreated placebo subjects,
simultaneously test different treatment regimens, and assess treatment safety. A
computer simulation of possible outcomes would be generated with pre-specified
stopping points. Patients could be randomized into four groups: statin + placebo;
ARB + placebo; statin + ARB, and placebo + placebo. With this trial design,
investigators would periodically stop enrolling patients in a poorly performing group
(e.g., placebo + placebo), and enrol additional patients in better performing groups
(a “pick the winner” approach). The trial design would yield results that are
statistically valid while ensuring that the maximum number of study subjects
receives active treatment.
It must be emphasized that treatment with these agents will not prevent or cure
Ebola virus infection of individual patients, but it might allow them to survive long
enough to develop an immune response that eliminates the virus. If treatment
reduces mortality, it might make it easier to control the outbreak. More important, it
would give greater hope to all Ebola patients where now there is very little. 3
Unfortunately, most Ebola scientists and health officials are not interested in this
approach to treatment, and no one has proposed testing agents that modify the host
response to Ebola virus disease. In a recent article, two Ebola scientists wrote of
their concerns about the risk this might entail:
"The risk scenario applies in particular to the more recent demands for the testing of
certain drugs approved/licensed for other medical applications, which counteract
human host responses that have been implied in the pathogenesis of EHF (i.e., Ebola
hemorrhagic fever), but without preclincial efficacy data for those drugs against EHF.
Safety of a drug targeting a host response mechanism predicted to be relevant
during ebolavirus infection seems too weak as a justification considering the
potentially disastrous consequences of a failure in efficacy on the ground. [7]"
There are several problems with this argument. True, there are no data on the
efficacy of any of these agents in animal models of Ebola, but to our knowledge no
Ebola scientist has undertaken such studies in nonhuman primates. Furthermore,
endothelial dysfunction figures prominently in the pathophysiology of pneumonia
and influenza, and both statins and ARBs significantly reduce 30-day mortality when
given to patients hospitalized with community-acquired pneumonia, and the same is
true for statin treatment of those hospitalized with laboratory-confirmed influenza
[3]. Statins have also been shown to reduce the replication of at least five other RNA
viruses (DS Fedson, unpublished observation). In view of their known safety when
given to patients with acute critical illness, there is no good reason to think that
treatment with statins and ARBs would lead to “potentially disastrous consequences”
for Ebola patients. There is no guarantee that treatment would reduce Ebola
mortality or forestall complications in those given preventive treatment, and failure
to show efficacy would be disappointing. However, this would be no more
disappointing than the failure of current efforts to reduce the already high mortality
rates in these patients.
Studies of treating the host response should be part of current efforts to confront
Ebola virus disease in West Africa. If treatment is successful, it could have
implications for treating other forms of acute critical illness throughout the world.
Acknowledgment
All authors declare they have no potential conflicts of interests involving this work,
no relevant outside financial activities related to this work and no other relationships
or activities that could be perceived to have influenced or give the appearance of
potentially influencing this work. This work received no outside financial or material
support.
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References
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case of severe Ebola virus infection complicated by gram-negative septicemia. N Engl
J Med 2014; 371: 2394-401.
2. Lyon GM, Mehta AK, Varkey JB, Brantly K, Plyler L, McElroy AK, et al. Clinical care
of two patients with Ebola virus disease in the United States. N Engl J Med 2014;
371: 2402-9.
3. Fedson DS. A practical treatment for patients with Ebola virus disease. J Infect Dis
2014; 211: 661-2.
4. Escudero-Perez B, Volchkova VA, Dolnik O, Lawrence P, Volchkova VE. Shed GP of
Ebola virus triggers immune activation and increased vascular permeability. PLoS
Pathog 2014; 10: e1004509.
5. Chen W, Pendyala S, Natarajan V, Garcia JG, Jacobson JR. Endothelial cell barrier
protection by simvastatin: GTPase regulation and NADPH oxidase inhibition. Am J
Physiol Lung Cell Mol Physiol 2008; 295: L575-L583.
6. Bodor C, Nagy JP, Vegh B, et al. Angiotensin II increases the permeability and PV-1
expression of endothelial cells. Am J Physiol Cell Physiol 2012; 302: C267-276.
7. Hoenen T, Feldman H. Ebolavirus in West Africa, and the use of experimental
therapies or vaccines. BMC Biol 2014; 12: 80.