1 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. 2 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. 4 References 1. Kreuls B, Wichmann D, Emmerich P, Schmidt-Chanasit J, deHeer G, Kluge S, et al. A case of severe Ebola virus infection complicated by gram-negative septicemia. N Engl J Med 2014; 371: 2394-401. 2. 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