Wanted: Ebola test with perfect negative predictive value at time zero
The fact that the most sensitive Ebola virus diagnostic test (PCR applied to a blood sample) may not be positive until 3 days after symptom onset is well known, however. The reason for this has to do with the pathogenesis of Ebola virus infection. The point of entry and initial replication for Ebola is the “dendritic” cell. Present in large numbers in the skin, mucosa and intestinal lining, dendritic cells are sentinels, guarding the interface between the human immune system and a hostile environment. They encounter invaders, engulf them, and present their antigens to cells of the adaptive immune system. Dendritic cells carry the virus to lymph nodes and other organs of the “reticuloendothelial system” (liver, spleen). So before the virus reaches detectable levels in the blood, there may be hours-to-days of replication in these cells and organs, along with symptoms of fever and fatigue. A test, even a very sensitive test, that is applied to blood will not detect the virus until it appears in the bloodstream in larger numbers.
This lack of a rapid and accurate diagnostic test early in the Ebola disease course is a major problem—not only for early initiation of therapy for those infected, but also for the management of “persons under investigation” (who may require Ebola-level isolation precautions for several days while awaiting a negative test that has been taken at least 3 days after symptom onset).
But this problem plagues infectious diseases diagnostics generally. As this recent Lancet ID article points out, the lack of early and sensitive diagnostic testing is one reason why so many patients in our hospitals receive days of unnecessary antimicrobials. More on this study later, perhaps from Eli, one of the authors!
Image by Sean Gallup, Getty Images
Dan, I read the Lancet article quite a bit differently. Physicians are not requesting rapid tests (no hospitals in the study had implemented rapid testing), and even when standard test results are available, they make little use of them. This is exactly why there are a dearth of rapid/accelerated ID/AST tests - there is very little demand for them, despite their obvious potential clinical utility. I found this out the hard way as CSO for MicroPhage. Our 5 hour ID/AST test for S. aureus BSIs was an utter market failure, and we went bankrupt within 18 months of FDA clearance. As long as many physicians have the attitude of "Give them vancomycin and it's all good", the IVD industry will have little incentive to invest in the type of tests you are calling for.
ReplyDeleteIt may seem ideal to have a "perfect negative" Ebola test at "time zero," but in my opinion, it would not be perfect. This is because, if we have access to a person who has "most likely" been exposed to an Ebola virus infection, so that we can test him/her for Ebola, then we also have access to that person for something else, namely, for the injection or oral administration of an antidote to Ebola. Now, if we use the Ebola test, without using the antidote, we end up with either a "perfect negative" test, or a "probable positive" or even a "true positive" Ebola test. But if we use the antidote, assuming we have a highly effective antidote, at this time, then we may later test the person for Ebola, but due to the administration of a highly effective antidote, it may make more sense not to test for Ebola unless and until more Ebola consistent symptoms arise in this patient. At that time, the antidote can be administered again. The point here is that the "test" is not an ideal option, that is, IFF we have a highly effective antidote or therapy or "cure" for Ebola virus. This is precisely what the Department of Defense stated they did have, in a report by their Threat Reduction Agency, declassified in 2009. So, in my opinion it is incumbent on epidemiologists to call for the US DOD antidote to be provided to all Ebola patients with the utmost urgency, without any cost to patients in West Africa or anywhere else.
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