Wednesday, October 15, 2014

Expanded Oct. 19: Current Clinical Thoughts on Ebola

My thoughts on handling Ebola, which garnered so much interest that I have expanded the original ideas, including updates and links:

1. Personal Protective Equipment

Even the best containment gear, combined with a diluted bleach solution to spray down workers as layers are removed, and a buddy system that requires another healthcare professional to watch how healthcare workers put on and take off their personal protective equipment, is not perfect. When Medicins Sans Frontieres/ aka Doctors Without Borders/ aka MSF healthcare workers used the best equipment and methods we know, still 16 MSF staff, including a French nurse and Norwegian doctor, became infected with Ebola, and nine of them have died.  (There are 3,000 MSF workers in west Africa now.) It is unlikely that we will be able to achieve 100% protection for healthcare workers.  Hospital isolation rooms and procedures were designed for tuberculosis and flu, not for organisms with 50-70% mortality, and for which there are no drugs or vaccines (yet).  Mortality for healthcare workers, hospitalized in Africa, has been 56%.

Here is a great description of the travails inherent in using personal protective equipment.

UPDATE Oct. 24:  The WaPo said that 24 MSF workers have now been infected and 13 have died.

2. Biosafety Containment Facilities

The best place to care for any Ebola patient is in a high containment lab where staff have practiced many drills and are accustomed to biosafety level 4 procedures and containment, which were designed for organisms such as Ebola. There are five such clinical centers in the United States. These are located in Missoula, Montana, at Emory University in Atlanta, at NIH in Bethesda, Maryland, at Fort Detrick (possibly closed, operated previously) in Frederick, Maryland and at the University of Nebraska. These are the safest places to care for Ebola patients.  They are also places where the entire structure was designed for dealing with organisms like Ebola, which is not the case for community hospitals in the United States. It has been said that combined, they have less than 20 patient care beds, for the entire US. Although Nebraska has 10 beds, it says it can only handle 2-3 Ebola patients. How can that number be increased?  Can the Fort Detrick unit be made serviceable?

UPDATE:  NIH's Fauci said we need more of these units on October 19.

UPDATE:  On October 21, Texas Governor Rick Perry said two treatment centers had been designated for patients with Ebola, one at UT Medical Branch, Galveston, and one in a now-empty ICU at a satellite campus of Methodist Health System in Dallas.

Although we cannot duplicate their architecture elsewhere, might their procedures and protocols be useful to publish?  And can we do some quick and dirty room conversions to create extra changing areas?  Can some of the apparent excess BL-4 research capacity built since 2001 be converted to clinical treatment centers?  Also see this article.

UPDATE:  Here is a very detailed report of how a researcher with an Ebola needlestick was treated in such a facility at Fort Detrick.  Here is a video demo of Emory's containment unit, followed by another video demonstrating the personal protective equipment (PPE) being used there, modeled after what is used in west Africa.

UPDATE Oct. 19: A 30 person military team will be trained for one week in infection control and personal protective equipment, to be deployed at the request of DHHS to help with civilian ebola care.  This is a great idea; it demonstrates a new acknowledgement that you need significant training and equipment to care for Ebola patients.

Probably the whole country will benefit if clinicians at these centers develop greater expertise in the clinical care of Ebola patients, and can then share their knowledge with the rest of the medical community. Clinicians at the centers will also have easier access to experimental drugs than doctors elsewhere.

3.  How can we improve survival from Ebola?

My early hope that simple fluid and electrolyte replacement might save many lives appears to have been overly optimistic.  Even with this treatment in Africa, at least 50% of cases treated by MSF seem to die.  The fact that deaths are occurring in Europe and the US, in patients receiving top medical care long before they become moribund, tells us that the usual treatments will in many cases not be sufficient for Ebola.  To be blunt, it appears that even the highest level of supportive healthcare we can currently provide is simply not good enough.  A limited discussion of clinical care for Ebola patients, coauthored by Peter Jahrling, is here.

[UPDATE:  An MSF official guesstimated to me that with the highest level of tertiary care, perhaps the mortality rate could be reduced to 15%.]

The overwhelming illness seen in Ebola patients is due to an interaction between the virus and the immune system.  For those more technically inclined, read this. It may be that damping down parts of the immune response will improve survival. Is this being investigated?

To survive other serious viral infections, a person needs to be kept alive for a period of 2-3 weeks of illness, after which almost everyone should recover.

Antiviral drugs may be beneficial for Ebola, as may certain drugs that affect ion channels. Are clinical trials being done with these already-licensed drugs in Ebola patients yet?  [When a drug is licensed in the US, a doctor may legally use it for other conditions (off-label use) if there seems to be a good reason to do so.]  What about other drugs that did well in animal or other studies, like this, thisthis and this?

UPDATE:  FDA permission was granted on Oct. 17 to test Brincidofovir in clinical trials.

4.  Antibody Treatments

Historically, antibody-containing immune serum from patents who recovered has been the most effective treatment for Ebola.  This treatment has been used for decades.  Hyperimmune serum obtained from animals has been used as well. Serum can be used even after freezing. What agencies are banking serum, and how are decisions being made about who gets this life-saving serum? How is serum being tested for the presence of other diseases that might preclude donation, such as HIV?

UPDATE:  Oct 22: WHO spokesperson "Kieny said in remarks reported by the BBC that a serum was also being developed for use in Liberia based on antibodies extracted from the blood of Ebola survivors. “There are partnerships which are starting to be put in place to have capacity in the three countries to safely extract plasma and make preparation that can be used for the treatment of infective patients."

Even patients who were not recently ill, but who test positive for Ebola antibodies, could be used as donors.  There is one caveat:  antibodies in some cases inhibit the immune response, and can predispose to, or worsen, an infection.  This is why adequate human testing is always needed before widespread use of any therapeutic product. Animal studies are unable to accurately predict all effects in humans.

UPDATE Oct 23: Testing of convalescent serum to begin next month in Guinea.  David Heymann describes his experience in several Ebola outbreaks and the use of blood products from survivors.

The most effective antibodies against the Ebola virus can be selected and turned into monoclonal antibodies, which can be grown in large quantities, for infusion into patients.  ZMapp is a combination monoclonal product made up of three separate antibodies.  Although ZMapp uses tobacco plants as the platform to grow these monoclonal antibodies, other platforms could also be used, to provide more rapid recovery of product for Ebola patients, such as cell culture.  Is this being done?  

UPDATE: On Oct. 17, it was reported that Amgen and the Gates Foundation would work together on an alternative production method for ZMapp.

Are there other monoclonal antibodies that show promise for treating Ebola infections?  How is production being ramped up?

UPDATE: On October 17, the US government finally requested proposals for manufacturing ZMapp, due on November 10.  Brett Giroir of Texas A and M, said, "If selected, we are prepared to take action immediately to ramp up production" of ZMapp.  Seems like no one is in a big hurry on this.  

Yet the federal government bought and paid for Giroir's center at Texas A and M as a public-private partnership for the purpose of producing emergency medical products in a hurry. Texas A and M, along with Novartis and (anthrax vaccine manufacturer) Emergent BioSolutions were designated "Centers for Innovation in Advanced Development and Manufacturing, [and] were established by the U.S. government in 2012 with $440 million in seed money. They are required to develop flexible manufacturing capabilities to allow them to produce countermeasures against chemical, biological, and other threats..." Why aren't they already making experimental products?

5.  Vaccine and Drug Testing

Vaccines and drugs have been developed in multiple countries.  They need to be tested in head to head trials. We can't wait for them to be tested individually against a placebo, and then still not know how they compare to each other.  We need to identify the best existing drugs and vaccines now, while continuing to develop newer drugs, monoclonal antibodies and tests that may be more specific to the currently raging Ebola strain, compared to prior versions of Ebola Zaire.

Yet again, it seems most of these drugs have not begun human trials.

UPDATE Oct 22: Why is information being provided on vaccine trials contradictory?  First we were told there had been no human trials.  But an NIH website (last updated in July 2013) says "NIH's Biodefense Research Section (BRS) has developed highly effective vaccine strategies for Ebola virus infection in non-human primates. The vaccines are currently being tested in human trials conducted by the VRC Clinical Trials Core Laboratory in Bethesda, Maryland, and Makerere University in Uganda." Elsewhere it is claimed vaccine was tested in Bethesda and Oxford, England.

The Oct. 22 Guardian says, "One of the vaccines that Kieny mentioned, Okairos AG, is being developed by the US National Institutes of Health and GlaxoSmithKline from a modified chimpanzee-cold virus and an Ebola protein. It is being made in Rome, according to GSK, with clinical trials under way in Britain and Mali.

Oct 22 WSJ says J and J to begin testing a vaccine in partnership wth Bavarian Nordic in January.

6.  Laboratory Testing:  A Huge Gap in Readiness

Tests to determine who is infected need to be more sensitive.  Right now we cannot tell who is incubating Ebola; the rtPCR test that is currently CDC's gold standard is said to be unreliable until a patient has been clinically ill for 3-10 days.  Other tests are even less sensitive.

UPDATE: On October 22, CDC approved 15 labs in the US to test Ebola samples.

If clinicians cannot diagnose patients early in the course of illness, they will not be able to effectively isolate them, nor provide the best treatments, until late in the game... long after they have become infectious to others, and possibly when their chance of survival has shrunk.

The ability to diagnose an early Ebola patient at the time they present for treatment is crucial. Without this ability, hospitals and clinics become places where Ebola is likely to be caught.  You cannot accurately isolate patients with Ebola from those without it. This can shut down the healthcare system:  people won't come seeking care for ordinary illness if they might share a waiting room or bathroom with an undiagnosed Ebola patient.

What is being done to develop or provide more sensitive tests for this strain of Ebola?  rtPCR should be highly sensitive, given the right reagents.  Are such being developed for the latest strain of Ebola?

UPDATE:  The genome for Ebola virus, isolated from patients infected at the start of the current outbreak, has been sequenced, and the authors of the paper suggest this may lead to better primers for rtPCR diagnostic tests.

UPDATE:  Corgenix is working on a rapid diagnostic test that could be used in the field.

What other tests are in development?  Are tests developed in other countries, like Japan, being appraised carefully?

7.  When Do Patients Stop Being Contagious?

When can recovered patients be considered no longer infectious?  We only know a little about this. However, viable Ebola virus has been recovered in semen more than 2 months after a patient recovered from the disease, making him still contagious.  Ebola virus has been recovered from breast milk more than a month after disease recovery. One person was still producing viable virus at 82 days post-recovery.

What studies are being done of newly 'recovered' patients to assess the possibility they are still excreting live virus?  Of those highly exposed but not ill, like Eric Duncan's family?

UPDATE:  "Ebola virus appears to persist in humans during convalescence after acute infection. In one study, virus was isolated fromsemen samples 39 and 61 days after onset of illness (14). In another study, Ebola virus was isolated from a patient 82 days after recovery (34)."  The BBC reported on a survivor who infected his girlfriend, who died.

8.  Improving Our Knowledge of the Role of the Immune Response in Ebola Infection

The disease Ebola results from infection with the virus, coupled with a susceptible patient whose immune system will mount an extremely robust inflammatory response, which likely contributes to death.  Right now, we cannot predict which patients are most likely to develop fulminant illness, and which are likely to have only a subclinical infection and make a full recovery, with (probably lifelong) immunity.

Are staff members at the centers where Ebola patients have been treated being tested, to see if they develop an antibody response to Ebola?  This would tell us whether others were inadvertently exposed to Ebola virus, but were fortunate to have an immune system that successfully defended them from severe illness.

Studies of the genetics of the Ebola immune response might lead to the ability to predict which healthcare workers are most likely to avoid severe illness, and which are more susceptible.  This might allow us to triage healthcare workers into those who care for Ebola patients and those who don't.  Understanding how cytokines, chemokines and other immune parameters can both enhance and impede recovery from infection will be very useful knowledge.  Is this an area of active investigation?

9.  Survivors Can Be Protected Caregivers

Patients who have recovered from Ebola will be immune.  In addition to providing antibodies that are effective for treatment, they should be offered jobs in healthcare, at least in Africa, where unemployment rates often top 50%.  Survivors will be very important to our control efforts, and should be paid well to help out.

10.  How May Ebola Spread in Air?

There is no question from the scientific literature that Ebola may be transmitted in animals by droplet nuclei, formed during coughing, sneezing or speech, in the air.  CDC's recommendations for air travel seem to acknowledge this, suggesting that suspected Ebola patients be given masks to wear to reduce airborne droplets, and noting, "Do NOT use compressed air, pressurized water or similar procedures, which might create droplets of infectious materials." Although Ebola virus is sensitive to drying, UV, bleach, etc., it may remain viable (floating in air) for an hour.  It can remain infectious on a moist surface for hours and in some special cases, for days. 

The problem is that it only takes a minute amount of Ebola to cause human infection:  only 1 to 10 virus particles. It takes (generally) at least 50,000 spores of anthrax to cause infection; this is why there were so few cases in 2001, despite widespread anthrax contamination of surfaces, when tested.

Late in the illness, a person might harbor 5 billion virus particles in a teaspoon of body fluid:  enough to theoretically infect a billion people in a teaspoon. You can therefore imagine that even a minute amount could be transmitted on a doorknob or sink, enough to cause an occasional infection.  

Have studies of insect transmission been undertaken?  I hope Ebola will not survive in an insect, but so far, we cannot say so with certainty. Former USAMRIID biodefense researcher and venture capitalist Tom Monath raised this question in 1999.

UPDATE:  Emory University's Bruce Ribner demonstrates biocontainment helmets and hoods used to protect healthcare workers when patients may be "generating lots of droplets that may be contagious." (at 1:30 mins)... an inadvertent acknowledgement that the protective gear is designed to prevent workers from contact with aerosolized droplet nuclei.

Meryl Nass, M.D.

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