Sunday, October 19, 2014

Extreme Abundance of Caution Versus Extreme Abundance of Hubris in Ebola Scare

From NBC news today:  
A helicopter landed aboard a cruise ship Saturday to pick up a blood sample from a passenger who may have handled fluids from an Ebola patient, ahead of the Carnival Magic’s planned docking at Galveston, Texas, Sunday.
Carnival said Texas health officials requested that a sample be taken from the passenger and tested, but that the ship is still scheduled to arrive Sunday morning. The company said of the passenger, who is in quarantine, that “she’s feeling absolutely fine."
Absolutely fine. Really?  Why isn't everyone else who came into contact with an Ebola patient being tracked down and asked for blood samples?  Why was her cruise ship prevented from offloading her in Belize, and failed to stop as scheduled in Cozumel, Mexico?

Instead of telling us this is due solely to "an extreme abundance of caution" why not simply tell the truth and regain some credibility on this issue?

On October 16, the New Jersey Health Department said it expects all NJ hospitals to be able to handle an Ebola case.  Well, I hope this uninformed hubris does not come back to bite NJ healthcare workers, who intelligently suggested that cases go to biocontainment facilities, instead.

Friday, October 17, 2014

MSF's Ebola Clinical Guidelines

This is a book compiled by Doctors Without Borders (MSF) in 2008 to explain the clinical care of Ebola and other filovirus patients:

http://www.medbox.org/ebola-guidelines/filovirus-haemorrhagic-fever-guideline/preview?

Thursday, October 16, 2014

Aerosolization tests of Ebola in Animals at USAMRIID confirms disease can spread via air

Because there is so much confusion about the issue of airborne spread of Ebola, this article should clarify the fact that our premier biodefense lab clearly shows that transmission through air may cause infection.  The article is titled, "Development of a Murine (mouse) Model for Aerosolized Ebolavirus Infection Using a Panel of Recombinant Inbred Mice." The URL below will give you the full text article, for free.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528275/

Elizabeth E. Zumbrun, Nourtan F. Abdeltawab, [...], and Aysegul Nalca
Abstract
Countering aerosolized filovirus infection is a major priority of biodefense research. Aerosol models of filovirus infection have been developed in knock-out mice, guinea pigs and non-human primates; however, filovirus infection of immunocompetent mice by the aerosol route has not been reported. A murine model of aerosolized filovirus infection in mice should be useful for screening vaccine candidates and therapies. In this study, various strains of wild-type and immunocompromised mice were exposed to aerosolized wild-type (WT) or mouse-adapted (MA) Ebola virus (EBOV). Upon exposure to aerosolized WT-EBOV, BALB/c, C57BL/6 (B6), and DBA/2 (D2) mice were unaffected, but 100% of severe combined immunodeficiency (SCID) and 90% of signal transducers and activators of transcription (Stat1) knock-out (KO) mice became moribund between 7–9 days post-exposure (dpe). Exposure to MA-EBOV caused 15% body weight loss in BALB/c, but all mice recovered. In contrast, 10–30% lethality was observed in B6 and D2 mice exposed to aerosolized MA-EBOV, and 100% of SCID, Stat1 KO, interferon (IFN)-γ KO and Perforin KO mice became moribund between 7–14 dpe. In order to identify wild-type, inbred, mouse strains in which exposure to aerosolized MA-EBOV is uniformly lethal, 60 BXD (C57BL/6 crossed with DBA/2) recombinant inbred (RI) and advanced RI (ARI) mouse strains were exposed to aerosolized MA-EBOV, and monitored for disease severity. A complete spectrum of disease severity was observed. All BXD strains lost weight but many recovered. However, infection was uniformly lethal within 7 to 12 days post-exposure in five BXD strains. Aerosol exposure of these five BXD strains to 10-fold less MA-EBOV resulted in lethality ranging from 0% in two strains to 90–100% lethality in two strains. Analysis of post-mortem tissue from BXD strains that became moribund and were euthanized at the lower dose of MA-EBOV, showed liver damage in all mice as well as lung lesions in two of the three strains. The two BXD strains that exhibited 90–100% mortality, even at a low dose of airborne MA-EBOV will be useful mouse models for testing vaccines and therapies. Additionally, since disease susceptibility is affected by complex genetic traits, a systems genetics approach was used to identify preliminary gene loci modulating disease severity among the panel BXD strains. Preliminary quantitative trait loci (QTLs) were identified that are likely to harbor genes involved in modulating differential susceptibility to Ebola infection.e article] [PubMed]

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 50%.

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.

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 2011 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.


[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?

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.

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..." 

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.

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.

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.

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.

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?

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.  I have seen no information about insect transmission, but the possibility should not be discarded out of hand.

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.

Thursday, October 2, 2014

Drilling Down Into the Facts Regarding Airborne Spread of Ebola/ CIDRAP (U MInnesota)

I will post this article in its entirety, but will put the most interesting bits in red so readers can skim the piece for these if they wish--Meryl

http://www.cidrap.umn.edu/news-perspective/2014/09/commentary-health-workers-need-optimal-respiratory-protection-ebola

COMMENTARY: Health workers need optimal respiratory protection for Ebola
cidrap.umn.edu /news-perspective/2014/09/commentary-health-workers-need-optimal-respiratory- protection-ebola

Lisa M Brosseau, ScD, and Rachael Jones, PhD | Sep 17, 2014
Editor's Note: Today's commentary was submitted to CIDRAP by the authors, who are national experts on respiratory protection and infectious disease transmission. In May they published a similar commentary on MERS-CoV. Dr Brosseau is a Professor and Dr Jones an Assistant Professor in the School of Public Health, Division of Environmental and Occupational Health Sciences, at the University of Illinois at Chicago.

Healthcare workers play a very important role in the successful containment of outbreaks of infectious diseases like Ebola. The correct type and level of personal protective equipment (PPE) ensures that healthcare workers remain healthy throughout an outbreak—and with the current rapidly expanding Ebola outbreak in West Africa, it's imperative to favor more conservative measures.
The precautionary principle—that any action designed to reduce risk should not await scientific certainty— compels the use of respiratory protection for a pathogen like Ebola virus that has:
No proven pre- or post-exposure treatment modalities A high case-fatality rate Unclear modes of transmission
We believe there is scientific and epidemiologic evidence that Ebola virus has the potential to be transmitted via infectious aerosol particles both near and at a distance from infected patients, which
means that healthcare workers should be wearing respirators, not facemasks.1
The minimum level of protection in high-risk settings should be a respirator with an assigned protection factor greater than 10. A powered air-purifying respirator (PAPR) with a hood or helmet offers many advantages over an N95 filtering facepiece or similar respirator, being more protective, comfortable, and cost-effective in the long run.
We strongly urge the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) to seek funds for the purchase and transport of PAPRs to all healthcare workers currently fighting the battle against Ebola throughout Africa—and beyond.
There has been a lot of on-line and published controversy about whether Ebola virus can be transmitted via aerosols. Most scientific and medical personnel, along with public health organizations, have been unequivocal in their statements that Ebola can be transmitted only by direct contact with virus-laden
fluids2,3 and that the only modes of transmission we should be concerned with are those termed "droplet"
and "contact."
These statements are based on two lines of reasoning. The first is that no one located at a distance from an infected individual has contracted the disease, or the converse, every person infected has had (or must have had) "direct" contact with the body fluids of an infected person.
This reflects an incorrect and outmoded understanding of infectious aerosols, which has been institutionalized in policies, language, culture, and approaches to infection control. We will address this below. Briefly, however, the important points are that virus-laden bodily fluids may be aerosolized and inhaled while a person is in proximity to an infectious person and that a wide range of particle sizes can be inhaled and deposited throughout the respiratory tract.
The second line of reasoning is that respirators or other control measures for infectious aerosols cannot be recommended in developing countries because the resources, time, and/or understanding for such
measures are lacking.4
Although there are some important barriers to the use of respirators, especially PAPRs, in developing countries, healthcare workers everywhere deserve and should be afforded the same best-practice types of protection, regardless of costs and resources. Every healthcare worker is a precious commodity whose well-being ensures everyone is protected.
If we are willing to offer infected US healthcare workers expensive treatments and experimental drugs free of charge when most of the world has no access to them, we wonder why we are unwilling to find the resources to provide appropriate levels of comparatively less expensive respiratory protection to every healthcare worker around the world.
How are infectious diseases transmitted via aerosols?
Medical and infection control professionals have relied for years on a paradigm for aerosol transmission of infectious diseases based on very outmoded research and an overly simplistic interpretation of the data. In the 1940s and 50s, William F. Wells and other "aerobiologists" employed now significantly out-of-date sampling methods (eg, settling plates) and very blunt analytic approaches (eg, cell culturing) to understand the movement of bacterial aerosols in healthcare and other settings. Their work, though groundbreaking at the time, provides a very incomplete picture.
Early aerobiologists were not able to measure small particles near an infectious person and thus assumed such particles existed only far from the source. They concluded that organisms capable of aerosol transmission (termed "airborne") can only do so at around 3 feet or more from the source. Because they thought that only larger particles would be present near the source, they believed people would be exposed only via large "droplets" on their face, eyes, or nose.
Modern research, using more sensitive instruments and analytic methods, has shown that aerosols emitted from the respiratory tract contain a wide distribution of particle sizes—including many that are
small enough to be inhaled.5,6 Thus, both small and large particles will be present near an infectious person.
The chance of large droplets reaching the facial mucous membranes is quite small, as the nasal openings are small and shielded by their external and internal structure. Although close contact may permit large- droplet exposure, it also maximizes the possibility of aerosol inhalation.
As noted by early aerobiologists, liquid in a spray aerosol, such as that generated during coughing or sneezing, will quickly evaporate,7 which increases the concentration of small particles in the aerosol.
Because evaporation occurs in milliseconds, many of these particles are likely to be found near the infectious person.
The current paradigm also assumes that only "small" particles (less than 5 micrometers [mcm]) can be inhaled and deposited in the respiratory tract. This is not true. Particles as large as 100 mcm (and perhaps even larger) can be inhaled into the mouth and nose. Larger particles are deposited in the nasal passages, pharynx, and upper regions of the lungs, while smaller particles are more likely to deposit in the lower, alveolar regions. And for many pathogens, infection is possible regardless of the particle size or deposition site.
It's time to abandon the old paradigm of three mutually exclusive transmission routes for a new one that considers the full range of particle sizes both near and far from a source. In addition, we need to factor in other important features of infectivity, such as the ability of a pathogen to remain viable in air at room temperature and humidity and the likelihood that systemic disease can result from deposition of infectious particles in the respiratory system or their transfer to the gastrointestinal tract.
We recommend using "aerosol transmissible" rather than the outmoded terms "droplet" or "airborne" to describe pathogens that can transmit disease via infectious particles suspended in air.
Is Ebola an aerosol-transmissible disease?
We recently published a commentary on the CIDRAP site discussing whether Middle East respiratory syndrome (MERS) could be an aerosol-transmissible disease, especially in healthcare settings. We drew comparisons with a similar and more well-studied disease, severe acute respiratory syndrome (SARS).
For Ebola and other filoviruses, however, there is much less information and research on disease transmission and survival, especially in healthcare settings.
Being at first skeptical that Ebola virus could be an aerosol-transmissible disease, we are now persuaded by a review of experimental and epidemiologic data that this might be an important feature of disease transmission, particularly in healthcare settings.
What do we know about Ebola transmission?
No one knows for certain how Ebola virus is transmitted from one person to the next. The virus has been
found in the saliva, stool, breast milk, semen, and blood of infected persons.8,9 Studies of transmission in Ebola virus outbreaks have identified activities like caring for an infected person, sharing a bed, funeral
activities, and contact with blood or other body fluids to be key risk factors for transmission.10-12
On the basis of epidemiologic evidence, it has been presumed that Ebola viruses are transmitted by contaminated hands in contact with the mouth or eyes or broken skin or by splashes or sprays of body fluids into these areas. Ebola viruses appear to be capable of initiating infection in a variety of human cell
types,13,14 but the primary portal or portals of entry into susceptible hosts have not been identified.
Some pathogens are limited in the cell type and location they infect. Influenza, for example, is generally restricted to respiratory epithelial cells, which explains why flu is primarily a respiratory infection and is most likely aerosol transmissible. HIV infects T-helper cells in the lymphoid tissues and is primarily a bloodborne pathogen with low probability for transmission via aerosols.
Ebola virus, on the other hand, is a broader-acting and more non-specific pathogen that can impede the proper functioning of macrophages and dendritic cells—immune response cells located throughout the
epithelium.15,16 Epithelial tissues are found throughout the body, including in the respiratory tract. Ebola
prevents these cells from carrying out their antiviral functions but does not interfere with the initial inflammatory response, which attracts additional cells to the infection site. The latter contribute to further dissemination of the virus and similar adverse consequences far beyond the initial infection site.
The potential for transmission via inhalation of aerosols, therefore, cannot be ruled out by the observed risk factors or our knowledge of the infection process. Many body fluids, such as vomit, diarrhea, blood, and saliva, are capable of creating inhalable aerosol particles in the immediate vicinity of an infected person. Cough was identified among some cases in a 1995 outbreak in Kikwit, Democratic Republic of the
Congo,11 and coughs are known to emit viruses in respirable particles.17 The act of vomiting produces an
aerosol and has been implicated in airborne transmission of gastrointestinal viruses.18,19 Regarding diarrhea, even when contained by toilets, toilet flushing emits a pathogen-laden aerosol that disperses in
the air.20-22
Experimental work has shown that Marburg and Ebola viruses can be isolated from sera and tissue culture medium at room temperature for up to 46 days, but at room temperature no virus was recovered from
glass, metal, or plastic surfaces.23 Aerosolized (1-3 mcm) Marburg, Ebola, and Reston viruses, at 50% to 55% relative humidity and 72°F, had biological decay rates of 3.04%, 3.06%. and 1.55% per minute, respectively. These rates indicate that 99% loss in aerosol infectivity would occur in 93, 104, and 162
minutes, respectively.23
In still air, 3-mcm particles can take up to an hour to settle. With air currents, these and smaller particles can be transported considerable distances before they are deposited on a surface.
There is also some experimental evidence that Ebola and other filoviruses can be transmitted by the
aerosol route. Jaax et al24 reported the unexpected death of two rhesus monkeys housed approximately 3 meters from monkeys infected with Ebola virus, concluding that respiratory or eye exposure to aerosols was the only possible explanation.
Zaire Ebola viruses have also been transmitted in the absence of direct contact among pigs 25 and from pigs to non-human primates,26 which experienced lung involvement in infection. Persons with no known direct contact with Ebola virus disease patients or their bodily fluids have become infected.12
Direct injection and exposure via a skin break or mucous membranes are the most efficient ways for Ebola to transmit. It may be that inhalation is a less efficient route of transmission for Ebola and other filoviruses,
as lung involvement has not been reported in all non-human primate studies of Ebola aerosol infectivity.27 However, the respiratory and gastrointestinal systems are not complete barriers to Ebola virus. Experimental studies have demonstrated that it is possible to infect non-human primates and other
mammals with filovirus aerosols.25-27
Altogether, these epidemiologic and experimental data offer enough evidence to suggest that Ebola and
other filoviruses may be opportunistic with respect to aerosol transmission.28 That is, other routes of entry may be more important and probable, but, given the right conditions, it is possible that transmission could also occur via aerosols.
Guidance from the CDC and WHO recommends the use of facemasks for healthcare workers providing routine care to patients with Ebola virus disease and respirators when aerosol-generating procedures are performed. (Interestingly, the 1998 WHO and CDC infection-control guidance for viral hemorrhagic fevers in Africa, still available on the CDC Web site, recommends the use of respirators.)
Facemasks, however, do not offer protection against inhalation of small infectious aerosols, because they
lack adequate filters and do not fit tightly against the face.1 Therefore, a higher level of protection is necessary.
Which respirator to wear?
As described in our earlier CIDRAP commentary, we can use a Canadian control-banding approach to
select the most appropriate respirator for exposures to Ebola in healthcare settings.29 (See this document for a detailed description of the Canadian control banding approach and the data used to select respirators in our examples below.)
The control banding method involves the following steps:
1. Identify the organism's risk group (1 to 4). Risk group reflects the toxicity of an organism, including the degree and type of disease and whether treatments are available. Ebola is in risk group 4, the most toxic organisms, because it can cause serious human or animal disease, is easily transmitted, directly or indirectly, and currently has no effective treatments or preventive measures.
2. Identify the generation rate. The rate of aerosol generation reflects the number of particles created per time (eg, particles per second). Some processes, such as coughing, create more aerosols than others, like normal breathing. Some processes, like intubation and toilet flushing, can rapidly generate very large quantities of aerosols. The control banding approach assigns a qualitative rank ranging from low (1) to high (4) (eg, normal breathing without coughing has a rank of 1).
3. Identify the level of control. Removing contaminated air and replacing it with clean air, as accomplished with a ventilation system, is effective for lowering the overall concentration of infectious aerosol particles in a space, although it may not be effective at lowering concentration in the immediate vicinity of a source. The number of air changes per hour (ACH) reflects the rate of air removal and replacement. This is a useful variable, because it is relatively easy to measure and, for hospitals, reflects building code requirements for different types of rooms. Again, a qualitative ranking is used to reflect low (1) versus high (4) ACH. Even if the true ventilation rate is not known, the examples can be used to select an appropriate air exchange rate.
4. Identify the respirator assigned protection factor. Respirators are designated by their "class," each of which has an assigned protection factor (APF) that reflects the degree of protection. The APF represents the outside, environmental concentration divided by the inside, facepiece concentration. An APF of 10 means that the outside concentration of a particular contaminant will be 10 times greater than that inside the respirator. If the concentration outside the respirator is very high, an assigned protection factor of 10 may not prevent the wearer from inhaling an infective dose of a highly toxic organism.
Practical examples
Two examples follow. These assume that infectious aerosols are generated only during vomiting, diarrhea, coughing, sneezing, or similar high-energy emissions such as some medical procedures. It is possible that Ebola virus may be shed as an aerosol in other manners not considered.
Caring for a patient in the early stages of disease (no bleeding, vomiting, diarrhea, coughing, sneezing, etc). In this case, the generation rate is 1. For any level of control (less than 3 to more than 12 ACH), the control banding wheel indicates a respirator protection level of 1 (APF of 10), which corresponds to an air purifying (negative pressure) half-facepiece respirator such as an N95 filtering facepiece respirator. This type of respirator requires fit testing.
Caring for a patient in the later stages of disease (bleeding, vomiting, diarrhea, etc). If we assume the highest generation rate (4) and a standard patient room (control level = 2, 3-6 ACH), a respirator with an APF of at least 50 is needed. In the United States, this would be equivalent to either a full-facepiece air- purifying (negative-pressure) respirator or a half-facepiece PAPR (positive pressure), but standards differ in other countries. Fit testing is required for these types of respirators.
The control level (room ventilation) can have a big effect on respirator selection. For the same patient housed in a negative-pressure airborne infection isolation room (6-12 ACH), a respirator with an assigned protection factor of 25 is required. This would correspond in the United States to a PAPR with a loose- fitting facepiece or with a helmet or hood. This type of respirator does not need fit testing.
Implications for protecting health workers in Africa
Healthcare workers have experienced very high rates of morbidity and mortality in the past and current Ebola virus outbreaks. A facemask, or surgical mask, offers no or very minimal protection from infectious aerosol particles. As our examples illustrate, for a risk group 4 organism like Ebola, the minimum level of protection should be an N95 filtering facepiece respirator.
This type of respirator, however, would only be appropriate only when the likelihood of aerosol exposure is very low. For healthcare workers caring for many patients in an epidemic situation, this type of respirator may not provide an adequate level of protection.
For a risk group 4 organism, any activity that has the potential for aerosolizing liquid body fluids, such as medical or disinfection procedures, should be avoided, if possible. Our risk assessment indicates that a PAPR with a full facepiece (APF = 50) or a hood or helmet (APF = 25) would be a better choice for patient care during epidemic conditions.
We recognize that PAPRs present some logistical and infection-control problems. Batteries require frequent charging (which requires a reliable source of electricity), and the entire ensemble requires careful handling and disinfection between uses. A PAPR is also more expensive to buy and maintain than other types of respirators.
On the other hand, a PAPR with a loose-fitting facepiece (hood or helmet) does not require fit testing. Wearing this type of respirator minimizes the need for other types of PPE, such as head coverings and goggles. And, most important, it is much more comfortable to wear than a negative-pressure respirator like an N95, especially in hot environments.
A recent report from a Medecins Sans Frontieres healthcare worker in Sierra Leone 30 notes that healthcare workers cannot tolerate the required PPE for more than 40 minutes. Exiting the workplace every 40 minutes requires removal and disinfection or disposal (burning) of all PPE. A PAPR would allow much longer work periods, use less PPE, require fewer doffing episodes, generate less infectious waste, and be more protective. In the long run, we suspect this type of protection could also be less expensive.
Adequate protection is essential
To summarize, for the following reasons we believe that Ebola could be an opportunistic aerosol- transmissible disease requiring adequate respiratory protection:
Patients and procedures generate aerosols, and Ebola virus remains viable in aerosols for up to 90 minutes.
All sizes of aerosol particles are easily inhaled both near to and far from the patient.
Crowding, limited air exchange, and close interactions with patients all contribute to the probability that healthcare workers will be exposed to high concentrations of very toxic infectious aerosols.
Ebola targets immune response cells found in all epithelial tissues, including in the respiratory and gastrointestinal system.
Experimental data support aerosols as a mode of disease transmission in non-human primates.
Risk level and working conditions suggest that a PAPR will be more protective, cost-effective, and comfortable than an N95 filtering facepiece respirator.
Acknowledgements
We thank Kathleen Harriman, PhD, MPH, RN, Chief, Vaccine Preventable Diseases Epidemiology Section, Immunization Branch, California Department of Public Health, and Nicole Vars McCullough, PhD, CIH, Manager, Global Technical Services, Personal Safety Division, 3M Company, for their input and review.
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Tuesday, September 30, 2014

US Ebola: Frieden Said Every Hospital Was Ready. He is Wrong.

Have you ever been face to face with a doctor dressed in rubber boots, a rubber suit, 2-3 pairs of gloves, 2 pairs of goggles and a hood?  I haven't.  Doctor journalist Richard Besser described the get-up he had to wear in an Ebola ward in Liberia.  I would faint if I had to wear all this for more than a few minutes, being unaccustomed to temperatures over 100 degrees coupled with high humidity.

If this outfit is truly necessary to care for Ebola patients, we are simply NOT prepared.  I do not believe hospitals have stockpiled rubber suits and boots, nor many pairs of goggles, as they have never been needed before for any infections transmitted within the US.

Hospitals do have isolation rooms, and a few negative pressure rooms, but not enough for dealing with a large outbreak.  

Despite the occasional disaster drill, very few of our medical staff have ever had to protect themselves from (life-threatening) hemorrhagic fever infections in their patients.  Hospital-acquired infections, due to infection control challenges such as the fact of shared doorknobs, sinks and toilets, still are common in the US. These infections affect both staff and patients. How well hospital staff will do, faced with possible Ebola cases, is unclear.

How well we will be able to separate Ebola from non-Ebola febrile patients will be a major problem.  The US could easily see healthcare facilities become places where Ebola spreads, just as is happening in Africa.  Why?  You can't isolate Ebola patients from other patients effectively, until after those with Ebola have become highly contagious, because you cannot diagnose them any earlier: the tests available today are not sensitive enough.  I cannot imagine everyone in a waiting room wearing a moon suit. One person vomiting would negate all that personal protective equipment.

Where would they safely gown up? In a bathroom, where the disease is most likely to spread?  How would doctors and nurses know which patients to wear the gear for, and which not?

A significant related problem is the current inability to diagnose the infection at the local hospital level, coupled with the inability to diagnose cases until after they are highly infectious.  Only a few centers can currently perform tests for Ebola.  CDC's website has detailed information about shipping specimens to CDC for testing  But the website currently has no information on any other laboratories that can safely and accurately perform these tests at the local or regional level.  (Texas' state public health lab apparently has this capacity. Who else does?)  How long will it take to get a confirmatory test result when the CDC's lab capacity is overwhelmed?

Tests (according to CDC) are only expected to be positive after 3-10 days of clinical illness. Most people will be critically ill (or dead) by the time a confirmed laboratory diagnosis can be made. 

You have to ship the specimen carefully as it is infectious.  (See packaging instructions below.) You have to get permission from CDC before you ship any material for testing.  CDC does not accept materials for testing on weekends. From CDC:
Diagnostic Testing for Ebola Performed at CDC
Several diagnostic tests are available for detection of EVD. Acute infections will be confirmed using a real-time RT-PCR assay (CDC test directory code CDC -10309 Ebola Identification) in a CLIA-certified laboratory. Virus isolation may also be attempted. Serologic testing for IgM and IgG antibodies will be completed for certain specimens and to monitor the immune response in confirmed EVD patients (#CDC-10310 Ebola Serology).
Lassa fever is also endemic in certain areas of West Africa and may show symptoms similar to early EVD. Diagnostic tests available at CDC include but are not limited to RT-PCR, antigen detection, and IgM serology all of which may be utilized to rule out Lassa fever in EVD-negative patients.
Packaging and Shipping Clinical Specimens to CDCPackaging and Shipping Clinical Specimens DiagramPACKAGING DIAGRAM
Specimens collected for EVD testing should be packaged and shipped without attempting to open collection tubes or aliquot specimens.
The following steps should be used in submitting samples to CDC.
  • Hospitals should follow their state and/or local health department procedures for notification and consultation for Ebola testing requests and prior to contacting CDC.
  • NO specimens will be accepted without prior consultation. For consultation call the EOC at 770-488-7100.
  • Contact your state and/or local health department and CDC to determine the proper category for shipment based on clinical history and risk assessment by CDC. State guidelines may differ and state or local health departments should be consulted prior to shipping.
  • Do not ship for weekend delivery unless instructed by CDC...

UPDATE:  USAMRIID in Frederick, Maryland is one of the few facilities in the US with a specially designed clinical unit for treating patients infected with biosafety level 4 pathogens, such as Ebola. (Nebraska and CDC have two others.  Forbes says there are 5 such isolation units in the US.)  Ten years ago a researcher was stuck with a needle from Ebola-infected mice.  Dr. Mark Kortepeter describes the USAMRIID center and the circumstances of care of the affected researcher.  It is apparent that the facilities deemed necessary for such care of biodefense researchers go way beyond what is available in community hospitals in the US.


UPDATE:  The Forbes article mentions other logistical challenges of treating Ebola:
“At its peak, we were up to 40 bags a day of medical waste, which took a huge tax on our waste management system,” according to Emory’s Dr. Aneesh Mehta. But Emory’s waste management company wasn’t willing to take the infectious waste off of Emory’s hands, at first...

Sunday, September 28, 2014

Ebola Opinion: What do you do when you can't tell those with Ebola from patients with other conditions?

Distinguishing Ebola cases from others is the most immediate need for health care providers and patients.  If you cannot determine immediately who is infected, patients with other conditions will be lumped with possible Ebola patients, and may contract Ebola as a result of healthcare!

Even worse (from the point of view of medical providers) is that nurses and doctors will not know for which patients extreme personal protection measures are needed.  Dr. Brantly felt he was exposed to Ebola not in the Ebola ward, but when caring for patients in other areas who had not been diagnosed with Ebola, but had it and were spreading it, while they were believed to have a different problem.

What is the solution?  Reverse transcriptase PCR is used currently.  It requires fancy equipment, plenty of training and a clean lab.  This is not a test that can be performed in the bush.  Immunoassays can also be done, but are not suitable for early detection nor use in rural communities.

According to UpToDate:

Virus is generally detectable by RT-PCR between 3 and 10 days after the onset of symptoms [1]. The demonstration of genetic diversity and rapid accumulation of sequence changes of Ebola virus in the West African epidemic indicates that careful monitoring will be needed to ensure the continued sensitivity of RT-PCR diagnostics [2]. Antigen detection may be used as a confirmatory test for immediate diagnosis [3].
In some cases, testing for IgM or IgG antibodies to Ebola virus may also be useful to monitor the immune response over time and/or evaluate for past infection.

What is needed to deal with Ebola at the village level is a test that could be performed in rural clinics, such as a urine antigen test, and it would need to detect low levels of antigen for earlier, asymptomatic detection. Preferably, the test would employ a card, with a spot that changes color when Ebola virus antigen is detected. Serious consideration should be given to developing rectal and saliva Ebola antigen tests as well.

Were such a test available, it could be performed daily on patients so, as soon as patients began to excrete even low levels of virus, they would be moved to an isolation facility. Testing patients for Ebola just once, using any current method, will miss some number of cases, and those missed cases could infect their families and medical personnel.

Until Ebola can be quickly identified and non-Ebola patients are safely managed (away from all Ebola patients) the healthcare systems in Ebola-ravaged countries will remain crippled.
  1. The Centers for Disease Control and Prevention. Interim Guidance for specimen collection, transport, testing, and submission for Patients with Suspected Infection with Ebola Virus.Disease http://www.cdc.gov/vhf/ebola/pdf/ebola- lab-guidance.pdf (Accessed on August 25, 2014).
  2. Gire SK, Goba A, Andersen KG, et al. Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. http://www.sciencemag.org/content/early/2014/08/27/science.1259657.full.pdf.
  3. Feldmann H. Ebola - A Growing Threat? N Engl J Med 2014.

Wednesday, September 17, 2014

New Evidence that Artificial Sweeteners are Poisons/ WaPo

If you were ever my patient and asked about artificial sweeteners, you would have gotten an earful. There is so much available data on the problems with them.  

And the study referenced here suggests artificial sweeteners actually cause the problem that are supposed to be helping to prevent or ameliorate:  glucose intolerance. From today's WaPo:
Artificial sweeteners might be triggering higher blood-sugar levels in some people and contributing to the problems they were designed to combat, such as diabetes and obesity, according to new findings published Wednesday in the journal Nature.
Although the precise reasons behind the blood-sugar changes remain uncertain, researchers suspect that artificial sweeteners could be disrupting the microbiome, a vast and enigmatic ecosystem of bacteria in our guts.
In a series of experiments, researchers found that several of the most widely used types of non-calorie sweeteners in food and drinks — saccharin, sucra­lose and aspartame — caused mice to experience increased risk of glucose intolerance, a condition that can lead to diabetes.
“We are talking about very dramatic increases,” said one of the study’s co-authors, Eran Segal, a computational biologist at the Weizmann Institute of Science in Israel.
The same scientists also monitored what happened to seven human volunteers who did not typically use artificial sweeteners but were given regular doses of saccharin over the course of a week. Four developed significant glucose intolerance. Separately, the researchers analyzed nearly 400 people and found that the gut bacteria of those who used artificial sweeteners were noticeably different from people who did not...

Friday, September 12, 2014

Cuba Responds To Ebola Crisis As Black Market For Convalescent Serum Emerges/ Forbes

Where can you find hundreds of doctors who can leave their practices and deploy to Africa?  In Cuba, where they have deployed large numbers of doctors to Africa many times before.  
Cuba has a higher doctor-patient ratio than the US. Cuba uses American medical textbooks to train its doctors and has a very high standard of medical care; it also trains many medical professionals from poor nations, so can connect easily with medical professionals in countries where its people are deployed.  What it lacks is money.  Fortunately, the WHO will pick up the tab.  

The sobering news is that there are no more Cuba's waiting in the wings to provide medical professionals for a potentially deadly assignment in Africa.  Other nations do not maintain a doctor surplus, nor do they encourage the "esprit de corps" culture that makes doctors willing to volunteer for potentially deadly assignments.  From Forbes:

Cuba will be sending 63 doctors and 102 nurses, epidemiologists, specialists in infection control, intensive care specialists and social mobilization officers to set up World Health Organization-funded Ebola clinics in Sierra Leone. The workers will deploy in the beginning of October and stay for six months...
Dr. Margaret Chan, WHO Director-General, said that the Cuban response was the first since her United Nations visit last week and “international rescue call” by UN Secretary-General Ban Ki-moon for a scale-up of aid and personnel to combat Ebola in west Africa.
Chan said today, “The thing we need most of all is people: health care workers...”

Graphing Ebola Deaths in Africa/ BBC

IMHO, many cases and deaths have not been included in these numbers because they occurred in areas without the infrastructure to count them, or were hidden.  Still the rate of increase in cases is chilling and tells me we have likely lost the battle to contain this epidemic.  From the BBC:Cumulative deaths - up to 5 September
Ebola deaths
Only going up
The stories of healthcare workers being stretched beyond breaking point are countless.
A lack of basic protective gear such as gloves has been widely reported.

Start Quote

If current trends persist we would be seeing not hundreds of cases per week, but thousands of cases per week and that is terribly disturbing”
Dr Christopher DyeWorld Health Organization
The charity Medecins Sans Frontieres has an isolation facility with 160 beds in Monrovia. But it says the queues are growing and they need another 800 beds to deal with the number of people who are already sick.
This is not a scenario for containing an epidemic, but fuelling one.
Dr Dye's tentative forecasts are grim: "At the moment we're seeing about 500 new cases each week. Those numbers appear to be increasing.
"I've just projected about five weeks into the future and if current trends persist we would be seeing not hundreds of cases per week, but thousands of cases per week and that is terribly disturbing.
"The situation is bad and we have to prepare for it getting worse."
The World Health Organization is using an educated guess of 20,000 cases before the end, in order to plan the scale of the response.

But the true potential of the outbreak is unknown and the WHO figure has been described to me as optimistic by some scientists...

Thursday, September 11, 2014

Ebola strategies/ Nass

I anticipate a huge loss of life from Ebola in Africa, due to the lack of medical and all other infrastructure in so much of the continent.

Africans are like everyone else:  they want to save their family members.  If treatment centers are available that will increase the chance of survival, they will utilize them.  The capability to give appropriate iv fluids and replace electrolytes is what is needed, at a minimum. But if all the healthcare system can do is provide quarantine centers, which guarantee exposure to ebola victims without effective treatments, why would anyone go there?  Instead, cases will be hidden from the authorities, making case-finding impossible.

Africa does not have enough people who can manage the needed number of iv's, especially when drawing blood exposes the health care worker to the disease.  Africa's medical systems lack iv fluids, medicines, personal protective equipment, laboratories and well-trained staff who can safely use these products. To give the correct iv fluids and electrolytes, you need frequent lab tests and blood draws.  (I cannot even imagine using arterial lines in bush hospitals, so will not discuss them further; they would be part of ICU monitoring here.)  The bottom line is that there will never be sufficient 'first world-style' treatment centers, given the rate of increase in cases and the inability to identify many cases and contacts, and isolate them.

But maybe there is a somewhat effective, low tech partial solution.  Dr. Brantly said that patients with Ebola sometimes would grab their chests and fall over dead.  From his own case and others, we have learned that Ebola causes electrolyte and fluid abnormalities that are associated with life-threatening cardiac arrhythmias.

What saves lives in cholera epidemics, when intensive medical car is unavailable, is oral rehydration fluid.  These products contain sugar, salts, bicarbonate and water.  If the patient can keep the fluids and electrolytes down, they rapidly enter the bloodstream from the stomach and small intestine, creating a similar effect as iv fluids.

The treatment is cheap.  It requires no trained medical staff.  It works when toxins have led to efflux of sodium, potassium, bicarbonate and water from intestinal cells.  Ebola diarrhea might require a slightly different mix or ratio of electrolytes.  From looking at what the 4 Americans, who were brought back to the US for treatment, received via iv fluids, some good guesses can be made about the best oral rehydration fluids to try.

Such "bush treatment" might save lives and encourage families to bring their loved ones to less well equipped centers for treatment, if the oral rehydration is found to be effective.  This could have a positive impact on case-finding.  Families would also potentially be able to purchase the fluid packets in the markets, for treatment at home.  (Similar packets are sold for at-home treatment of infant diarrheas.)

This idea is worthy of testing, as case numbers are bound to grow exponentially--and the world's resources are unlikely to be able to create hospitals and supply health care professionals in adequate numbers to provide standard treatments to most of those affected.  This could be a stand-in, while we await more targeted treatments.

UPDATE:  From the WaPo, a piece titled, "The World Yawns as Ebola Takes Hold in West Africa" by Richard Besser, MD and former head of Emergency Response at CDC:
... There’s no cure for Ebola, but supportive treatment as simple as supplementary fluids can save lives and slow the spread of the disease. But many treatment centers are unable to provide even rudimentary care. Last week, the World Health Organization and the U.S. Centers for Disease Control and Prevention called for more support for the region. CDC Director Tom Frieden talked about the window of opportunity for the world to respond — a window that is quickly closing...

Tuesday, August 19, 2014

Over 1,100 "Incidents" (aka escapes) with dangerous "Select Agents" were reported in the US during 2008-2012/ USA Today

Just in case you thought that CDC and federal regulators had things under control regarding research on microorganisms that can be used in bioterrorism, think again.  There were an average of 4 reported escapes each week over the 5 years that ended with 2012.

From USA Today, "The only thing unusual about the CDC's recent anthrax and bird flu lab incidents, Ebright said, is that the public found out about them. 'The 2014 CDC anthrax event became known to the public only because the number of persons requiring medical evaluation was too high to conceal,'  he said."  Here is another excerpt; it is chilling:

More than 1,100 laboratory incidents involving bacteria, viruses and toxins that pose significant or bioterror risks to people and agriculture were reported to federal regulators during 2008 through 2012, government reports obtained by USA TODAY show.
More than half these incidents were serious enough that lab workers received medical evaluations or treatment, according to the reports. In five incidents, investigations confirmed that laboratory workers had been infected or sickened; all recovered.
In two other incidents, animals were inadvertently infected with contagious diseases that would have posed significant threats to livestock industries if they had spread. One case involved the infection of two animals with hog cholera, a dangerous virus eradicated from the USA in 1978. In another incident, a cow in a disease-free herd next to a research facility studying the bacteria that cause brucellosis, became infected due to practices that violated federal regulations, resulting in regulators suspending the research and ordering a $425,000 fine, records show.
But the names of the labs that had mishaps or made mistakes, as well as most information about all of the incidents, must be kept secret because of federal bioterrorism laws, according to the U.S. Department of Agriculture, which regulates the labs and co-authored the annual lab incident reports with the Centers for Disease Control and Prevention...