Thursday, October 30, 2014

Hospitals are not ready, and cannot get ready in time for Ebola/ AP

On Sept 30 I wrote a blog post about how CDC's Director Frieden was wrong to claim that any US hospital could manage an Ebola patient.  Circumstances sadly proved me right in the case of Dallas, Texas.  Has that changed now that we have had more time to prepare?

After the death of Thomas Eric Duncan, every Ebola patient in the US was treated in one of 4 specialized US bio-containment ICU-level facilities, and survived.  Then Dr. Spencer developed Ebola, and he was placed in NYC's Bellevue Hospital, in an Ebola-designated isolation ward.  As best we know, he has done well.  Does this mean US hospitals have gotten up to speed on Ebola?

No.  Most people are not aware that both Mr. Duncan and Dr. Spencer were treated in ICUs where they were the only patient.  Everyone else was moved out before they got there. Bellevue had to transfer patients to another hospital to free up the many staff needed to care for him.  Nurse Pham had 25 health care providers working on her alone, at NIH.  The WSJ noted that building an appropriate isolation room, comparable to a hospital within a hospital, cost Bellevue $3-4 million dollars per patient room.

Last night, the Associated Press did an in-depth story about the Ebola preparedness of US hospitals. It echoed my concerns.  Specifically:
  • 75% of ER and Infectious Disease docs felt their facilities were not prepared for Ebola
  • the average number of protective suits with powered air-purifying respirators (PAPRs) per hospital is ten
  • Despite hundreds of millions of dollars spent on Ebola research, there are no countermeasures
  • As of last week, there "were no [federal] emergency stockpiles of the waterproof gowns, surgical hoods, full face shields, boot covers or other gear that the CDC recommends for treating Ebola patients." 
  • "Among isolation care doctors and nurses, 14 percent said they'd call in sick, and one in four critical care and emergency staff said the same. Among the isolation care staff, 17 percent said they wouldn't work near Ebola patients; half of critical care and emergency staff said the same.
  • Adalja, a member of the Public Health Committee of the Infectious Disease Society of America, called the survey findings troubling and contended they show that many medical staffers "are not confident in the infection control procedures at their hospital.'"
Both the AP story, and the head of Johns' Hopkins Emergency Services, note the need for more bio-containment units, where patients can be safely treated without exposing healthcare workers or other patients to Ebola.  But Bio-Containment units will be insufficient if the US has hundreds or thousands of Ebola patient, as the number of patients will exceed the entire country's ability to safely and effectively provide them the very complex care that is needed to pull them through.

Ebola causes a clinical illness characterized by cytokine storm, capillary leak syndrome, disseminated intravascular coagulation, and multiorgan failure.  This is why some patients have needed dialysis and ventilation.  Dr. Bruce Ribner, who cared for several Ebola patients at Emory, notes:

"The general dogma in our industry in July was that if patients got so ill that they required dialysis or ventilator support there was no purpose in doing those interventions because they would invariably die," Ribner said."I think we have changed the algorithm for how aggressive we can be in caring for patients with Ebola virus."
Even with the best of care at US hospitals, patients with these syndromes have an approximately 50% survival rate.  It is unlikely that the US healthcare system will be able to duplicate the current  89% survival rate, once the number of Ebola patients needing care increases.  And the dogma could revert to one of not performing such aggressive measures, which place healthcare workers at the most risk, once case numbers rise.

Wednesday, October 29, 2014

Emerging targets and novel approaches to Ebola virus prophylaxis and treatment.

This article discusses literally a couple dozen vaccines and drugs that are in development for Ebola.  How is their testing being fast-tracked ?

 2013 Dec;27(6):565-83. doi: 10.1007/s40259-013-0046-1.
Choi JH1, Croyle MA.

Abstract

Ebola is a highly virulent pathogen causing severe hemorrhagic fever with a high case fatality rate in humans and non-human primates (NHPs). Although safe and effective vaccines or other medicinal agents to block Ebola infection are currently unavailable, a significant effort has been put forth to identify several promising candidates for the treatment and prevention of Ebola hemorrhagic fever. Among these, recombinant adenovirus-based vectors have been identified as potent vaccine candidates, with some affording both pre- and post-exposure protection from the virus. Recently, Investigational New Drug (IND) applications have been approved by the US Food and Drug Administration (FDA) and phase I clinical trials have been initiated for two small-molecule therapeutics: anti-sense phosphorodiamidate morpholino oligomers (PMOs: AVI-6002, AVI-6003) and lipid nanoparticle/small interfering RNA (LNP/siRNA: TKM-Ebola). These potential alternatives to vector-based vaccines require multiple doses to achieve therapeutic efficacy, which is not ideal with regard to patient compliance and outbreak scenarios. These concerns have fueled a quest for even better vaccination and treatment strategies. Here, we summarize recent advances in vaccines or post-exposure therapeutics for prevention of Ebola hemorrhagic fever. The utility of novel pharmaceutical approaches to refine and overcome barriers associated with the most promising therapeutic platforms are also discussed.

Tuesday, October 28, 2014

The survival of filoviruses (Ebola and Marburg) in liquids, on solid substrates and in a dynamic aerosol (Thx Washington's Blog)

 2010 Nov;109(5):1531-9.
The survival of filoviruses (Ebola and Marburg) in liquids, on solid substrates and in a dynamic aerosol

Abstract

AIMS:

Filoviruses are associated with high morbidity and lethality rates in humans, are capable of human-to-human transmission, via infected material such as blood, and are believed to have low infectious doses for humans. Filoviruses are able to infect via the respiratory route and are lethal at very low doses in experimental animal models, but there is minimal information on how well the filoviruses survive within aerosol particles. There is also little known about how well filoviruses survive in liquids or on solid surfaces which is important in management of patients or samples that have been exposed to filoviruses.

METHODS AND RESULTS:

Filoviruses were tested for their ability to survive in different liquids and on different solid substrates at different temperatures. The decay rates of filoviruses in a dynamic aerosol were also determined.

CONCLUSIONS:

Our study has shown that Lake Victoria marburgvirus (MARV) and Zaire ebolavirus (ZEBOV) can survive for long periods in different liquid media and can also be recovered from plastic and glass surfaces at low temperatures for over 3 weeks. The decay rates of ZEBOV and Reston ebolavirus (REBOV) plus MARV within a dynamic aerosol were calculated. ZEBOV and MARV had similar decay rates, whilst REBOV showed significantly better survival within an aerosol.

SIGNIFICANCE AND IMPACT OF THE STUDY:

Data on the survival of two ebolaviruses are presented for the first time. Extended data on the survival of MARV are presented. Data from this study extend the knowledge on the survival of filoviruses under different conditions and provide a basis with which to inform risk assessments and manage exposure to filoviruses.

Saturday, October 25, 2014

CDC now admits Ebola can float through the air, and land on doorknobs/ CDC

CDC issued a new poster Friday night October 24, which admits Ebola may in fact be airborne.

But CDC says it doesn't travel farther than 3 feet.  Well, at least CDC is starting to move the narrative.  Maybe tomorrow it will be 5 feet.  Then 10.  Maybe next month they will tell us why all the victims' possessions are being incinerated and apartments fumigated.  (This article could explain it.)

Just remember: historically, Ebola spread fast in healthcare facilities.  Even CDC agrees: "EVD (Ebola Virus Disease) is highly transmissible in healthcare setting especially with severely ill patients and patients who have died. "

UPDATE Oct. 28: Thanks to Washington's Blog for this piece about a study showing that particles expelled during coughing may travel 20 feet.  And see this piece, which I published on my blog earlier, that reviews in great detail the subject of spread by airborne droplet nuclei.  Finally, I just discovered this 4 week old piece from Washington's blog quoting many experts on aerosol transmissibility.

UPDATE Oct 28:  Today's NY Times acknowledges you can potentially get Ebola from a toilet (or bathroom).

5 Ebola patients in Kikwit outbreak had no physical contact to explain transmission, and scientists suggest other mechanisms


The following paper was written by CDC scientists in 1999.

 1999 Feb;179 Suppl 1:S92-7. 
Ebola Hemorrhagic Fever, Kikwit, Democratic Republic of the Congo, 1995: risk factors for patients without a reported exposure. 

Abstract

In 1995, 316 people became ill with Ebola hemorrhagic fever (EHF) in Kikwit, Democratic Republic of the Congo. The exposure source was not reported for 55 patients (17%) at the start of this investigation, and it remained unknown for 12 patients after extensive epidemiologic evaluation. Both admission to a hospital and visiting a person with fever and bleeding were risk factors associated with infection. Nineteen patients appeared to have been exposed while visiting someone with suspected EHF, although they did not provide care. Fourteen of the 19 reported touching the patient with suspected EHF; 5 reported that they had no physical contact. Although close contact while caring for an infected person was probably the major route of transmission in this and previous EHF outbreaks, the virus may have been transmitted by touch, droplet, airborne particle, or fomite; thus, expansion of the use of barrier techniques to include casual contacts might prevent or mitigate future epidemics.

Here is the free full text, from which the next 2 paragraphs were extracted:


Of the 23 patients in our study who were subsequently determined to have had previous exposure to a case of EHF, 19 had merely visited another patient with EHF and were not involved in patient care. None reportedly had any contact with patient blood, feces, vomitus, urine, or saliva, although 14 reported touching a patient with EHF. Recent immunohistochemical examination of skin biopsy specimens from patients with EHF has demonstrated viral antigens in skin and sweat glands [16], supporting the hypothesis that EHF may have been transmitted to these individuals in Kikwit (and others in previous outbreaks) by brief, unnoticed, superficial contact with EHF-in-fected persons.
The transmission mode in the 5 patients who became infected without any physical contact remains enigmatic. However, animal experiments have documented transmission of EBO virus via noncontact routes. For example, both guinea pigs and monkeys have been infected experimentally with EBO virus by direct installation of drops into the eye and throat [17]. Transmission of EBO virus from experimentally infected monkeys to control monkeys in separate cages has also been documented [18]. Furthermore, airborne spread was suggested during the EBO epizootic outbreak in Reston, Virginia [19, 20, 21]. In a review, Peters et al. [22] concluded that although the major mode of interhuman transmission of hemorrhagic fevers is direct contact, transmission via large droplets, aerosolized particles, or fomites cannot be excluded. This may explain the mode of transmission in the 5 patients without reported physical contact

NY/NJ/IL impose health care worker quarantine after NYC doctor and unidentified heallthcare worker at Newark Airport hospitalized for potential Ebola/ WaPo

A quarantine will help stop cases appearing in the US in the near-term, but may mean that fewer medical professionals will volunteer to work in Africa, making control of Africa's epidemic harder, thus making things worse for the US in the long-term.  (Only 0.5% of MSF staff or less have developed Ebola.) From today's WaPO:
...A health-care worker who flew into Newark Liberty International Airport on Friday and had no symptoms at the time would still be quarantined because she had treated Ebola patients in West Africa, Christie said.
The New Jersey Department of Health announced Friday evening that the unidentified woman had “developed a fever and is now in isolation and being evaluated at University Hospital in Newark...”
Finally, today's WaPo includes an article that instead of trying to assuage panic or imply Ebola may come from Russia, is telling the truth:  Michael Gerson's The World is In Denial About Ebola's True Threat.
Oh, and can someone explain why BioRecovery Corp is cleaning out Dr. Spencer's apartment if Ebola can only be transmitted by direct contact with bodily fluids?  And why Nurses Pham and Vinson had their property carted away and incinerated? 

Friday, October 24, 2014

Look, CDC is simply lying. Its own publications acknowledge that Ebola may aerosolize, and must be contained in BSL-4 facilities (that are not currently available in any ordinary hospitals) / CDC

Ebola is a designated BSL-4 (Biosafety Level 4) virus.  It requires the maximal level of containment possible.  [Anthrax, by the way, is less dangerous, requiring less containment (BSL-3) than Ebola.]  Ebola's mortality rate is the highest I know of, for any infectious disease.

CDC acknowledges (below, in a 2009 publication on page 45) that Ebola requires BSL-4 containment because it "pose[s] a high individual risk of aerosol-transmitted laboratory infections and life-threatening disease that is frequently fatal, for which there are no vaccines or treatments..."

http://www.cdc.gov/biosafety/publications/bmbl5/bmbl.pdf
Biosafety Level 4 is required for work with dangerous and exotic agents that pose a high individual risk of aerosol-transmitted laboratory infections and life-threatening disease that is frequently fatal, for which there are no vaccines or treatments, or a related agent with unknown risk of transmission. Agents with a close or identical antigenic relationship to agents requiring BSL-4 containment must be handled at this level until sufficient data are obtained either to confirm continued work at this level, or re-designate the level. Laboratory staff must have specific and thorough training in handling extremely hazardous infectious agents. Laboratory staff must understand the primary and secondary containment functions of standard and special practices, containment equipment, and laboratory design characteristics.  
All laboratory staff and supervisors must be competent in handling agents and procedures requiring BSL-4 containment. The laboratory supervisor in accordance with institutional policies controls access to the laboratory.
There are two models for BSL-4 laboratories: (Neither exists in regular hospitals--Nass)
1. A Cabinet Laboratory—Manipulation of agents must be performed in a Class III BSC; and2. A Suit Laboratory—Personnel must wear a positive pressure supplied air protective suit.BSL-4 cabinet and suit laboratories have special engineering and design features to prevent microorganisms from being disseminated into the environment.
And for those needing additional confirmation, on page 251 of this same CDC publication, CDC lists the required level of bio-containment for each known arbovirus and hemorrhagic fever virus.  Ebola is among a small group that requires BioSafety Level 4.

The Federation of American Scientists describes how a BSL-4 facility is designed and functions:
BSL-4, Biosafety Level 4
Required for work with dangerous and exotic agents which pose a high individual risk of life-threatening disease. The facility is either in a separate building or in a controlled area within a building, which is completely isolated from all other areas of the building. Walls, floors, and ceilings of the facility are constructed to form a sealed internal shell which facilitates fumigation and is animal and insect proof. A dedicated non-recirculating ventilation system is provided. The supply and exhaust components of the system are balanced to assure directional airflow from the area of least hazard to the area(s) of greatest potential hazard. Within work areas of the facility, all activities are confined to Class III biological safety cabinets, or Class II biological safety cabinets used with one-piece positive pressure personnel suits ventilated by a life support system. The Biosafety Level 4 laboratory has special engineering and design features to prevent microorganisms from being disseminated into the environment. Personnel enter and leave the facility only through the clothing change and shower rooms, and shower each time they leave the facility. Personal clothing is removed in the outer clothing change room and kept there. A specially designed suit area may be provided in the facility to provide personnel protection equivalent to that provided by Class III cabinets. The exhaust air from the suit area is filtered by two sets of HEPA filters installed in series. Supplies and materials needed in the facility are brought in by way of double-doored autoclave, fumigation chamber, or airlock, which is appropriately decontaminated between each use. Viruses assigned to Biosafety Level 4 include Crimean-Congo hemorrhagic fever, Ebola, Junin, Lassa fever, Machupo, Marburg, and tick-borne encephalitis virus complex (including Absettarov, Hanzalova, Hypr, Kumlinge, Kyasanur Forest disease, Omsk hemorrhagic fever, and Russian Spring-Summer encephalitis). 
BTW, since BSL-4 agents are considered potential biowarfare threats, BSL-4 labs (such as that at Rocky Mountain Laboratory in Hamilton, Montana) require an iris scan for entry and have armed guards, to prevent theft of microorganisms.  Will Bellevue Hospital add these features? 

I should have earlier linked to this excellent piece by David Willman (LA Times) that explores potential aerosol transmission, the problems identifying when people become infectious, and the limitations of airport screening.

Thursday, October 23, 2014

Ebola Causes Chronic Illnesses in Those Who Manage to Recover/ CBS and USAMRIID

From CBS:
But unfortunately, Ebola survivors do often develop certain chronic inflammatory conditions that affect the joints and eyes, problems that can follow a survivor through the remainder of their life. Dr. Amar Safdar, associate professor of infectious diseases and immunology at NYU Langone Medical Center, told CBS News these chronic conditions are a result of the body's immune response.

He said Ebola survivors are at risk for arthralgia, a type of joint and bone pain that can feel similar to arthritis. Ebola survivors also frequently report complications with eyes and vision, an inflammatory condition known as uveitis which can cause excess tearing, eye sensitivity, eye inflammation and even blindness.
 "No one knows exactly why," Safdar told CBS News. "Certain infections or certain viruses have been known to cause uveitis. It is treated with giving steroids and primarily something that will dilate the pupil."
As acknowledged by scientists at USAMRIID:  
Moreover, the quality of life of patients following infection and treatment may require additional development efforts or the combination of multiple therapeutic approaches. As seen in outbreaks, the clinical sequelae observed in patients that survive infection are severe and life changing. These observations emphasize the need for medical countermeasures that not only provide survival but also decrease morbidity and long-term pathological outcomes following infection.

Indemnifying Pharma for Ebola Vaccines: Recipe for Problems?

When did pharmaceutical manufacturers demand to be indemnified by governments, when previously asked to produce vaccines?

First time:  1976 swine flu.  One soldier died of swine flu at Fort Dix, the virus never did spread through the US population, but 45 million Americans were vaccinated with an unecessary vaccine, several hundred developed Guillain Barre syndrome (GBS), and about 30 died from GBS.

Second time:  2009 Swine flu.  This H1N1 influenza A pandemic turned out to be no more dangerous than usual yearly flu A.  But adjuvanted Glaxo vaccine Pandemrix caused about 800 cases of narcolepsy in children, and additional cases in adults.

Now they want to be indemnified for Ebola vaccines.  What do the vaccine companies know about the risk, this time?  Once they gain indemnification. as they surely will, there is no incentive for them to make the safest vaccines.

Airborne Spread of Ebola from Pigs to Macaques/ Nature

Not sure why this is still a subject for debate.  Animal models establish that Ebola can be transmitted via aerosol secretions under lab conditions.  The question remaining is how often this happens in humans. Maybe it does; maybe it doesn't.

Despite CDC protestations regarding airborne spread, the new guidelines for personal protective equipment issued by CDC on Oct 20 demonstrate that CDC is as concerned as I am about aerosolized droplet spread of Ebola. These measures include:
  • Respirators, including either N95 respirators or powered air purifying respirator(PAPR)
  • Single-use, full-face shield that is disposable
  • Surgical hoods to ensure complete coverage of the head and neck
Here is the Nature article that got a lot of attention, in which pigs spread Ebola to macaques in a nearby cage via aerosols.  Here is a pdf of the article.

Transmission of Ebola virus from pigs to non-human primates
Hana M. WeingartlCarissa Embury-HyattCharles NfonAnders LeungGreg Smith, Gary Kobinger    15 November 2012

Ebola viruses (EBOV) cause often fatal hemorrhagic fever in several species of simian primates including human. While fruit bats are considered natural reservoir, involvement of other species in EBOV transmission is unclear. In 2009, Reston-EBOV was the first EBOV detected in swine with indicated transmission to humans. In-contact transmission of Zaire-EBOV (ZEBOV) between pigs was demonstrated experimentally. Here we show ZEBOV transmission from pigs to cynomolgus macaques without direct contact. Interestingly, transmission between macaques in similar housing conditions was never observed. Piglets inoculated oro-nasally with ZEBOV were transferred to the room housing macaques in an open inaccessible cage system. All macaques became infected. Infectious virus was detected in oro-nasal swabs of piglets, and in blood, swabs, and tissues of macaques. This is the first report of experimental interspecies virus transmission, with the macaques also used as a human surrogate. Our finding may influence prevention and control measures during EBOV outbreaks.

And from the Discussion:

"The present study provides evidence that infected pigs can efficiently transmit ZEBOV to NHPs in conditions resembling farm setting. Our findings support the hypothesis that airborne transmission may contribute to ZEBOV spread, specifically from pigs to primates, and may need to be considered in assessing transmission from animals to humans in general. The present experimental findings would explain REBOV seropositivity of pig farmers in Philippines23 that were not involved in slaughtering or had no known contact with contaminated pig tissues." 


Wednesday, October 22, 2014

MSF discusses treatment approaches and its role in therapeutic drug trials

Below are excerpts from a longer discussion here. 
As one of the main providers of Ebola treatment in West Africa, MSF has chosen to take an active role in trialling experimental treatments. We add value to the trial process as we have access to large numbers of patients and therefore potential recipients of the experimental treatments. MSF will work in collaboration with organisations, academics, companies, the Ministries of Health in the affected countries and the WHO in order to implement fast-tracked clinical trials for some of the new treatments for Ebola at existing treatment sites. Experimental treatments are currently being selected and trial designs are being developed to ensure that disruption to patient care is minimal, that medical and research ethics are respected, and that sound scientific data is produced. MSF does not usually engage in research and trials for drug development, but faced with this massive outbreak, we’re taking exceptional measures...
The two most promising candidate vaccines have been identified as one developed by GlaxoSmithKline (GSK) and a second developed at the Public Health Agency of Canada in Winnipeg. There are other vaccines in development, however, and they should also be pushed through the pipeline as quickly as possible.
There are a handful of experimental treatments that also look promising, but that haven’t yet been tested for safety and efficacy in humans. The WHO has identified a number of these treatments and compiled them on a pre-selection list. As mentioned above, a number of these treatments are being selected to be tested in clinical trials. The treatments vary in type and include monoclonal antibodies, small inhibitory RNA, and antivirals... 

Tuesday, October 21, 2014

Excellent review of experimental vaccine and drug approaches to Ebola/ 2nd Canadian drug review

I read the full text but can't post it due to copyright.  The first review is from U Texas. 

 2013 Dec;27(6):565-83. doi: 10.1007/s40259-013-0046-1.
Emerging Targets and Novel Approaches to Ebola Virus Prophylaxis and Treatment

Abstract

Ebola is a highly virulent pathogen causing severe hemorrhagic fever with a high case fatality rate in humans and non-human primates (NHPs). Although safe and effective vaccines or other medicinal agents to block Ebola infection are currently unavailable, a significant effort has been put forth to identify several promising candidates for the treatment and prevention of Ebola hemorrhagic fever. Among these, recombinant adenovirus-based vectors have been identified as potent vaccine candidates, with some affording both pre- and post-exposure protection from the virus. Recently, Investigational New Drug (IND) applications have been approved by the US Food and Drug Administration (FDA) and phase I clinical trials have been initiated for two small-molecule therapeutics: anti-sense phosphorodiamidate morpholino oligomers (PMOs: AVI-6002, AVI-6003) and lipid nanoparticle/small interfering RNA (LNP/siRNA: TKM-Ebola). These potential alternatives to vector-based vaccines require multiple doses to achieve therapeutic efficacy, which is not ideal with regard to patient compliance and outbreak scenarios. These concerns have fueled a quest for even better vaccination and treatment strategies. Here, we summarize recent advances in vaccines or post-exposure therapeutics for prevention of Ebolahemorrhagic fever. The utility of novel pharmaceutical approaches to refine and overcome barriers associated with the most promising therapeutic platforms are also discussed.

From Canada's Special Pathogens Lab:

 2014 Aug;22(8):456-63. doi: 10.1016/j.tim.2014.04.002. Epub 2014 Apr 30.
Post-Exposure Therapy of Filovirus Infections

Abstract

Filovirus infections cause fatal hemorrhagic fever characterized by the initial onset of general symptoms before rapid progression to severe disease; the most virulent species can cause death to susceptible hosts within 10 days after the appearance of symptoms. Before the advent of monoclonal antibody (mAb) therapy, infection of nonhuman primates (NHPs) with the most virulent filovirus species was fatal if interventions were not administered within minutes. A novel nucleoside analogue, BCX4430, has since been shown to also demonstrate protective efficacy with a delayed treatment start. This review summarizes and evaluates the potential of current experimental candidates for treating filovirus disease with regard to their feasibility and use in the clinic, and assesses the most promising strategies towards the future development of a pan-filovirus medical countermeasure.

This review from USAMRIID.  You can get the free full text here.

 2012 Sep;4(9):1619-50. doi: 10.3390/v4091619. Epub 2012 Sep 21.
Potential vaccines and post-exposure treatments for filovirus infections

  • 1United States Army Medical Research Institute of Infectious Diseases, Division of Virology, Frederick, MD 21702, USA. brian.m.friedrich.ctr@us.army.mil

Abstract

Viruses of the family Filoviridae represent significant health risks as emerging infectious diseases as well as potentially engineered biothreats. While many research efforts have been published offering possibilities toward the mitigation of filoviral infection, there remain no sanctioned therapeutic or vaccine strategies. Current progress in the development of filovirus therapeutics and vaccines is outlined herein with respect to their current level of testing, evaluation, and proximity toward human implementation, specifically with regard to human clinical trials, nonhuman primate studies, small animal studies, and in vitro development. Contemporary methods of supportive care and previous treatment approaches for human patients are also discussed.

CDC defined infectious respiratory droplet transmission as different than airborne

Here are CDC's definitions for the different modes of spread of infectious agents.  Scroll down to IB3b and c and you will see that CDC has defined droplet transmission as a form of contact transmission. This may be CDC's technical justification for insisting that Ebola does not spread via the airborne route, when there is ample evidence it may spread via airborne droplets.

Is This A New, More Virulent Ebola?

The West Africa Ebola mortality rate with treatment is very high. Normally, mortality drops when doctors gain experience with new diseases and learn how best to care for patients. This seems not to be the case with this Ebola.

West African Ebola may be spreading more easily than other Ebola outbreaks.  [Thanks to Washington's Blog for alerting me to Michael Osterholm's speech on C-SPAN2.]

Two very knowledgeable scientists have suggested as much.  Peter Jahrling, PhD, of NIAID (formerly USAMRIID) who has worked with Ebola for 25 years, said that the concentration of virus in patients seemed to be twice as high as in earlier epidemics.
Yes. I have a field team in Monrovia. They are running [tests]. They are telling me that viral loads are coming up very quickly and really high, higher than they are used to seeing. It turns out that in limited studies with the evacuated patients, they continued to express virus in blood and semen. What does that mean? Right now, we just don't know.
Michael Osterholm, PhD, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, is a prominent public health scientist and a nationally recognized biosecurity expert.  In a speech at Johns Hopkins on October 14, he said he had just been given permission to say that Canada's Gary Kobinger found that the pathological lesions in the lungs from macaques infected with west African Ebola were "much much more severe" than expected. "It was unlike any of the [earlier] ebola viruses they have seen in monkeys." [at 20 minutes]
He warned the audience to expect the unexpected as the epidemic continues: "Do not expect that anything carved in stone today won't be blown up by some stick of dynamite."
... In other comments, Osterholm said an international Ebola research agenda is urgently needed to answer a number of questions. For example, more virus isolates are needed for genetic studies, and information on clinical virology is sorely lacking. 
Government experts and the media tell us that Ebola can only be spread by direct contact, and is easily killed with diluted bleach.  Why, then, have virtually all the belongings of nurses Nina Pham and Amber Vinson been removed from their apartments?  Everything removed has been burned.

From San Antonio Eyewitness News:



... TCEQ photos of nurse Nina Pham's home after decontamination tell the story. The apartment looks practically back to the way it was before she moved in. The refrigerator and cabinets are empty, and only a few large items remain. They are proof of her life before the virus, and another symbol of how Ebola has turned it upside down.
In all, the TCEQ said it filled 53 barrels with Vinson's belongings, 21 from Pham and five from the City of Dallas. All were driven to a Port Arthur Texas facility, where they were incinerated.

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


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


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 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.