Ebola Screening: Hey CDC! Is it an AND or an OR?

Like many of you, we've all been assisting with Ebola planning for the past several months. Just today, Mike and I were in another planning meeting and the subject of our screening algorithm came up. Mike had noticed that the September 4th CDC Definition of Person Under Investigation (PUI) that we've been using: "fever of greater than 38.6 degrees Celsius or 101.5 degrees Fahrenheit, AND additional symptoms such as severe headache, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage" is now different in the PDF algorithm that the CDC posted on October 2nd. It now says "FEVER OR EVD symptoms." I've included the relevant portion of the PDF algorithm above.

This may seem like a minor change, but for many facilities it will be a big deal. To go from a relatively sensitive "fever AND" to a very sensitive "fever OR" is not a small change. This may require EDs and clinics to screen additional patients and result in a large increase in laboratory tests being sent for Ebola diagnosis. I think that CDC meant to suggest that fever is enough to prompt a travel history, but now anyone with fever, headache, weakness, muscle pain, vomiting, diarrhea, abdominal pain or hemorrhage will also need to be asked a travel history. In practice this will mean that every patient that walks into an ED or clinic should be asked a travel history first and then asked about symptoms. I'm not convinced this should happen and feel much more comfortable with having symptoms guide travel history. But since almost any general complaint is now included, we may be left with no other choice but to ask travel history first. And of course, we don't know what CDC wants us to do since both documents are live and offer conflicting advice.

So, which is it CDC?  Is it an AND or an OR?

Guest Post: The Danger of Ebola

This is a guest post by Philip Lederer, an ID fellow at Massachusetts General Hospital and Brigham and Women’s Hospital. He was a CDC Epidemic Intelligence Service officer and has also worked in Mozambique as clinical director of the UCSD-Maputo Central Hospital Educational Collaboration.

The danger of Ebola goes well beyond the thousands of cases reported so far in Liberia, Sierra Leone, Guinea, and neighboring countries. It goes beyond the models which estimate that up to 1.4 million cases could occur by next year (1). The danger doesn’t have to do with Ebola becoming airborne or spreading widely across the United States. 

Ebola is still centered in West Africa, and the danger is of collateral damage. Malaria control programs have shut down in the 3 countries, according to a recent report (2). Cholera could reemerge, as there was a 2012 outbreak in Sierra Leone (3). People are losing their jobs. Starvation and violence could kill many more people than the Ebola virus. It’s time for the world to act.

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References:
1) Meltzer MI, Estimating the Future Number of Cases in the Ebola Epidemic — Liberia and Sierra Leone, 2014–2015 http://www.cdc.gov/mmwr/preview/mmwrhtml/su6303a1.htm?s_cid=su6303a1_w


2) Hayden EC, Ebola outbreak shuts down malaria-control efforts http://www.nature.com/news/ebola-outbreak-shuts-down-malaria-control-efforts-1.16029

3) Nguyen VD et al, Cholera epidemic associated with consumption of unsafe drinking water and street-vended water--Eastern Freetown, Sierra Leone, 2012. http://www.ncbi.nlm.nih.gov/pubmed/24470563

Ebola and WHO budget cuts

Anthony Harris used to (and may still) include this New Yorker cartoon in his antibiotic resistance talks. I've always thought it summed up the resistance crisis quite well. We don't have effective antibiotics, so we must resort to the ridiculous. One of the major reasons we lack new classes of antibiotics is the lack of public funding for basic research of bacterial pathogens. It's pretty simple really. Years of ignoring the problem have us in this situation and it will take many years of reinvestment to build up the laboratory and professional resources needed to be fully engaged in antibiotic discovery.

A similar situation has played out in public health preparedness. I encourage you to read Dan's posts (here and here) covering the Prevention and Public Health Fund. And it's not just the US. In the Guardian today, Peter Piot - the discover of Ebola, expressed his fears that the outbreak is out of control. It's an amazing account of how he discovered and named the virus. It also highlights the almost tragic accidents that occurred in his lab, yet no one caught the virus. When asked why the WHO responded so late to the Ebola outbreak in Africa, he responded:

"On the one hand, it was because their African regional office isn't staffed with the most capable people but with political appointees. And the headquarters in Geneva suffered large budget cuts that had been agreed to by member states. The department for haemorrhagic fever and the one responsible for the management of epidemic emergencies were hit hard...I think it is what people call a perfect storm: when every individual circumstance is a bit worse than normal and they then combine to create a disaster. And with this epidemic there were many factors that were disadvantageous from the very beginning."

I'm not a military historian, but this situation seems terribly similar to what I've read about simultaneous wars on two fronts. Although in public health, it can be four or five fronts. We have Ebola, MERS, avian influenza and Enterovirus D68 knocking on our doors (and I'm sure I left out a few.) These are all on top of the CDC and WHO's "day jobs" fighting foodborne outbreaks, antibacterial resistant bacteria, TB, HIV and malaria (and I'm sure I left out many). Long term cuts to public health infrastructure can't be repaired in one month or one year. You can't go buy extra diseases detectives quickly off the shelf much like you can't quickly buy an extra aircraft carrier. We can already see how outbreaks respond to intensive budget cuts.

image source: Conde Naste

Whither infectious diseases?

One morning in October 1983, when I was a 22-year-old second year medical student just recovering from infectious mononucleosis, I arrived at school for my medical microbiology lecture. At that point, several weeks into the course, I found myself with no real affinity for the subject matter. The lectures seemed to focus on the minutiae of biochemical tests for various bacteria that I planned to memorize for the exam then forget. But that October morning we were scheduled to have a clinical correlation lecture. I always looked forward to those lectures--talks about real diseases by real doctors. The lecture was on meningitis and given by Rashida Khakoo (shown in photo), a young infectious diseases doctor. It was incredibly fascinating and I was forever hooked. Over the course of the next several years, I rotated with Rashida several times on the Infectious Diseases consultation service, and knew that ID was my calling. It's hard for me to estimate how much I learned from her. She's an amazingly brilliant physician and incredible bedside teacher who reads incessantly and has the capacity to remember everything that she has ever read. The joke among the medical students was that you could not find a bound journal in the library that did not have her name on the library check-out card (I realize younger readers won't get that joke). Three decades later, I still believe she's the best doctor I have ever encountered.

For me and many others, Infectious Diseases remains a fascinating specialty. What other field has new diseases and challenges continuing to emerge at the rate of our specialty? We remain the disease detectives, the go-to doctors when no one else can figure out what is wrong with the patient (think Gregory House, MD, only nicer!). We add value in many other ways by working as hospital epidemiologists, antibiotic stewards, and public health experts. This morning's New York Times has multiple articles regarding infectious diseases. This should be our heyday. But instead, the field of infectious diseases appears to be in rapid decline. This past year, only 137 US medical school grads applied for fellowship positions in Infectious Diseases and only 41% of available positions were filled. We have recently heard numerous reports that fellowship programs, increasingly desperate for trainees, are violating rules of the National Resident Matching Program (NRMP) and offering candidates positions outside of the match process.

The cause of ID's demise is purely economic. Put yourself in the shoes of a 30-year-old 3rd year internal medicine resident with two young children and a $300,000 educational debt. You find the field of infectious diseases to be very interesting but you are forced to make a choice between 2-3 years of additional training at a fellow's salary or entering the workforce now as a hospitalist. The median annual salary of a hospitalist currently exceeds $250,000 and on average a hospitalist works 40 hours per week. As a hospitalist you will earn a salary 30% higher than your ID colleagues and work 30% fewer hours. Most hospitalist positions offer predictable hours and frequent, extended periods of time off. Can we blame young doctors for choosing the hospitalist option?

Unfortunately, most physician compensation plans reward volume not value, and that's a losing proposition for us. You can't evaluate a patient with fever of unknown origin in 20 minutes. There are no RVUs earned for spending three hours reviewing the medical records of a highly complex patient. In my previous job, the departmental administrator chastised me for spending too much time with my patients. Although I knew my work was important, that referring physicians were pleased and that my patients were grateful, I no longer felt valued.

The work of the ID doctor has never been glamorous, the pay has never been as good as most other specialties, and the hours have always been long. You don't enter ID to have a good lifestyle or get rich. But what has changed over the past decade is that internal medicine residents now have an option that offers higher pay and better hours, without pursuing additional training. Until ID becomes more economically competitive with hospital medicine, the odds of a comeback are slim. This isn't rocket science. And it's really a shame that the Infectious Diseases Society of America, our professional society that should be advocating for us, seems incapable of articulating an effective message about the crisis that the field of ID faces, the value that we add to health care, or potential economic solutions.

Sadly, we must ask: will the last ID doctor please turn out the lights?

Ebola: Hospital Epidemiologists in the News

It's been amazingly active week for hospital infection control with adult deaths and paralysis in children linked to Enterovirus 68 and there have also been some issues with Ebola. Practically every Hospital Epidemiologist* has been called upon to explain the transmissibility of Ebola and describe how they've been planning to protect healthcare workers and the community. Of course, I can't possibly list all of the mentions in local, national and international media, but if you have a particular clip that you'd like us to post, let us know.

I've been impressed by the clarity and skill that my SHEA colleagues have demonstrated. For example, earlier today Dan was on Public Radio International (PRI) discussing the difference between the virulence and contagiousness of infections and how it's easy to confuse the two. Specifically he said "In the case of Ebola, it is not true that it is airborne, it's not true that you can catch it just by being in the same room as an infected person. It really does require direct contact." Head on over to PRI, to hear the whole interview.

Kent Sepkowitz was on CNN yesterday describing the contagiousness of Ebola with the money quote: "so the super contagious body compartment is blood and it's blood and it's blood." And one of the stalwarts of hospital epidemiology and mentor to many, Leonard Mermel, was on MSNBC's All in With Chris Hayes tonight describing the well-developed screening algorithm that's been implemented at Rhode Island Hospital. I've added the video below. If you want to jump directly to Len Mermel's discussion, it occurs around 12:00. (apologize for the brief ad)

*A hospital epidemiologist is typically an infectious disease physician specialist who develops infection control plans to protect patients and healthcare workers in clinical settings including acute care hospitals and long term care facilities. During outbreaks the hospital epidemiologist helps identify the source of the infection and determines how best to contain its spread. They educate clinicians about the optimal ways to prevent infections (e.g. hand hygiene), while also tracking the use and misuse of antibiotics and the emergence of antibiotic-resistant bacteria. Other goals include preventing post-operative surgical wound infections and infections associated with central venous catheters. They are each hospital's very own disease detective!

Ebola: CDC Algorithm for Evaluation of the Returned Traveler

This algorithm might be useful, given the stories coming out of Dallas. The main CDC infection control page is here (last updated Aug 19) and the returned traveler algorithm PDF is available here.

Ebola vaccine - do we really need a placebo-controlled RCT?

The last time that I waded into the world of vaccine effectiveness, it maybe didn't go as well as planned. Though I've learned that I get knocked down, but I get up again just as Chumbawamba tells me to do every morning.

There are several candidate Ebola vaccines in various stages of evaluation. Recently, in response to the huge increase in cases, there have been calls to speed the evaluation, manufacture and distribution of vaccines to help control the outbreak. Science, NPR and even Gizmodo had recent posts describing the urgent need to rush vaccines to the field and the barriers to widespread testing and distribution of novel vaccines. Mike Osterholm has a sobering article in Politico where he outlines the public health crisis and strongly argues for the production of 500,000,000 vaccines. He reminds us that this effort "will require mobilizing people and resources on a massive scale (and) it has to be the international community’s top priority."

Scientists, companies and governments met at WHO this week to establish ways to speed up the development and testing of the candidate vaccines. Major barriers include paperwork (agreements) and things like insurance coverage for possible vaccine side-effects. Thus, most barriers are not scientific in nature, which is encouraging.

However there may be another barrier to the testing of novel Ebola vaccines: the individual randomized double-blind placebo controlled trial. Now, we all understand that this study design is the gold standard for internal validity; however, sometimes ethical or logistical concerns may outweigh internal validity. This Ebola outbreak may be one of those times. But let me explain.

In several of the articles, Dr. Anthony Fauci, Director of NIAID, and several others have stated their preference for the placebo-controlled RCT. On NPR Dr. Fauci said "Some scientists think moving forward without a control group of people who don't get the vaccine isn't worth the risk - if you did it in the way where you never could tell whether it worked well, worked a little, didn't work at all, or actually made people worse ... you could actually propagate a disaster." In the Science article Dr. Fauci was said to believe "that a randomized, controlled trial, in which people receive either the actual Ebola vaccine or an unrelated shot such as the hepatitis B vaccine, will be needed and if you are going to deploy a vaccine widely within a country, you better be sure it’s effective." I agree with most of what Dr. Fauci is suggesting, although I think placebo controls and individual (vs cluster) RCT have significant limitations in this outbreak.

For example, I don't think placebos are acceptable during the 2014 pandemic in Africa. There is no practical way to administer Hepatitis B vaccine as a placebo in this desperate situation - I suspect there might be riots. Additionally, a placebo controlled RCT is not the only study design with strong internal validity. One option is the cluster-randomized trial (cluster-RCT) where vaccine is administered to some communities and not others. Given that there will initially be limited vaccine supplies, this distribution pattern could be more practical. For example, some towns in each country could receive vaccine and others won't (no placebo - just no vaccine) and infection rates could be compared in both groups.

To get a litter more technical, Ebola vaccine cluster-RCTs could follow a stepped wedge design. Stepped wedged designs are used when ethical, financial, or logistical (e.g. geographic) constraints prevent the use of individually randomized or parallel cluster-RCT (i.e. treatment and control groups enrolled at the same time). In this design, vaccine would be rolled out randomly to communities as it became available (purple boxes in the figure above from Brown and Lilford), so that after one community is vaccinated then the next community would be vaccinated and then the next. Eventually every community is vaccinated. In this design, time-periods before the community is vaccinated serve as controls (white boxes in the figure). The stepped wedge cluster-randomized design has been used effectively in numerous settings including HIV and other infectious diseases.

This post is already too long. For those still interested in stepped wedge designs, please read the Brown/Lilford study or the Hussey/Hughes review. I'm sure scientists and political officials are considering numerous options for testing the safety and efficacy of candidate vaccines while simultaneously delivery potentially life-saving immunity to the millions at risk. Given that an estimated 21,000 people have already been infected and that 1.4 million may be infected by January 2015, I hope that vaccine trials aren't delayed because some insist on an individual RCT. The really good internal validity of the stepped wedge cluster RCT is not far from the excellent internal validity of the individual RCT. Really good is good enough.

10/1 Update: WHO considering a stepped wedge design. Good news.

10/10 Update: new Lancet Editorial Adebamowo et al. discussing the ethics and practical issues of the individual randomized trial h/t @HelenBranswell