Three years in: what has the $42M Atopic Dermatitis Research Network produced?

In July it will be three years since the NIH awarded National Jewish Health in Denver, CO $31 million to create and administer the Atopic Dermatitis Research Network, a consortium of five academic sites across the US. A contractor, Rho Federal Systems of Chapel Hill, NC, won an $11 million contract to operate a center to coordinate statistics and clinical trials for the project.

That makes $42 million—spread over five years—which puts the project on the large end of NIH funding for individual biomedical efforts. The typical NIH research grant ranges from $100 thousand to $2 million, and anything bigger is fodder for university news releases. Which raises the question: what have US taxpayers gotten in return?

I ask this as a patient who is grateful that these scientists are working to understand a disease that affects me, my family, and millions in the US and worldwide.

The answer is not obvious, since the publications page on the ADRN website hasn’t been updated since July 2011.

According to the website:

The Atopic Dermatitis Research Network (ADRN) is a consortium of academic medical centers that will conduct clinical research studies in an attempt to learn more about skin infections associated with atopic dermatitis (AD). The studies will focus on antibiotic-resistant Staphylococcus aureus infections and widespread viral infections of the skin, both of which are more prevalent among AD patients. The ADRN will build on the work of the Atopic Dermatitis and Vaccinia Network (ADVN) which conducted clinical studies focused on making smallpox vaccinations safer for people with AD. 

This research will lead to a greater understanding of the immune system in AD patients and may lead to novel therapeutic strategies to manage or prevent infectious complications associated with this disease. 

The ADRN will conduct a number of clinical studies over the next five years and will be enrolling large numbers of people with AD.

A search on clinicaltrials.gov returns two entries for the ADRN: one (open) to create a database of patients for the study of genetic markers connected to susceptibility to infections, and one (completed) to look into how AD patients respond to a new flu vaccine.

The ADRN’s NIH contract number is HHSN272201000020C. A search in the NIH’s PubMed database returns 12 papers that acknowledge funding by that contract number. Three of those are review papers (which did not involve new research).

So that makes  two clinical trials and nine research papers, three years into a five-year $42 million project.

Should US taxpayers expect more; be satisfied; or be impressed?

The answer is probably that we will have to wait to find out.

In each year, a typical top university research lab operates on about $2-3M a year and publishes somewhere around ten papers. That’s roughly $200k a paper.

Three of the five years in the ADRN contract are up; three-fifths of $42M is around $24M. We might therefore naively estimate that we should have seen upwards of 100 papers produced so far.

Most likely the reasons there are only 12 at the moment are that you don't start publishing papers right at the outset of a project. The research must be done first and then written up; and the process of getting accepted to a journal takes months. And the ADRN appears largely to rely on clinical trials--which take time to set up.

So why do we only see two trials listed on clinicaltrials.gov?

I've never had anything to do with a clinical trial, but when I was a researcher, I conducted animal experiments, and there were formidable administrative hurdles to get over before I could start work. I imagine that trials with human subjects are heavily regulated by the government, and for good reason. So the apparently small output of the ADRN to date is, I'm guessing, because it takes a long time to plan trials, get approval, and conduct them, before you can begin analyzing data and reporting it.

Still, let's keep in mind that the ADRN is an extension of the ADVN. It’s not like the ADRN began from scratch—the scientists had the momentum of existing expertise and administration and research aims.

Looking at the titles of the published papers, I can't immediately judge which are the most important. So I emailed Donald Leung, the principal investigator for the ADRN (he's a professor and head of the Division of Pediatric Allergy and Immunology at National Jewish Health), and asked him whether he could summarize the consortium’s findings so far and highlight key points. I hope to hear back from him soon and perhaps to interview him on the phone.

I’d like to know what ADRN scientists have found that surprises them. What have they learned that is truly new?

And what is going to be truly useful to patients in the end? Publishing papers should not be the be-all and end-all of scientific research. What about patents? I’d like to know whether anyone in the ADRN has thought about controlling intellectual property and commercialization. While it’s true that clinical studies may highlight the ideal dosing amount or schedule for existing therapies, and this does not involve creating a new commercial enterprise, most medical technology must pass through the marketplace before it can benefit the consumer/patient.

Someone has to do the dirty work of developing scientific discovery into therapy, and it’s not academic scientists.

More to come.

Anomalies in the immune system of patients who have experienced eczema herpeticum

Scientists have discovered that eczema patients who have suffered an outbreak of eczema herpeticum possess a subset of T cells that appear to be less effective at fighting viruses than T cells in the rest of the population. The results, published online in the British Journal of Dermatology, may point to an impaired arm of the immune system, a weakness that enables the herpes simplex virus (HSV), the agent of eczema herpeticum, to thrive.

Eczema herpeticum (EH) is a nasty skin infection caused by the HSV. The researchers, led by Donald Leung at National Jewish Health in Denver, took T cells (specifically, the class of T cells that fights viral infection) from 24 eczema patients who had experienced EH. The scientists analyzed various aspects of the T cells, comparing them to T cells taken from control patients—with and without eczema—who had not been infected by HSV. The scientists found that T cells from the EH group were producing less of a signaling molecule called “interferon-gamma” than those from the control groups.

Interferon-gamma is known to play many important roles in the immune response, especially in fighting viral infections.

The researchers also tested the DNA of the patients and found that the EH group were statistically more likely to possess copies of genes encoding “HLA B7” proteins, which hold chopped-up viral fragments on the cell membrane as markers so that T cells can identify and destroy infected cells.

It seems clear to me that a lack of interferon-gamma might be a liability against viruses. (I wouldn't expect this deficiency to be an effect of EH infection rather than a contributing cause, but the authors don't discuss the possibility.)

Owning a copy of HLA B7 might seem to improve your ability to fight infection--especially since that group of proteins have been shown to present fragments of vaccinia virus. However, as Leung pointed out to me in an email, having HLA B7 didn't prevent many of the patients in this study from getting eczema herpeticum.

These results don't have any immediate application to helping patients, but the area they highlight might prove important in protecting patients from eczema herpeticum in the future.

This is the first paper I have seen that acknowledges funding by the Atopic Dermatitis Research Network. I am sure there are many more papers out there, but this is the first I have noticed since the inception of the $31 million program, founded in 2010 to explore skin infections related to eczema.

New path discovered by which vitamin D reduces inflammation

Scientists have identified a new path by which vitamin D reduces inflammation.

According to a group led by Elena Goleva at National Jewish Health Center in Denver, vitamin D binds to a receptor in monocytes, a type of white blood cell. The receptor then binds to DNA in the cells and directs the cells to make more of an enzyme that shuts down inflammatory signaling.

The researchers found that vitamin D at or above a concentration of 30 nanograms per milliliter was enough to do the job. 30 ng/ml is a widely accepted lower limit for vitamin D in blood serum. (I recently had my own vitamin D level assayed and found it was 32 ng/ml.)

The research was published in the Journal of Immunology. [paper] [media summary] The authors say that vitamin D not only is important in maintaining calcium levels and bone health, but also plays an important role in the immune response.

That’s what I’ve found in my reading, although there’s also a lot of people on the internet who would like you to believe that taking vitamin D supplements—sometimes to an extreme degree—is a good idea for your health and in particular for relieving eczema. I remain wary. If vitamin D is so important then you need to maintain a proper level, not overdose yourself.  All drugs are toxic when ingested beyond ranges established to be safe in clinical trials.

What I like about this paper is that the authors have gone out of their way to conduct their experiments in an environment that is similar to the human body, as far as concentrations of various substances go (including vitamin D). They also used monocytes taken from human donors instead of cells from some purified, genetically altered strain, as is so often the case with cell biologists dabbling in medical applications. So their results mean something to you and me.

One question that I do have is whether the same kind of inflammation studied here—caused by LPS, a bacterial molecule that triggers an anti-infection response—is at work in chronic eczema. Is there one major inflammatory response, or are there several?

Most definitely no definite answer for vitamin D and eczema

As with most of the posts on this blog, I wrote the last one in a hurry--there's only so much free time if you've got a job and a commute and two kids. Being in a rush makes blogging unsatisfying as a writing exercise, both for the strength of argument and the quality of prose. A blog is nothing more than a series of first drafts, and the expression "shitty first drafts" (Google it) exists for a reason.

So I thought perhaps I'd been too quick to diss vitamin D as potentially having benefit for patients with eczema. A PubMed search turned up this review paper, which I am inclined to trust as credible for several reasons:

1. one of the two authors is Donald Leung, head of pediatric allergy and immunology at National Jewish Health Center in Denver; editor-in-chief of the Journal of Allergy and Clinical Immunology; and principal investigator for the Atopic Dermatitis Research Network
2. the authors cite 73 papers instead of just one or two selected to support their cause; they present a balanced view with opposing data
3. they don't use scary headings like "Is This Nutritional Deficiency Ruining Your Heart?" or provide a convenient link to an online store with products such as krill oil, vitamin spray, and bidets.

Anyway, I learned quite a bit. In short, vitamin D deficiency is a real phenomenon in the US population. There are a number of molecular mechanisms in which a lack of vitamin D might increase the severity of eczema. And a few trials have been done with small numbers of people that show that a short course of increased vitamin D improves symptoms.

That's not enough to make me rush out and buy barrels of vitamin D though, especially since there are multiple side effects of an overdose, including kidney damage. As Caroline commented after my last post, the issue is really whether you're deficient or not, not that it's a good idea to take an excessive dose. (I sent her a copy of the paper so we can look forward to learning her perspective.)

A reading of the paper turns up a bewildering number of studies in cells and mice that produced conflicting results. E.g. mice deficient in vitamin D had helper T cell responses greatly slanted toward type 1 instead of type 2; but it's known that, in humans, eczema patients have overactive type 2 helper T cells. If you were to take that one paper as gospel, you'd try to deprive yourself of vitamin D to cure your eczema.

Another paper shows that adults who received vitamin D supplements as infants were more likely to develop atopy and allergy. But then opposing papers balance this out. Dosage and timing could be crucial.

So, as with most science, the conclusion is the familiar "more research needed."