Saturday, April 24, 2010

Mining for malaria cures

Malaria, as I've written about many times before, kills for reasons that we're not completely sure of yet. We give medications that work directly against the parasite itself, but oftentimes it's insufficient, and people die due to their body's inflammatory response to the invading parasite. Predicting, early on, who will die, and what we can do about it, is an active field of research, with some innovative discoveries over the past few years.

Adding to this is a mouse study looking at charcoal in the treatment of malaria. Oral charcoal doesn't get absorbed through your gut and has been safely used for years for adsorbing ingested toxins; it also has been shown to be an anti-inflammatory through unconfirmed mechanisms. It may be able to adsorb any intestinally-mediated toxins, as well as cytokines from the blood through a mechanism that I don't completely understand. Regardless of mechanism, these investigators randomized mice experimentally infected with malaria to oral charcoal or not, and the results were striking. All untreated mice died and only 55% of treated mice died. They reconfirmed their results with just the charcoal itself, and not its diluent - this time none of the untreated mice survived and 60% of the treated mice survived at day 10.

Mechanistically, there seems to be a moderate effect on the production of inflammatory cytokines, specifically by various T-cell lineages. They also looked at whole blood global gene expression analysis and found a significantly different profile amongst the treated mice, one that more closely resembled uninfected mice. Most importantly, they also wisely included a phase I human study, seeing if charcoal had any effects on the pharmacokinetics of antimalarials, one of the main concerns of this potential treatment (antimalarial overdose is often treated with activated charcoal, for example). It didn't have any effect on drug levels, but they used intravenous antimalarials - it remains to be seen if it is safe with administered with the more commonly given oral antimalarials.

Like they mention in their discussion, charcoal can never be used as a stand-alone therapy. As an adjunct in severe cases, it holds promise, given its safety and affordability. More importantly, understanding its molecular mechanism of activity in using the gut to reduce systemic inflammation in the malarial response could yield many other avenues of research. Human trials will need to happen, and I'm skeptical as to whether or not it can be given with oral medications, but a valuable addition to the adjunctive therapy in malaria literature.

de Souza, J., Okomo, U., Alexander, N., Aziz, N., Owens, B., Kaur, H., Jasseh, M., Muangnoicharoen, S., Sumariwalla, P., Warhurst, D., Ward, S., Conway, D., Ulloa, L., Tracey, K., Foxwell, B., Kaye, P., & Walther, M. (2010). Oral Activated Charcoal Prevents Experimental Cerebral Malaria in Mice and in a Randomized Controlled Clinical Trial in Man Did Not Interfere with the Pharmacokinetics of Parenteral Artesunate PLoS ONE, 5 (4) DOI: 10.1371/journal.pone.0009867

Monday, February 15, 2010

Sneezing at the sun

From the consequential to the less so...

About a quarter of humanity will sneeze after being in the dark and then being exposed to the sun. Why we do this has yet to be understood, and, really, hasn't had much investigation, for understandable reasons. In this week's PLOS One, investigators from Switzerland tried to figure this out. In a simple experiment, they took ten known 'photic sneezers' and matched them by age and sex with non-photic sneezers. They then showed them a checkerboard display or a bright photic stimulus, and measured their electroencephalogram patterns.

Their findings? Photic sneezers, when exposed to a bright stimulus, had increased excitability of the visual cortex, not in the brainstem or lower centers of the brain, meaning that higher brain controls are responsible for this, not reflexive controls. Why some people photic sneeze and others don't and what this means in terms of neural pathways, remains unclear. Most importantly of all, however, I just learned that there is a proposed ACHOO acronym, meaning Autosomal Cholinergic Helio-Ophtalmologic Outburst, signifying the powers of acryonyms to confuse people even more.

Nicolas Langer*, Gian Beeli, Lutz Jäncke (2010). When the Sun Prickles Your Nose: An EEG Study Identifying Neural Bases of Photic Sneezing PLOS One

Saturday, January 30, 2010

HIV and Herpes, together forever

What we know, in terms of herpes and HIV, and everybody can mostly agree upon:
1) Co-infection with herpes simplex virus increases the risk of transmission of HIV, mostly
from the decreased mucosal damage from herpes ulcers.
2) Acyclovir, our preferred antiviral for herpes simplex, reduces HSV levels in blood.
3) Acyclovir also has effects on HIV, with both in vitro and in vivo activity, either indirectly through HSV or directly on HIV replication itself.
An exacerbation of HSV is associated with worsening HIV disease.

So, it makes sense that co-infected people who are on acyclovir, take it well, and get subsequent suppression of their herpes would have lower transmissibility of their HIV. Unfortunately, as this trial in this week's New England Journal of Medicine shows, this isn't the case.

It's probably the best-done, largest study that can be done looking at the issue, effectively closing the door on being able to reduce HIV transmission solely through HSV treatment. Finding 3400 willing couples where one partner is HIV and HSV positive and the other is negative for both must have been incredibly difficult. Also, the strict, but necessary, inclusion criteria, such as not yet being on antiretroviral treatment and being otherwise well, must have limited recruitment.

In the end, they reduced blood HIV levels and the incidence of genital ulcers, but, sadly, couldn't reduce HIV transmission, their primary outcome. The ultimate goal of bringing down HIV blood levels, through antiretrovirals or the treatment of other concomitant infections and illnesses, might use acyclovir as part of a multi-factorial approach. By itself, however, it doesn't seem to work, at least to the degree hoped for.

One point is that those enrolled in the study received fairly intensive counseling regarding safe sexual practices for serodiscordant couples, meaning that the overall transmission rate was lower than for the general population, increasing the numbers needed to find a difference in transmission rate. Everybody, however, should be receiving this support, and that can't be taken as a criticism of the study itself. In addition, almost 30% of the new infections in the study were with different viruses than their partners, meaning they were infected by somebody else's virus, reinforcing the need for effective counselling and support.

In the end, managing serodiscordant couples will continue to be a challenge, and will likely involve more aggressive use of antiretrovirals and counselling, similar to that in this study.

Celum, C., Wald, A., Lingappa, J., Magaret, A., Wang, R., Mugo, N., Mujugira, A., Baeten, J., Mullins, J., Hughes, J., Bukusi, E., Cohen, C., Katabira, E., Ronald, A., Kiarie, J., Farquhar, C., Stewart, G., Makhema, J., Essex, M., Were, E., Fife, K., de Bruyn, G., Gray, G., McIntyre, J., Manongi, R., Kapiga, S., Coetzee, D., Allen, S., Inambao, M., Kayitenkore, K., Karita, E., Kanweka, W., Delany, S., Rees, H., Vwalika, B., Stevens, W., Campbell, M., Thomas, K., Coombs, R., Morrow, R., Whittington, W., McElrath, M., Barnes, L., Ridzon, R., Corey, L., & , . (2010). Acyclovir and Transmission of HIV-1 from Persons Infected with HIV-1 and HSV-2 New England Journal of Medicine DOI: 10.1056/NEJMoa0904849

Wednesday, January 13, 2010

Haiti & Disaster Aid

As we learn more about the massive earthquake in Port-au-Prince yesterday, it gives us the opportunity to look at the science behind a lot of the disaster aid that is going to happen over the next few days, weeks, and years. [The International Federation of Red Cross and Red Crescent Societies have the most on-the-ground experience, and are probably the best place for you to send money. And please, don't send t-shirts and old blankets.] Contrary to popular belief, there is a method behind all of the madness, and operations will be scaled up in a (hopefully) thoughtful and organized fashion, based on years of experience and publications. Unfortunately, we don't have the scientific rigor that other fields have, with their randomized trials and the like, but for a literature that, by its very nature, has to be spontaneous, the disaster response academic community is robust. A lot of it comes from the Katrina experience, and while things will be drastically different in Port-au-Prince because of the underlying infrastructure, there are definitely lessons to be applied.

The Sphere Project has been the guiding light for this formalization of a previously informal community, setting standards and codes for any humanitarian or disaster response. The seminal paper in the literature is from the CDC, published in the Lancet in 2002, where, retrospectively, and across various camps, they found exactly what you would expect. That refugee camps located close to the conflict or disruption, further from hospitals, or where there was less water, had higher mortality rates.

Nutrition is obviously crucial, and there are many review papers looking at the best way to feed a displaced, post-emergency population. The most thorough is this one, once again from the Lancet in 2004.

The dictum of epidemiologists (the ones that I know, anyway) is "don't just do something, stand there (and measure something)". No disaster response is effective without mapping out what you're responding to, and our modern satellite technology has changed how this is done. We all remember how Google Earth was used during the Katrina response, and the GIS (geographic information systems) technology has exponentially grown since then.

Lastly, shelter creation is one of the most important facets of disaster response. Here's a link to the USAID site on shelters and settlements, and some of the innovative things happening globally with creating that perfect new shelter, which must be cheap, weather-proof, easy to deploy and transport, culturally appropriate, and therefore, almost impossible to create.

SPIEGEL, P., SHEIK, M., GOTWAYCRAWFORD, C., & SALAMA, P. (2002). Health programmes and policies associated with decreased mortality in displaced people in postemergency phase camps: a retrospective study The Lancet, 360 (9349), 1927-1934 DOI: 10.1016/S0140-6736(02)11915-5

YOUNG, H., BORREL, A., HOLLAND, D., & SALAMA, P. (2004). Public nutrition in complex emergencies The Lancet, 364 (9448), 1899-1909 DOI: 10.1016/S0140-6736(04)17447-3

Nourbakhsh, I., Sargent, R., Wright, A., Cramer, K., McClendon, B., & Jones, M. (2006). Mapping disaster zones Nature, 439 (7078), 787-788 DOI: 10.1038/439787a

Saturday, January 9, 2010

What lives in foreskin

The range of bacteria that live in and around our bodies is striking. With the advance of molecular techniques and the ability to isolate organisms that traditional methods had huge problems detecting, we're learning more and more about what lives where. More importantly, how these symbiotic organisms affect us, both in terms of protecting us from or predisposing us to, various diseases, is going to be a tremendous growth area both for research and therapeutics over the coming years. We've already begun to alter the normal microflora, sometimes to good effect, like in the guts of premature babies to prevent them from getting infection, or to bad effect, like with antibiotic-related diarrhea.

Moving beyond the expected micro-organism dense area that is the human digestive tract, two recent papers in PLOS One look at the bacterial communities in two other parts of the human body: the penis and the lungs. The first is based on the now well-proven concept that circumcision is protective against sexually transmitted infections, and most tantalizingly, HIV. The theory behind this is under dispute, and the practicality of this as a population-level intervention still needs to be defined, but this paper lends even more biologic credence. There's reasonable in vivo evidence that HIV infection, in the presence of some specific bacteria, is more robust. Taking this piece of data, these authors show that circumcision drastically changes the microbial community isolated from the distal shaft of the penis. As fully expected, but never proven, the numbers of anaerobic bacteria, or bacteria that can live in oxygen-depleted environments, drops after circumcision, which is intuitive. In addition to the prevailing theory of decreasing the HIV-infected lymphoid cells in the penis region, this may help explain the significant effect circumcision has on HIV transmission, since the altered environment may not be as cozy an environment for the virus to live.

The second looks at the lower airways of asthmatics, which have long been thought to be mostly sterile. With newer molecular techniques, the authors isolated a host of micro-organisms, finding a fairly significant difference between sick and healthy lungs in the lower airway micro-environment. This time, the sick lungs had higher concentrations of a group of bacteria called proteobacteria, bugs that have been implicated in a number of respiratory illnesses in the past.

Moving forward, we still don't have the molecular basis for why having a different microflora effects whether or not we humans get disease. Both of these studies had very small numbers, and only looked at one geographic region, making generalizing specifics from these investigations challenging. Obviously, however, environmental factors have a large impact, since every person on the planet is exposed to different environmental micro-organisms throughout their life. Genetic factors will also be found to play a large role. Large-scale integration of human microbiome data with available human genome data, with attempts to figure out which host genetic factors lead to host colonization will be tremendously useful, but are still a work in progress. We're beginning to grasp the genetic susceptibilities to infection; what's next is integrating the genetic susceptibility to colonization, and figuring how that relates to human disease.

Price, L., Liu, C., Johnson, K., Aziz, M., Lau, M., Bowers, J., Ravel, J., Keim, P., Serwadda, D., Wawer, M., & Gray, R. (2010). The Effects of Circumcision on the Penis Microbiome PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008422

Hilty, M., Burke, C., Pedro, H., Cardenas, P., Bush, A., Bossley, C., Davies, J., Ervine, A., Poulter, L., Pachter, L., Moffatt, M., & Cookson, W. (2010). Disordered Microbial Communities in Asthmatic Airways PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008578

Friday, December 18, 2009

Malaria: Forcing us to destroy our own brains...

From a recent PLOSOne study, some interesting findings on malaria pathogenesis. What we know is that getting cerebral malaria is both very bad and very unpredictable, so that it's very difficult to decide which patient will require closer monitoring than others. Management is non-specific and supportive, and we still don't exactly know why it happens. There are a lot of theories out there, many of which center around the sludging of blood in the cerebral vessels, causing decreased brain blood flow and the symptoms we see. This has always been suspect, since there are a great deal of inconsistencies with this hypothesis, so investigation has continued.

Adding to some prior work that they've done, these investigators looked at a population in India where malaria is endemic. From screening the serum of patients with both severe malaria and cerebral malaria, they found some interesting differences. Notably, the patients with cerebral malaria had a specific cytokine response that seemed to induce a reaction to a series of brain-specific proteins in the form of antibody production. What the effect of this auto-antibody production is on the symptoms seen in cerebral malaria remains unclear, especially since their concentration wasn't related to disease severity. Determining whether these antibodies contribute to disease, or serve as simply a marker for disease progression or existence, still has to be sussed out. Interestingly, however, the strongest signal was to a different brain protein compared with their prior study in African patients, suggesting a variant host response, although there was some overlap in this data.

Getting more people into this study would have powered their results a bit more, and perhaps helped pinpoint the brain protein a bit better, but nevertheless, it's an interesting theory that deserves some more study, since it has sizable implications, both for therapeutic and for prognostic purposes. Given that we are making only slow progress in the battle against this disease, the more information and research on the topic, the better.

Bansal, D., Herbert, F., Lim, P., Deshpande, P., Bécavin, C., Guiyedi, V., de Maria, I., Rousselle, J., Namane, A., Jain, R., Cazenave, P., Mishra, G., Ferlini, C., Fesel, C., Benecke, A., & Pied, S. (2009). IgG Autoantibody to Brain Beta Tubulin III Associated with Cytokine Cluster-II Discriminate Cerebral Malaria in Central India PLoS ONE, 4 (12) DOI: 10.1371/journal.pone.0008245

Saturday, December 5, 2009

Justifying my existence

As somebody training in both critical care and infectious diseases, I'm often left trying to explain what I hope to do with my career, struggling with coherent answers to both laypeople and other doctors. People get sick because of infections. Also, sick people end up getting infections. That's how I look at it, and hence my training.

This study, published by some of my bosses, helps validate all of this. Looking at one day in ICUs across the planet, they captured a point-in-time, just to see what the burden of 'infection' is in our planet's ICUs. Obviously, there are huge problems with potential reporting bias and the like, but it's as good a global survey as you can justifiably get. And the results are interesting, showing that half of all patients in ICUs were considered infected, with these patients doing significantly worse overall. Nearly three quarters of the patients were receiving antibiotics, some just for propylaxis. Also, the longer that you were sick, the more likely you were to have an infection. There was also a correlation between national GDP and rates of ICU infection, which, once again, isn't surprising, since we know that infection control procedures aren't always cheap

The types of bacteria and infections reported were interesting, with pneumonias as the most common infection, and a reasonable distribution of types of bacteria. There is an increasing prevalence of dangerous gram-negative bacteria, and a persistently worrisome rate of antibiotic-resistant bacteria. I've talked about this quandary before, since as we're able to care for sicker and sicker patients, we're also using more and more antibiotics, leading to all sorts of resistance problems for future generations. Also, what constitutes an 'infection' is a difficult distinction, one that we typically err on the side of caution by treating. In the end, with very few new antibiotics coming down the research pipeline, we will face a tremendous challenge outwitting these ever-shifting, diverse group of organisms.

Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, Moreno R, Lipman J, Gomersall C, Sakr Y, Reinhart K, & EPIC II Group of Investigators (2009). International study of the prevalence and outcomes of infection in intensive care units. JAMA : the journal of the American Medical Association, 302 (21), 2323-9 PMID: 19952319