Study: Statins & Cerebral Malaria

Photo Credit CDC

 

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Increasingly, statins – common cholesterol lowering drugs – are being looked at for their inflammation-reducing properties in the treatment of other diseases.

 

Long time readers of this blog will recall that Dr. David Fedson - former Professor of Medicine at the University of Virginia School of Medicine and formerly Director of Medical Affairs, Aventis Pasteur MSD – has advocated research into the potential role of low-cost statins during an influenza pandemic (see Lancet: David Fedson On Statins For Pandemic Influenza).

 

For more on statins, and how they might be used against pandemic influenza, you may wish to revisit:

 

Study: Statins, Influenza, & Mortality

Another Study On Statins And Pneumonia

Dr. David Fedson: The Case For Using Statins In A Pandemic

Statins Revisited

 

A couple of years ago we saw a video presentation at the 2010 ICAAC Conference called A Role for Statins in Infectious Disease? #ICAAC) (excerpt below).

 

Statins are well-known as a class of drugs that are used to help lower cholesterol but recent evidence suggests they might be good for more than your heart. They may play a role in preventing and treating certain bacterial infections including pneumonia and sepsis. Presenters at ICAAC discuss the latest research on the potential of these drugs.

• Reimar Thomsen, Aarhus University Hospital, Aalborg, Denmark
• Matthew Falagas, Alfa Institute of Biomedical Sciences, Athens, Greece
• Nasia Safdar, University of Wisconsin, Madison, WI, United States

 

These presenters suggest that statins may directly affect viruses and fungi, as well as help dampen the body’s inflammatory response. One study discussed found a 30% reduction in 30-day pneumonia mortality among patients already on statins.

 

The caveat being that much of the evidence for statins efficacy comes from in vitro studies, or observational studies that can sometimes be influenced by what is known as the `healthy user bias’.  

 

Simply put, patients who are already on statins when they develop pneumonia, sepsis, or influenza may be more likely to have a healthy lifestyle than those not on statins, potentially skewing the results.

 

Still, the results to date have been intriguing, if not totally convincing.

 

Which brings us to a a new study, appearing in PloS Pathogens, that looks at the potential role of statins in the treatment of cerebral Malaria.

 

According to the WHO:

There were about 219 million cases of malaria in 2010 and an estimated 660 000 deaths. Africa is the most affected continent: about 90% of all malaria deaths occur there.

 

Between 2000 and 2010, malaria mortality rates fell by 26% around the world. In the WHO African Region the decrease was 33%. During this period, an estimated 1.1 million malaria deaths were averted globally, primarily as a result of a scale-up of interventions.

 

Rarely mentioned in all of these figures are the (often life-long) neurological sequelae that cerebral malaria may produce, particularly among children.

 

These may include blindness, epilepsy, decreased motor skills, hearing impairment, aphasia (loss of speech), and behavioral problems, as noted in the following BMC Research Note.

 

 

Severe neurological sequelae and behaviour problems after cerebral malaria in Ugandan children

Richard Idro, Angelina Kakooza-Mwesige, Stephen Balyejjussa, Grace Mirembe, Christine Mugasha, Joshua Tugumisirize and Justus Byarugaba

Conclusions

In addition to previously described neurological and cognitive sequelae, severe behaviour problems may follow cerebral malaria in children. The observed differences in patterns of sequelae may be due to different pathogenic mechanisms, brain regions affected or extent of injury. Cerebral malaria may be used as a new model to study the pathogenesis of ADHD.

 

The PloS Pathogens study, which looks at the potential use of statins for cerebral malaria in a murine (mouse) model, involved infecting lab mice with the malaria parasite, and then treating half of them with just chloroquine, and the other half with chloroquine and Lovastatin. 

 

Mice that received the combination treatment saw a significantly reduced rate of post-infection cognitive dysfunction.

 

Statins Decrease Neuroinflammation and Prevent Cognitive Impairment after Cerebral Malaria

Patricia A. Reis mail, Vanessa Estato, Tathiany I. da Silva, Joana C. d'Avila, Luciana D. Siqueira, Edson F. Assis, Patricia T. Bozza, Fernando A. Bozza, Eduardo V. Tibiriça, Guy A. Zimmerman, Hugo C. Castro-Faria-Neto

Author Summary

Cerebral malaria (CM) is the direst consequence of Plasmodium falciparum infection. Cognitive impairment is a common sequela in children surviving CM. Identification of adjunctive therapies that reduce the complications of CM in survivors is a priority. Statins have been suggested for the treatment of neuroinflammatory disorders due to their pleiotropic effects.

 

Here, we examined the effects of lovastatin on neuroinflammation in experimental CM, and its effect on the prevention of cognitive impairment. Lovastatin reduced adhesion and rolling of leukocytes in brain vessels, inhibited blood-brain barrier disruption, and reversed decreases in cerebral capillary density. Lovastatin also inhibited ICAM-1 and CD11b mRNA expression while increasing HMOX-1 mRNA levels. Proinflammatory cytokines and markers of oxidative stress were lower in the brains of infected mice treated with lovastatin.

 

Lovastatin administered together with antimalarial drugs during the acute phase of the disease-protected survivors from impairment in both contextual and aversive memory 15 days after infection. Similar results were observed in a model of bacterial sepsis.

 

Our findings support the possibility that statins may be valuable pharmacologic tools in treatment of patients with neuroinflammation associated with severe systemic inflammatory syndromes. Clinical trials with statins in CM and sepsis should be speedily considered to examine this point.

Of course, what works in mice isn’t guaranteed to work in humans.  The authors caution:

 

These models may provide important insights into the pathogenesis of cognitive dysfunction associated with cerebral malaria and related disorders that may be relevant to human conditions [7]. While differences between murine models of CM and the human syndrome are often emphasized [10], [11], there are also important similarities [3], [7], [12]–[14]. Nevertheless, caution must be exerted when translating experimental findings to the clinical scenario.

 

 

The VOA has a nice write up of this study (see Mice Study Indicates Cholesterol Drug Might Help Treat Serious Malaria Cases), including an interview with one of the authors, who recommends that:

 

Zimmerman recommends lovastatin be added to treatments for malaria as well as for sepsis, a systemic blood infection commonly known as blood poisoning that sickens and threatens the lives of more people worldwide than cerebral malaria.

 

The problem with statins is that these are are cheap, generic drugs.  They provide little financial incentive for their manufacturers to mount expensive human trials in order to prove their effectiveness against malaria, pneumonia, sepsis, or influenza.

 

So, while the evidence continues to suggest benefits to using statins for `off label’ purposes,  real proof of their effectiveness may be a long time in coming.

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PLoS: Human-Type H5N1 Receptor Binding In Egypt

 

 

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The mantra over the past five years or so on H5N1 bird flu has been that:

 

The H5N1 virus remains poorly adapted to human physiology, and despite ample opportunities in places like Egypt and Indonesia, only causes rare, sporadic infections in humans.

 

 

H5N1 is generally a gastrointestinal malady in birds, and the virus is usually spread via infected feces. The virus binds preferentially to the kind of receptor cells commonly found in avian digestive and respiratory tracts; alpha 2,3 receptor cells.

 

Human influenzas, on the other hand, are adapted to bind to the kind of receptor cells that line the surfaces of the human respiratory system; alpha 2,6 receptor cells.

 

While not an absolute, flu viruses that bind to one type of receptor cell, tend not to bind well to the other.

 

This ability to bind to a specific type of cell has often been described as the host cell being a padlock, and the virus needing a specific key (determined by the genetics of the virus’s Receptor Binding Domain: RBD) to unlock it.

 

(A Very Simplified Illustration of RBDs)

 

 

Now humans do have some avian-like alpha 2,3 receptor cells, particularly deep in the lungs.

 

This has been suggested as the reason that - when on rare occasions humans contract H5N1 - it is usually a deep lung infection.

 

It has also been postulated that H5N1’s deeper lung infections may reduce human-to-human transmission, as sneezing is a less common symptom.

 

The concern is that over time, the H5N1 (or some other avian flu) virus might mutate in such a way as to be able to bind to human α2,6 receptor cells of the upper airway.

 

And while that may not be the only obstacle keeping the virus from becoming a pandemic strain, it does appear to be a major one.

 

Although only introduced to the region in 2006, Egypt has rapidly become a hotspot for avian flu (see this list of human cases maintained on FluTrackers). 

 

Unlike some Asian countries, where the virus has proved fatal in 80% of reported cases, the CFR (Case fatality ratio) in Egypt has ranged from 10% (2009) to 34% (2010).

 

This variability in virulence has sparked concerns that important changes were taking place in the virus. 

 

Which brings us to an open access research article (excerpts slightly reformatted for readability) appearing today in PLoS Pathogens called:

 

Acquisition of Human-Type Receptor Binding Specificity by New H5N1 Influenza Virus Sublineages during Their Emergence in Birds in Egypt

Yohei Watanabe, Madiha S. Ibrahim, Hany F. Ellakany, Norihito Kawashita, Rika Mizuike, Hiroaki Hiramatsu, Nogluk Sriwilaijaroen Tatsuya Takagi, Yasuo Suzuki, Kazuyoshi Ikuta

PLoS Pathog 7(5): e1002068.

doi:10.1371/journal.ppat.1002068

AUTHOR SUMMARY

Even though highly pathogenic avian H5N1 influenza viruses lack an efficient mechanism for human-human transmission, these viruses are endemic in birds in China, Indonesia, Viet Nam and Egypt. Hotspots for bird-human transmission are indicated in areas where human cases are more than 80% of total H5N1 influenza cases.

 

Circulation among hosts may allow H5N1 virus to acquire amino acid changes enabling efficient bird-human transmission and eventually human-human transmission. The receptor specificity of viral hemagglutinin (HA) is considered a main factor affecting efficient transmissibility. Several amino acid substitutions in H5 virus HAs that increase their human-type receptor specificity have been described in virus isolates from patients, but their prevalence has been limited.

 

In contrast, we show here that new H5 sublineages in Egypt have acquired a change in receptor specificity during their diversification in birds. We found that viruses in those sublineages exhibited increased attachment and infectivity in the human lower respiratory tract, but not in the larynx.

 

Our findings may not allow a conclusion on the high pandemic potential of H5N1 virus in Egypt, but helps explain why Egypt has recently had the highest number of human H5 cases worldwide.

 

 

Since the entire research article is open access (and quite lengthy), I’ll not go into great detail on how they conducted this research here. 

 

Instead, we’ll focus on what all of this might mean.

 

While we tend to talk about the H5N1 virus as if it were a single, monolithic entity, in truth it is more akin to the mythical Hydra that is continually growing new heads.

 

The virus, as it spread from birds to other species and around the world, has evolved into a number of distinct genetic groupings called clades. As of 2009, the World Health Organization had classified the  H5N1 virus into 10 first order clades (0-9).

 

As  you can see from the chart below, while additional clades have been established over the past 10 years, the greatest diversity has been among the Clade 2 viruses.

 

 

 

Within each of these clades, the virus is continually evolving into subclades and sublineages. A few are biologically fit and manage to persist and spread, while others are not, and eventually die off.

 

Essentially H5N1 is a moving target; constantly changing, looking for an evolutionary advantage.

 

What the authors of today’s study found was that among recent human infections in Egypt, examination of viral isolates showed that several new H5 sublineages have emerged with an increased affinity for (human) α2,6 SA receptor cells while still retaining their binding ability to (avian) α2,3 SA receptor cells.

 

Using reverse genetics, they identified the the amino acid mutations that produced this new receptor binding affinity (essentially, a single mutation at HA residue 192 or a double mutation at HA residues 129 and 151).

 

They believe that the emergence of these new sublineages of H5N1 explains the increase in human cases in Egypt over the past three years.

 

Before anyone decides its time to head down to the bunker, it should be noted that this move towards greater `humanization’ of the H5N1 virus is far from complete.

 

The authors found `increased attachment and infectivity in the human lower respiratory tract, but not in the larynx.’

 

Many scientists believe the virus must learn to bind to, and replicate in, the upper airway of humans in order to transmit efficiently from human to human.

 

Something that hasn’t happened yet.

 

And there may very well be other – as yet unidentified -genetic changes that must occur before the virus can acquire human pandemic capability.

 

Something that could take years or even decades to evolve. Or admittedly, might never happen.

 

But today’s study is a not-so-gentle reminder that the H5N1 virus has not gone away, that it continues to try out new evolutionary tricks, and that it could still some day pose a pandemic threat to humanity.

 

Which is why the world remains at Pre-pandemic Phase III for the H5N1 virus.

 

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