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.

Bats, Viruses, And Their Immune Response

Common pipistrelle (Pipistrellus pipistrellus) – Credit Wikipedia

 

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For virologists and chiroptologists, an enduring mystery has been how bats are able to carry – without apparent ill effect – viruses that are normally deadly to most other mammals.

 

Long known for carrying rabies, over the past two decades we’ve discovered that bats can also harbor viruses such as Ebola, Marburg, Nipah, Hendra, and a variety of coronaviruses (including SARS). 

 

This week, in an article that appears in the Journal Science, we learn that some of the evolutionary changes that enable the bat to be the only mammal that can fly, may also help them to carry deadly viruses.

 

First a link to the Abstract (the whole paper is behind a pay wall), then excerpts from a Reuter’s news article that help flesh out the findings.

 

Published Online December 20 2012
< Science Express Index

Science DOI: 10.1126/science.1230835

• Report

Comparative Analysis of Bat Genomes Provides Insight into the Evolution of Flight and Immunity

Guojie Zhang, Christopher Cowled, Zhengli Shi, Zhiyong Huang, Kimberly A. Bishop-Lilly, Xiaodong Fang, James W. Wynne, Zhiqiang Xiong, Michelle L. Baker, Wei Zhao, Mary Tachedjian, Yabing Zhu, Peng Zhou, Xuanting Jiang, Justin Ng, Lan Yang, Lijun Wu, Jin Xiao, Yue Feng, Yuanxin Chen, Xiaoqing Sun, Yong Zhang, Glenn A. Marsh, Gary Crameri, Christopher C. Broder, Kenneth G. Frey, Lin-Fa Wang, Jun Wang

Abstract

Bats are the only mammals capable of sustained flight and are notorious reservoir hosts for some of the world’s most highly pathogenic viruses, including Nipah, Hendra, Ebola, and severe acute respiratory syndrome (SARS). To identify genetic changes associated with the development of bat-specific traits, we performed whole-genome sequencing and comparative analyses of two distantly related bat species, fruit bat Pteropus alecto and insectivorous Myotis davidii.

 

We discovered an unexpected concentration of positively selected genes in the DNA damage checkpoint and nuclear factor–κB pathways that may be related to the origin of flight, as well as expansion and contraction of important gene families. Comparison of bat genomes with other mammalian species has provided new insights into bat biology and evolution.

 

 

Admittedly, there is not much specificity in this abstract. 

 

Luckily, Tan Ee Lyn - Asia Health correspondent for Reuters – has an interview with the lead author -Professor Lin-Fa Wang, who reveals that some genetic changes necessary for flight may also help to moderate dangerous out-of-control immune responses known as Cytokine Storms.

Cytokines are a category of signaling molecules – proteins – that are released by immune cells that have encountered a pathogen, and are designed to alert and activate other immune cells to join in the fight against the invading pathogen.

 

Although poorly understood, the theory behind a `cytokine storm’ is this signaling process spirals out of control, resulting in an overwhelming immune response that can potentially kill the host.

 

According to Professor Lin-Fa Wang, this built-in suppression of the inflammatory (cytokine) response may be behind the bat’s unusual longevity (20 to 40 years), and their ability to `handle’ infection by normally deadly viruses.

 

 

Long-lived bats offer clues on diseases, aging

December 21, 2012 12:52 PM

HONG KONG: The bat, a reservoir for viruses like Ebola, SARS and Nipah, has for decades stumped scientists trying to figure out how it is immune to many deadly bugs but a recent study into its genes may finally shed some light, scientists said on Friday.Studying the DNA of two distant bat species,...

(Continue . . . )

 

 

In another article, this time in The Asian Scientist, the author talks about practical applications of this research, and is quoted as saying, “Our findings highlight the potential of using bats as a model system to study infection control, tumor biology, and the mechanisms of aging,”

 

 

Bats’ Immunity Against Deadly Viruses Linked To Their Ability To Fly

AsianScientist (Dec. 21, 2012) – An international team led by an infectious disease expert, Professor Lin-Fa Wang, at the Duke-NUS Graduate Medical School (Duke-NUS) in Singapore has found that the evolution of flight in bats may have contributed to the development of a highly effective immune system, allowing bats to harbor some of the world’s deadliest viruses such as Ebola and SARS.

(Continue . . . )

 

Both news articles are worth reading in their entirety.

 

For more on cytokine storms, and how they may affect pandemic influenza mortality, you may wish to revisit some of these earlier blogs.

 

Study: Calming The Cytokine Storm

Cytokine Storm Warnings

The Baskin Influenza Pathogenesis Study

Pt. 1   Pt. 2   Pt. 3

Study: Initial Flu Dose Dictates Immune Response

 

H3N2 influenza virions –CDC PHIL

 

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There’s a popular belief that once you’ve had a particular strain of the flu, your body’s immune system will protect you against it in the future. And under the right circumstances, that’s true.

 

But human physiology and its immune response is rarely as simple, and straightforward, as that.

 

Our immune systems vary considerably from one person to the next, and within a single individual, can change  radically over time. We’ve also discovered that some flu viruses leave a stronger `imprint’ on our immune system, than others.

 

Both of these factors can influence how strong . . . and how long lasting . . . any acquired immunity to a flu virus might be.

 

Which is one of the reasons why the CDC reminds us to get a flu shot every year, since the immunity from last year’s vaccine (or a bout with the flu) may have diminished over time – even if the same flu strains remain in circulation.

 

Now a study, published today in Journal of Leukocyte Biology, looks at another variable in influenza infection that appears to influence the type, and strength, of the immune response (at least in mice).

 

The initial viral dose.  The study is called:

 

Initial infectious dose dictates the innate, adaptive, and memory responses to influenza in the respiratory tract

Isabelle Marois, Alexandre Cloutier, Émilie Garneau and Martin V. Richter

Abstract

Factors from the virus and the host contribute to influenza virus pathogenicity and to the development of immunity. This study thoroughly examined the effects of an initial infectious dose of virus and unveiled new findings concerning the antiviral and inflammatory responses, innate and adaptive immunity, memory responses, and protection against secondary heterologous infection.

(Continue . . . )

 

In this experiment, researchers infected two groups of mice – one with a low dose and one with a high dose –of influenza A (H3N2), and then gauged various aspects of their immune response. Later, they exposed these mice to a different strain of flu to see what, if any, immune response was `left over’ from the initial infection.

 

As I’ve cautioned before, mouse models are often very useful in laboratory research, but what happens with mice doesn’t always correspond to what happens with human physiology. 

 

Still, they came up with some intriguing results. They found that the larger the initial infectious dose, the greater, broader, and longer-lived was the immune response.

 

The full study is behind a pay wall, but we’ve got a press release (slightly reparagraphed for readability) from the Federation of American Societies for Experimental Biology that provides the broad strokes to this research.

 

Flu immunity is affected by how many viruses actually cause the infection

New research published in the Journal of Leukocyte Biology suggests that the immune response differs depending on the amount of virus received during infection

Bethesda, MD—Not only does the type of flu virus affect a patient's outcome, but a new research report appearing in the Journal of Leukocyte Biology suggests that the number of viruses involved in the initial infection may be important too.

 

Scientists from Canada found that when mice were infected by relatively high concentrations of the flu virus, they not only developed immunity against the virus that infected them, but this also promoted the generation of a type of immune cell in the lungs poised to rapidly react against infections with other strains of the flu, as well.

 

Mice that were infected with a relatively low concentration of the virus developed weaker immunity against the strain that infected them, did not build up this crucial population of immune cells in the lungs, and showed only delayed immunity toward other flu strains.

 

This discovery could pave the way for new prophylactic strategies to fight flu infections and provides a novel basis for vaccine design.

 

"Hopefully, the findings of our study will help to develop better vaccine preparations that will be more effective in inducing protective cellular immunity to fight against infectious pathogens such as bacteria, viruses and fungi," said Martin V. Richter, Ph.D., the lead researcher involved in the work from the Department of Medicine at the Université de Sherbrooke and Centre de Recherche Clinique Étienne-Le Bel in Québec, Canada.

 

(Continue . . . )

 

 

While both are complex and multifaceted, our immune systems can be divided into two types of protection.

 

We have natural immunity – so called `innate immunity’ – that can detect, and launch a generic defense against a wide variety of invading pathogens

 

Were it not for this built-in immunity, none of us would survive past the first few hours or days of life; we'd be quickly overrun by opportunistic infections.

 

Innate immune system buys us time for our Adaptive Immune System to learn to recognize and fight specific pathogens.

 

The adaptive immune system produces pathogen-specific antibodies that can remember previous encounters with a virus, and provides us with varying degrees of acquired immunity.

 

For more information on some of the complexities of our immune system, you may wish to revisit some of these earlier blog posts.

 

 

Study: Vitamin D And The Innate Immune System

GM-CSF: An Innate Ability To Fight Flu

Cytokine Storm Warnings

PAMP and Circumstance

 

And for a fascinating look at the pathogenesis of influenza, the innate immune system, and the role of cytokines I would invite you to read my 3-part look at the Baskin pathogenesis study from 2009.

 

Dissecting the Influenza Pathogenesis Study Pt. 1

Dissecting the Influenza Pathogenesis Study Pt. 2

Dissecting the Influenza Pathogenesis Study Pt. 3

Study: Obesity, Influenza & Immunity

 

 

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Even in the earliest days of the 2009 H1N1 `swine’ flu outbreak, it was apparent that most people who contracted this novel virus experienced a relatively mild illness and recovered without incident.

 

There were exceptions, of course. 

 

Some small percentage of people were hit hard by the pandemic H1N1 virus, with some experiencing ARDS (Acute Respiratory Distress Syndrome) and a few sustaining severe lung damage.

 

Thousands died, with most of those deaths occurring in those under the age of 65. 

 

Many (but not all) of them had what was described as underlying `risk factors’; pregnancy, asthma, COPD, neurological disorders, heart failure, etc.

 

Extreme (or morbid) Obesity (BMI > 40) was one of the risk factors that emerged early in the 2009 outbreak, based primarily on anecdotal stories describing many of those admitted to intensive care units during the first wave of the illness. 

 

The earliest mention I can find in this blog of the link to obesity (and smoking) came on May 25th, 2009; scarcely one month after the first swine flu cases were announced in San Diego (see H1N1 Morbidity And Previously Existing Conditions).

 

During 2009 obesity was often mentioned as a possible risk factor (see Obesity Seen As Major Risk Factor For Flu Complications) - then later -  cautiously discounted as unproven (see More On The ACIP Meeting) in late July of 2009.

 

We saw more studies during 2010 that again raised the obesity question, and earlier this year in Extreme Obesity: A Novel Risk Factor For A Novel Flu we saw a study appearing in Clinical Infectious Diseases that found a three-fold increase in mortality among H1N1 patients who were morbidly obese.

 

Given the rising obesity rates in many countries around the world, an underlying risk factor that affects 25%-33% of the population is a pretty big deal.

 

 

All of which serves as prelude to a study that will appear later today in the International Journal of Obesity that looks at the immune response in those who are overweight, and finds significant differences from normal weight individuals.

 

This study found that while overweight people mounted a robust immune response from a flu vaccine during the first month after vaccination, within 12 months half saw a 4-fold decrease in antibody titers. 

 

That’s twice the rate of normal weight individuals.

 

Furthermore, they found significant differences in the immune response of obese subjects that suggest they are not only more susceptible to influenza, but are also more likely to see severe disease or complications.

 

While the study is not yet online, we have the press release from the University of North Carolina School of Medicine. Follow the link to read it in its entirety.

 

 

Study: Obesity limits effectiveness of flu vaccines

Public release date: 25-Oct-2011

 

New research from the University of North Carolina at Chapel Hill shows that obesity may make annual flu shots less effective.

 

The findings, published online Oct. 25, 2011, in he International Journal of Obesity, provide evidence explaining a phenomenon that was noticed for the first time during the 2009 H1N1 flu outbreak: that obesity is associated with an impaired immune response to the influenza vaccination in humans.

 

"These results suggest that overweight and obese people would be more likely than healthy weight people to experience flu illness following exposure to the flu virus," said Melinda Beck, Ph.D., professor and associate chair of nutrition at the UNC Gillings School of Global Public Health and senior author of the study.

 

"Previous studies have indicated the possibility that obesity might impair the human body's ability to fight flu viruses. These new findings seem to give us a reason why obese people were more susceptible to influenza illness during the H1N1 pandemic compared to healthy weight people."

 

The study reports for the first time that influenza vaccine antibody levels decline significantly in obese people compared to healthy weight individuals. What's more, responses of CD8+ T cells (a type of white blood cell that plays a key role in the body's immune system) are defective in heavier people.

 

(Continue . . . )

 

While the authors of this study can observe the decline in antibody response in the obese, the reasons behind it are less clear. They state:

 

"We need to continue to study the effect of obesity on the ability to fight virus infections. Influenza is a serious public health threat, killing up to half a million people a year worldwide. As rates of obesity continue to rise, the number of deaths from the flu could rise too.

 

We need to better understand this problem and to look for solutions."

 

 

Just as we’ve seen with those over 65 (see Study: Flu Vaccines And The Elderly and Flu Shots For The Elderly May Have Limited Benefits), those who are most at risk from influenza often see a reduced benefit from the current vaccine.

 

That isn’t to dismiss the flu vaccine as useless or a waste of time for these higher risk groups. Some protection is undoubtedly better than none.

 

But it is further evidence of the need to develop better flu shots that can help protect everyone.

 

Particularly those who mount a less-than-robust immune response to vaccines today.

GM-CSF: An Innate Ability To Fight Flu

 

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While just about everyone is familiar with vaccines and antivirals as preventatives or treatment for influenza, both have serious limitations.  

 

• Vaccines take months to develop and manufacture, must be well matched to the circulating virus, administered weeks in advance, and have a variable effectiveness rate.

 

• Antivirals often have a limited impact on the severity of illness and flu strains can over time develop resistance to them.

Today news about a new approach, that while years away from practical use, might one day help stimulate the body’s innate immune system into fighting the flu.

 

It’s called GM-CSF (granulocyte macrophage-colony stimulating factor), and according to a recent article in American Journal of Respiratory and Critical Care Medicine - in experiments performed on mice - it produced a remarkably effective immune response against influenza.

 

Specifically, it boosted levels of alveolar macrophages (AM) in the lungs.  Alveolar macrophages are part of the body’s innate immune system that seek out and destroy respiratory microbes.

A macrophage of a mouse forming two processes to phagocytize two smaller particles, possibly pathogens. – Wikipedia Commons

 

 

All of us are born with what is called an Innate Immune System that can detect, and launch a generic defense against, a wide variety of invading pathogens.

 

And if you think about it, were it not for this built-in immunity, none of us would survive past the first few hours or days of life.  We'd be quickly overrun by opportunistic infections.

 

This innate immune system also buys us time for our Adaptive Immune System to learn to recognize and fight specific pathogens. This adaptive immune system produces pathogen-specific antibodies that can remember previous encounters with a virus, and gives us acquired immunity.

 

Using three types of mice (wild-type, transgenic mice that do not express any GM-CSF, and transgenic mice that express GM-CSF only in the lungs), researchers inoculated them with three different influenza strains.

 

• Untreated Wild-type mice, and those that were genetically unable to express any GM-CSF, all died.  

• Mice that were genetically designed to express GM-CSF in the lungs, and Wild-Type mice treated with GM-CSF prior to infection all survived.

 

The major finding here is that the expression of GM-CSF in the lungs of mice provided extraordinary protection against lethal doses of several influenza virus strains.

 

Research further showed that it was the boost in alveolar macrophages, not T-cells or B-cells, that conveyed this protection.

 

While this could someday lead to a practical treatment for influenza in humans, for now this is mostly an important advance in our understanding of the way influenza works in the lungs and the workings of the innate immune system (in mice, anyway).

 

The standard caveats about mouse physiology vs. human physiology apply, and of course tinkering with something as complex (and incompletely understood) as the human immune system must be done cautiously.

 

But from a pure research standpoint, this is fascinating stuff.

 

First a link to the study, then some excerpts from the press release, and then I’ll be back with a little more.

 

Am. J. Respir. Crit. Care Med. 2011, doi:10.1164/rccm.201012-2036OC

GM-CSF in the Lung Protects Against Lethal Influenza Infection

Fang-Fang Huang, Peter F Barnes, Yan Feng, Ruben Donis, Zissis C Chroneos, Steven Idell, Timothy Allen, Daniel R Perez, Jeffrey A Whitsett, Kyri Dunussi-Joannopoulos, and Homayoun Shams

Conclusions: Granulocyte-macrophage colony stimulating factor confers resistance to influenza by enhancing innate immune mechanisms that depend on alveolar macrophages. Pulmonary delivery of this cytokine has the potential to reduce the morbidity and mortality due to influenza virus.

 

 

The following is a press release from the American Thoracic Society.

 

New approach to defeating flu shows promise

New research on mice has shown that pulmonary administration of granulocyte macrophage-colony stimulating factor (GM-CSF) significantly reduces flu symptoms and prevents death after a lethal dose influenza virus. While GM-SCF therapy for humans as a flu prophylaxis or treatment may be years away, the study results were striking: All of the mice treated with GM-SCF survived after being infected with the influenza virus, whereas untreated mice all died from the same infection.

 

"Such unique and unambiguous results demonstrate the great potential of GM-CSF and may be the remedy for a critical public health priority: developing strategies to reduce the morbidity and mortality from influenza," said Homayoun Shams, PhD, principal investigator of the study.

(Continue . . . )

 

GM-CSF is a type of cytokine.

 

Cytokines, broadly speaking, are a category of signaling molecules that are used extensively for cellular communication.

 

They are often released by immune cells that have encountered a pathogen, and are designed to alert and activate other immune cells to join in the fight against the invading pathogen.

 

In this case, GM-CSF stimulates the immune system to produce granulocytes – white blood cells (neutrophils, eosinophils, and basophils) -  and most importantly monocytes - which mature into macrophages.

 

Hence the name Granulocyte-macrophage colony-stimulating factor.

 

Already GM-CSF is used to treat humans dealing with neutropenia (low white cells), which may arise as the result of chemotherapy, radiation treatment, viral infections, or bone marrow diseases.

 

Whether GM-CSF turns out to be a viable treatment for influenza or not, this type of cutting edge research into the workings of the immune system will likely lead to new treatments for influenza, and hopefully other diseases as well.