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Infectious Disease

Big data, Emergency Medicine, Genetics, Infectious Disease, Research, Stanford News

Study means an early, accurate, life-saving sepsis diagnosis could be coming soon

Study means an early, accurate, life-saving sepsis diagnosis could be coming soon

image.img.320.highA blood test for quickly and accurately detecting sepsis, a deadly immune-system panic attack set off when our body wildly overreacts to the presence of infectious pathogens, may soon be at hand.

Sepsis is the leading cause of hospital deaths in the United States and is tied to the early deaths of at least 750,000 Americans each year. Usually caused by bacterial rather than viral infections, this intense, dangerous and rapidly progressing whole-body inflammatory syndrome is best treated with antibiotics.

The trouble is, sepsis is exceedingly difficult to distinguish from its non-infectious doppelganger: an outwardly similar but pathogen-free systemic syndrome called sterile inflammation, which can arise in response to traumatic injuries, surgery, blood clots or other noninfectious causes.

In a recent news release, I wrote:

[H]ospital clinicians are pressured to treat anybody showing signs of systemic inflammation with antibiotics. That can encourage bacterial drug resistance and, by killing off harmless bacteria in the gut, lead to colonization by pathogenic bacteria, such as Clostridium difficile.

Not ideal. When a patient has a sterile inflammation, antibiotics not only don’t help but are counterproductive. However, the occasion for my news release was the identification, by Stanford biomedical informatics wizard Purvesh Khatri, PhD, and his colleagues, of a tiny set of genes that act differently under the onslaught of sepsis from they way they behave when a patient is undergoing sterile inflammation instead.

In a study published in Science Translational Medicine, Khatri’s team pulled a needle out of a haystack – activity levels of more than 80 percent of all of a person’s genes change markedly, and in a chaotically fluctuating manner over time, in response to both sepsis and sterile inflammation. To cut through the chaos, the investigators applied some clever analytical logic to a “big data” search of gene-activity results on more than 2,900 blood samples from nearly 1,600 patients in 27 different data sets containing medical information on diverse patient groups: men and women, young and old, some suffering from sterile inflammation and other experiencing sepsis,  and (as a control) healthy people.

The needle that emerged from that 20,000-gene-strong haystack of haywire fluctuations in gene activity consisted of an 11-gene “signature” that, Khatri thinks, could serve up a speedy, sensitive, and specific diagnosis of sepsis in the form of a simple blood test.

The 11-gene blood test still has to be validated by independent researchers, licensed to manufacturers, and approved by the FDA. Let’s hope for smooth sailing. Every hour saved in figuring out a possible sepsis sufferer’s actual condition represents, potentially, thousands of lives saved annually in the United States alone, not to mention billions of dollars in savings to the U.S. health-care system.

Previously: Extracting signal from noise to combat organ rejection and Can battling sepsis in a game improve the odds for material world wins?
Photo by Lightspring/Shutterstock

Autoimmune Disease, Cancer, Infectious Disease, Microbiology, Nutrition, Stanford News

Getting to the good gut: how to go about it

Getting to the good gut: how to go about it

In a blog post a few years ago I wrote, The Good Gutwith misplaced parenthetical self-assuredness:

Anybody who’s ever picked up an M&M off the sidewalk and popped it into his or her mouth (and, really, who among us hasn’t?) will be gratified to learn that the more germs you’re exposed to, the less likely you are to get asthma … hay fever and eczema.

I soon learned to my surprise, if not necessarily to my embarrassment, that virtually nobody – at least nobody over 6 – cops to having stooped-and-scooped as I routinely did as a kid on what I called my “lucky-sidewalk” days.

But those M&Ms may have been the best pills I ever took.

Stanford microbiologists Justin Sonnenburg, PhD, and Erica Sonnenburg, PhD, (they’re married) have written a new book, The Good Gut, about the importance of restocking our germ-depleted lower intestines.

Massive improvements in public sanitation and personal hygiene, the discovery of antibiotics and the advent of sedentary lifestyles have taken a toll on the number and diversity of microbes that wind up inhabiting our gut. According to The Good Gut, we need more, and more varieties, of them. And we need to treat them better. The dearth of friendly microorganisms in the contemporary colon is due not just to a lack of bug intake but to a lack of fiber in the modern Western diet. Indigestible to us, roughage is the food microbes feast on.

The Good Gut packages that message for non-scientists. “We wanted to convey the exciting findings in our field to the general public,” Justin Sonnenberg recently told me. “We’d noticed we were living our life differently due to our new understanding. We were eating differently and had modified both our own lifestyle and the way we were raising our children.”

In simple language, the Sonnenburgs explain how the pieces of our intestinal ecosystem fit together, what can go wrong (obesity, cancer, autoimmunity, allergy, depression and more), and how we may be able to improve our health by modifying our inner microbial profiles. Their book includes everything from theories to recipes, along with some frank discussion of digestive processes and a slew of anecdotes capturing their family’s knowledge-altered lifestyle.

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Infectious Disease, Patient Care, Pediatrics, Research, Stanford News

Antibiotic use in California neonatal intensive care units varies widely, study finds

Antibiotic use in California neonatal intensive care units varies widely, study finds

baby in NICUCalifornia neonatal intensive care units have huge differences in their rates of antibiotic use, a new study has found. And when it comes to antibiotics for hospitalized babies, more is not better: The study found no connection between a NICU’s rate of antibiotic use and several measures of how its young patients fared.

The research, spearheaded by the California Perinatal Quality Care Collaborative and published last last week in Pediatrics, analyzed data from 52,061 infants in 127 California NICUs. Rates of antibiotic use varied 40-fold across the NICUs studied, as news reports about the research have explained. The study looked for correlations between antibiotic use and each NICU’s rate of proven infection, rate of a serious complication of prematurity called necrotizing enterocolitis, average length of hospital stay, surgical volume and rate of patient deaths. No links were found.

“Variation in antibiotic prescribing practice appears to hinge on variation in how practitioners frame, interpret and respond to clinical situations ultimately considered unproven infection,” said lead author Joseph Schulman, MD, of the California Department of Health Care Services, in an email about the research. “There are tradeoffs between benefits and harms when treating suspected but unproven infection.”

Overuse of antibiotics presents real risks for babies, according to an accompanying editorial (.pdf) in Pediatrics. In addition to the potential for development of antibiotic-resistant pathogens, new research on the human microbiome raises the possibility that antibiotics may alter colonization of the body with healthy bacteria, the editorial says, possibly increasing the risk of necrotizing enterocolitis and of childhood obesity.

Yet there’s also no question that, for many babies, antibiotics are lifesaving. Researchers and clinicians now face the tricky task of figuring out when antibiotics can safely be reduced.

“More research is needed, but there are important things we can do right now,” senior author and Stanford neonatologist Jeffrey Gould, MD, told me. For instance, preterm babies whose mothers have signs of chorioamnionitis (an infection of the membranes around the baby) “are solid candidates for antibiotic prescriptions, but should be promptly taken off of antibiotics when cultures are negative and they have no symptoms,” he said.

As the editorial concludes, “there is great potential to substantially reduce both risk and cost for this vulnerable population through more judicious use of antibiotics.”

Previously: Study finds gap in referring California’s tiniest babies to follow-up care, Stanford-led study suggests changes to brain-scanning guidelines for preemies and Helping families navigate the NICU
Photo, which originally appeared in Stanford Medicine News, courtesy of Lucile Packard Children’s Hospital Stanford

Ebola, Global Health, Infectious Disease, Microbiology, Research

Can a single drug outsmart many kinds of viral invaders?

Can a single drug outsmart many kinds of viral invaders?

blue virus

We’ve got plenty of effective antibiotics – maybe even too many– to knock off bacteria we don’t like. But when it comes to viruses, it’s a different story, Stanford infectious-disease specialist Shirit Einav, MD, and postdoc Elena Bekerman, PhD, write in a recently published perspective piece in Science.

“Although hundreds of viruses are known to cause human disease, antiviral therapies are approved for fewer than 10,” the authors write, before going on:

[Antiviral drugs that interfere with crucial viral enzymes] have shown considerable success in the treatment of HIV and hepatitis C virus… infections. However, this approach does not scale easily and is limited particularly with respect to emerging viruses against which no vaccines or antiviral therapies are approved.

Which is too bad, because viruses can be nasty. Not to mention creepy: They’re master puppeteers when it comes to manipulating us into submission. They can’t even replicate on their own. The little body-snatchers need our own cells, which they break into, bamboozle, and bully into producing copies of themselves and then squirting them out so they can infect other cells and, with luck, other people.

A partial list of merging and re-emerging viruses for which there are no decent treatments includes dengue, estimated to infect 400 million people each year; SARS and MERS, responsible for outbreaks of severe acute respiratory syndromes; and Ebola, which, as everybody now knows, caused an ongoing epidemic in Africa.

Developing antiviral drugs is a huge challenge. It takes, on average, more than $2 billion and about a decade, plus or minus a couple of years, to develop a new drug targeting just one single type of virus, Bekerman and Einav write. To make things worse, these nano-villains evolve even faster than bacteria do.

Einav’s research has been taking a different tack. She’s working on drugs that, instead of gumming up this or that viral enzyme (at least until it mutates into a form the drug can’t gum up), interfere with the activity of components in our cells that the viruses absolutely depend on for their own survival and replication. There are already drugs, many of them already approved for far different indications such as cancer, that can do just that – without, however, disabling our own cells so much that the cure becomes worse than the disease.

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Global Health, Immunology, Infectious Disease, Pediatrics, Stanford News

Researchers tackle unusual challenge in polio eradication

Researchers tackle unusual challenge in polio eradication

poliovaccinationPolio is a tricky foe. One of the biggest hurdles in the World Health Organization’s polio eradication campaign is that the virus causes no symptoms in 90 percent of people who contract it. But these silently infected individuals can still spread the virus to others by coughing, sneezing or shedding it in their feces. And those they infect may become permanently paralyzed by or die.

Polio’s evasiveness has also led to a big speed bump on the road to eliminate the disease. As I report in the current issue of Inside Stanford Medicine, scientists are trying to figure out how to stop a form of poliovirus that is derived from one type of  polio vaccine. Oral vaccines, which consist of live poliovirus that has been inactivated, can occasionally mutate in someone’s intestines to regain infectiousness. And, in rare instances, these viruses escape to the environment in feces, spreading to other people via sewage-contaminated water.

These “circulating vaccine-derived viruses” are threatening to overtake naturally occurring, “wild” poliovirus as the main source of paralysis in the communities where polio persists. The CDC’s most recent report on polio infections in Nigeria says that during the first nine months of 2014, the vaccine-derived viruses caused 22 cases of paralyzing poliomyletis, whereas wild virus caused six cases, for instance.

To tackle the problem, researchers are investigating how the injected polio vaccine, which is made with killed virus, might be substituted for the oral vaccine. The injected vaccine has some potential disadvantages for use in developing countries, so it’s not necessarily an easy substitution. In my story, Stanford’s Yvonne Maldonado, MD, who is studying the problem with a grant from the Bill & Melinda Gates Foundation, explains:

“We don’t really understand how well the killed vaccine is going to work in kids in developing countries, where there is lots of exposure to sewage, and malnutrition leaves children with weakened immune systems,” Maldonado said.

Her Gates Foundation grant examines semi-rural communities in Mexico where children now receive routine doses of the killed vaccine, followed by twice-a-year doses of the live vaccine.

“It’s an opportunity for us to study a natural experiment,” Maldonado said. Her team wants to know if the primary immune response to the killed vaccine will reduce shedding and transmission of later doses of live vaccine. They hope that starting with one or more doses of the injected vaccine will give kids the best of both worlds: from the shot, protection against circulating vaccine-derived viruses; from the oral vaccine, intestinal immunity.

Previously: TED talk discusses the movement to eradicate polio and New dollar-a-dose vaccine cuts life-threatening rotavirus complications by half
Photo of children in South Sudan receiving oral polio vaccine by United Nations Photo

Global Health, HIV/AIDS, Infectious Disease, Stanford News

Spread of drug-resistant HIV in Africa and Asia is limited, Stanford research finds

Spread of drug-resistant HIV in Africa and Asia is limited, Stanford research finds

In the last decade, millions more people in the developing world have gained access to anti-viral drugs to treat HIV, with nearly 12 million now on this life-giving treatment. But with more people on medication, there’s concern about the spread of drug-resistant strains of the virus, which can be transmitted from one individual to the next.

A new, multi-center study led by Stanford researchers offers some good news on this front: The transmission of drug-resistant strains thus far has been fairly limited in the hard-hit regions of Africa and Asia. The research involved more than 50,000 patients in 111 countries.

It is inevitable that transmitted drug resistance will increase further, so we need to continue ongoing monitoring to ensure successful, long-term treatment outcomes

“What we are showing is that the rates of transmitted drug-resistant HIV in the low- and middle-income countries most affected by HIV have increased modestly,” Stanford infectious disease expert Robert Shafer, MD, principal investigator on the study, told me. “The rate of increase in sub-Saharan Africa has been low, and an increase has not been detected in south Asia and Southeast Asia.”

Shafer is nonetheless cautious, as drug resistance remains a problem in these regions, where patients are prescribed drug regimens that are not as effective as those used in the West. And adhering to a daily regimen can be challenging for these patients, as transportation, drug supply and other issues may get in the way. Resistance can occur when there is a gap in treatment.

“It is inevitable that transmitted drug resistance will increase further, so we need to continue ongoing monitoring to ensure successful, long-term treatment outcomes for the millions of people on therapy worldwide,” Shafer said.

In the study, he and his colleagues identified four mutations that were linked to resistance to two HIV drugs, nevirapine and efavirenz. That result points to the possibility of creating a simple test that could be used to detect these mutations, he said. Clinicians then could tailor their treatment accordingly.

Another key finding was that the drug-resistant strains that did occur were not from a single line of resistant viruses, but were quite distinct. That means they developed independently, not as a result of a single transmission chain. That differs from some other microbes, such as malaria and tuberculosis, where resistant strains can move very quickly through the population.

“We are finding that the strains being detected in low-income countries are pretty much unrelated to one another,” Shafer said. “So that suggests these have not yet gained a foothold in the population and are less often being transmitted among people who have never received the drugs before.”

The study appears online today in PLoS Medicine.

Aging, Immunology, Infectious Disease, Research, Stanford News

Frenemies: Chronic cytomegalovirus infection boosts flu vaccination efficacy (IF you’re young)

Frenemies: Chronic cytomegalovirus infection boosts flu vaccination efficacy (IF you're young)

cheapo boost“The enemy of my enemy is my friend.” This phrase, or at least the thinking it embodies, is at least 2,400 years old. So, there must be something to it, right?

Of course, it’s arguably a vast oversimplification. The more nuanced and much newer term “frenemy,” dating back merely to the early 1950s, is more apt in the case of infection by the microbe known as cytomegalovirus (CMV, for short). If the name is unfamiliar, brace yourself: You’ve probably already been introduced. It’s ubiquitous.

“Between 50 percent and 80 percent of adults in the United States have had a CMV infection by age 40,” states a page on the National Institutes of Health’s website. (Worldwide, the proportion of people infection exceeds 90 percent.) Once CMV is in a person’s body, it stays there for life,” the page soberly adds.

For the most part in healthy people, CMV pretty much sits there inside of cells (particularly in the salivary glands), pretty much biding its time and getting slapped down by the immune system if it tries to act up.

On the other hand, the virus can cause serious trouble if you’re immune-compromised: say, getting a bunch of immune-suppressing drugs pending or after a transplantation operation, or carrying another virus, the infamous immune-deficiency-causing HIV (which as far as we know is nothing but an enemy, plain and simple.)

But in a new study published in Science Translational Medicine, Stanford immunology expert Mark Davis, PhD, and his colleagues show that carriers of CMV mount a more robust immune response to seasonal influenza vaccinations, increasing the chances that the annual vaccine will be more effective in those people.

That’s the good news. The not-so-great news is that this only holds for young people (20-30 years old), not the older ones (age 60 and up) who could really use a boost: The older you get, it’s well known, the less effective the standard seasonal flu vaccine is in helping you fight off an influenza infection.

Experimenting with mice, Davis and his associates went a step farther. They actually infected the animals with influenza itself. Sure enough, young mice who were carrying CMV fought off the bug better than the non-infected mice did.

That’s the good news. The not-so-great news is that the old mice didn’t.

And although the study didn’t say so, one wonders whether in young people whose immune systems are going strong, that extra rocket fuel CMV seems to provide may have a dark side, for example a tendency to autoimmunity. Women’s immune systems tend to be more robust than those of men (very possibly due to the effects of testosterone, as Davis and his crew found a little over a year ago. And they have several times the rate of many autoimmune diseases that men do.

Previously: In human defenses against disease, environment beats heredity, study of twins shows, Why do flu shots work in some but not others? Stanford researchers are trying to find out, In men, a high testosterone count can mean a low immune response and Mice to men: Immunological research vaults into the 21st century
Photo by Joe Lillibridge

Global Health, Haiti, Infectious Disease, Public Health, Technology

A sanitation solution: Stanford students introduce dry toilets in Haiti

A sanitation solution: Stanford students introduce dry toilets in Haiti

sanitation-toilet-movedIn the United States, we often take for granted the relationship between health and sanitation. Not so in Haiti, where some people dispose of their feces in plastic bags they throw into waterways. As a result, waterborne diseases like cholera are common.

But what’s to be done? Flush toilets guzzle gallons of water and depend on an entire sewage system — an unfeasible option in many developing nations. To fill the gap, a pair of Stanford civil and environmental engineering graduate students have developed a program called re.source, which provides dry household toilets, and empties them for about $5 a month.

From a recent Stanford News story:

Unlike most sanitation solutions that only address one part of a dysfunctional supply chain, container-based sanitation models, such as the re.source service, tackle the whole sanitation chain. The re.source toilets separate solid and liquid waste into sealable containers, and dispense a cover material made of crushed peanut shells and sugarcane fibers that eliminates odors and insect infestations. The solid waste is regularly removed by a service, which takes it to a disposal or processing site to be converted to compost and sold to agricultural businesses.

The re.source students — Kory Russel and Sebastien Tilmans — work under the guidance of Jenna Davis, PhD, an associate professor of civil and environmental engineering. They started small, with a free pilot phase in 130 households in a Haitian slum, but the service has expanded to include 300 additional households with plans to introduce a service in the capital, Port-au-Prince.

The project is part of a larger Stanford focus on water issues ranging from safe drinking water to environmental concerns.

Previously: Waste not, want not, say global sanitation innovators, Stanford pump project makes clean water no longer a pipe dream and Award-winning Stanford documentary to air on PBS tonight
Photo by Rob Jordan

CDC, Ebola, Global Health, In the News, Infectious Disease

All hands on deck: Doctor answers call to work on largest Ebola epidemic in history

DSCN0895 cropped and resizedIn the nearly 70-year history of the Centers for Disease Control and Prevention (CDC) only three disasters called for an “all hands on deck,” Level 1 emergency response – Hurricane Katrina in 2005, the H1N1 pandemic of 2009 and the Ebola epidemic of 2014. This Ebola epidemic – the largest one in history – was the first assignment for Christopher Hsu, MD, PhD, from the Epidemic Intelligence Services (EIS) officer training program at the CDC.

As an EIS officer in the Division of High-Consequence Pathogens and Pathology at CDC, Hsu investigates and studies deadly and exotic pathogens like chikungunya, monkeypox, rabies and Ebola.

Given Hsu’s work on disease at CDC, I was surprised to learn that the topic of his prestigious three-year fellowship at Stanford was cancer, not infectious disease. I asked Hsu about this and what it’s like working on the largest Ebola epidemic in the world. He summed it up this way: “I get to work with very deadly and interesting diseases. I travel, see new cultures and am immersed in my work. I’m not just studying the disease; I’m in the jungle, studying the disease where it began with the people from that region. It’s a great honor to be in that position.”

Hsu’s switch from studying cancer to investigating infectious disease sounds drastic, but it wasn’t much of a stretch, he explained. Hsu earned a PhD in veterinary pathobiology studying interspecies disease transmission before he began studying cancer at Stanford. “I enjoyed the work, but I also recalled some savvy advice a mentor once said to me, ‘you excel where your passion lies.’ I realized I lacked the fire in the belly.”

DSCN0828 cropped and resized-2When Hsu told his peers and mentors at Stanford he wanted to study infectious disease, Philip Pizzo, MD, former dean of the medical school and a specialist in oncology and infectious diseases, supported his decision. “I am very grateful to him,” Hsu said. “He probably doesn’t realize this, but he was a huge influence on where I am today after Stanford.”

Two years later, Hsu and his cohort of EIS officers, affectionately nicknamed “the Ebola Class,” learned the 2014 Ebola outbreak had just been classified as a Level 1 emergency. CDC Director Tom Frieden, MD, MPH, visited Hsu’s class and personally asked them to take up the call to work on Ebola. Hsu’s cohort was a mix of physicians, nurses, veterinarians, and scientists with specialties ranging from malaria to violence prevention, but after Frieden’s visit, their professional interests no longer mattered. “We decided we were all working on Ebola in some capacity,” Hsu said.

Many of the EIS officers in Hsu’s Ebola class have completed one or two 30 to 90-day deployments to prevent and control Ebola in West African countries with widespread transmission (Guinea, Liberia and Sierra Leone), or in one of the other countries where Ebola occurred in the past. Hsu describes his disease fieldwork as part detective work and part disease control. “I investigated who was sick, what their symptoms were and who had contact with them,” Hsu said.

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In the News, Infectious Disease, Nutrition, Pediatrics

Raw milk still a health hazard, says Stanford doctor

Raw milk still a health hazard, says Stanford doctor

MoooooooIn spite of looser regulations around the sale of unpasteurized milk, it’s still unsafe to drink. That’s the message from Stanford pediatric infectious disease expert Yvonne Maldonado, MD, who is quoted in a new story on Today.com about the relaxation of raw-milk regulations in West Virginia and Maine.

In the United States, each state writes its own rules for in-state sales of raw milk, and they vary — a lot. Until last week, West Virginia required all dairy products sold in the state to be pasteurized, or heated briefly to kill germs. The state’s new laws allow for “cow shares,” in which individuals can pay to share ownership of a cow in exchange for some of the cow’s unpasteurized milk. Maine, meanwhile, is considering relaxing its license regulations on farmers who sell milk directly to consumers. (Other states take different approaches, ranging from entirely banning raw milk sales to allowing it in retail stores.)

Raw-milk aficionados claim that unpasteurized dairy products are safe and have health benefits.

Not so fast, says Maldonado, who was the lead author of the American Academy of Pediatrics’ 2013 policy statement discouraging the consumption of raw milk. In the Today.com story, she explains:

“People want to be more responsible for their sustainable environment and what they are putting into their bodies but they conflate the two issues because natural doesn’t always equal healthy,” says [Maldonado].

… “Our recommendations are evidence-based and there is no scientific evidence that drinking raw milk is better than drinking pasteurized milk and milk products,” says Maldonado, an infectious disease expert and pediatrician at Lucile Packard Children’s Hospital. “But we do see a very large number of diseases and illnesses from raw milk and raw milk products and the infections can be just horrible,” causing diarrhea, fever, cramps, nausea and vomiting, and some may even become systemic.

Previously: Stanford pediatrician and others urge people to shun raw milk products and Stanford study spoils hopes that raw milk can aid those who are lactose-intolerant
Photo by Steven Zolneczko

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