Genome Sequencing Aids Hunt for Deadly Bugs
Disease Detectives Say Technique Could Revolutionize Response to Outbreaks
Public-health investigators were alarmed last year when they tried to solve an outbreak of a dangerous superbug at a large Denver hospital.
David Walter Banks for The Wall Street Journal
A Life Technologies chip helps sequence DNA at the Centers for Disease Control in Atlanta.
Eight patients had been infected with a strain of klebsiella pneumoniae bacteria that was resistant to nearly all antibiotics. To stop it, the disease detectives needed to know where and how it was spreading. But the patients had been all over the hospital, from operating rooms to intensive care. Standard lab tests showed the cases were related to one another, but offered no clues as to how the people had been infected.
So the disease detectives turned to a technology like the one used to decode the human genome. In a laboratory at the Centers for Disease Control and Prevention in Atlanta, scientists sequenced the bacteria samples' entire DNA. They found tiny mutations that the bacteria had made as they moved from patient to patient. That helped them divide the patients into smaller clusters and pinpoint transmission to two intensive-care and two other units of the hospital. New steps were taken to prevent the spread of infections in those units.
David Walter Banks for The Wall Street Journal
Mili Sheth worked in the core genome-sequencing lab at the Centers for Disease Control in Atlanta earlier this year
"We were able to clarify a lot that we could not otherwise," said Erin Epson, a CDC disease detective working at the Colorado Department of Public Health and Environment and a member of the investigative team.
Used for years now in research and academia, whole-genome sequencing has become faster and cheaper, allowing it to be deployed more widely. It is a powerful new weapon that public-health scientists have begun turning to in a bid to outflank deadly microbes emerging around the world.
Public-health leaders and scientists say decoding dangerous pathogens could revolutionize the fight against outbreaks.
"We can stop outbreaks quicker and figure out ways pathogens are spreading that we don't currently know," said Thomas Frieden, the director of the CDC, which is building its capacity to sequence and analyze pathogens.
President Barack Obama's administration is seeking $40 million in fiscal 2014 for an "advanced molecular detection" initiative to expand the CDC's capacity to sequence and analyze pathogens after a panel of experts determined the agency was behind with the technology. But it isn't clear whether Congress will approve the funding for the agency, whose budget was cut by $580 million to a total of $6.29 billion this fiscal year.
Sequencing a whole genome allows scientists to identify quickly how virulent a bug is and what drugs it is resistant to. They can see how it is mutating and evolving as it jumps from one person to another, allowing them to track—and, hopefully, stop—an outbreak in real time. "The accumulations of mutations in an organism are like its history," said Duncan MacCannell, senior adviser helping lead the CDC's advanced molecular-detection work.
Federal and state officials are experimenting with whole-genome sequencing to get to the bottom of food-borne outbreaks and avoid fingering the wrong source. Using current lab methods to analyze salmonella, "it's hard to say it came from this lettuce and not that spinach," said Jill Taylor, interim director of the Wadsworth Center, New York state's public-health lab, which is working with the Food and Drug Administration to hone use of the technology. "With next-generation sequencing, you can really see the person has the same isolate [sample] as came from that lettuce. It's a much better tool to be able to say what the source was for an outbreak."
Last month, investigating an outbreak of listeria, CDC scientists compared sequenced bacteria from the suspected source, cheese, and found it to be "indistinguishable" from isolates from several suspected cases, said Peter Gerner-Smidt, branch chief of the agency's division of food-borne, waterborne and environmental diseases. They also sequenced isolates of two patients they weren't sure were part of the outbreak, he said. One was, he said.
Tuberculosis officials are working on ways to use next-generation sequencing to more rapidly identify drug-resistant forms of the disease, which are dangerous but often take weeks to confirm with current tests.
Meanwhile, scientists say the technology also helps them more deeply probe flu viruses. Life Technologies Corp., a maker of next-generation sequencing technology, set up a global influenza network earlier this year to sequence more samples once they are taken from patients, in the hope of detecting emerging strains earlier. "You're able to sample more, so you get a better idea of what is the most prevalent strain for the flu season," said a company spokesman.
Write to Betsy McKay at betsy.mckay@wsj.com
Science of Healing the Heart
In a Surprise, a Temporary Device Provides a Long-Term Cure
more in Health & Wellness »
Doctors have discovered that a heart pump designed to help keep patients alive until a transplant becomes available may actually help the heart heal itself. WSJ's Larry Greenberg explains how it could bring new hope to seriously ill patients. (Photo: Getty)
A mechanical pump that was invented as a temporary life support for patients with advanced heart failure is emerging as a potential tool to help hearts heal and function for the long term on their own.
The device, called an LVAD, takes over most of the heart's main pumping function and was designed initially to enable patients to survive until a donor heart became available for transplant. But doctors have discovered to their surprise that the heart can get better on the pump. When they remove it later to perform a transplant, the heart is sometimes dramatically improved.
"An LVAD is like putting the heart on the disabled list," says Joseph Woo, surgical director of the heart transplant and LVAD program at the University of Pennsylvania in Philadelphia. As with sidelined athletes, taking the heart out of the game to ease its workload appears to enable it to recover.
Now doctors are mounting a multicenter clinical trial to see if using the left-ventricular assist device—the LVAD's full name—as a "bridge to recovery" might eventually become a viable new option for some of the thousands of patients with advanced heart failure, one of medicine's most debilitating ailments.
Congestive heart failure is characterized by an enlarged heart which loses its ability to effectively propel blood to the rest of the body. In advanced disease, fluid collects in the lungs and lower legs, leaving patients so short of breath that walking just a few steps is an ordeal. Among nearly six million Americans with heart failure, an estimated 150,000 have the disease in an advanced stage where a transplant or LVAD become potential options. Most LVAD patients are men, between the ages of 40 and 79.
Based on a small number of patients who have already tried the approach, the heart can get "almost back but not quite back to normal," says Eduardo Rame, medical director of mechanical circulatory support at Penn, a leader of the new trial.
Recent advances in LVAD technology, plus a treatment protocol successfully championed in England by Emma Birks, director of heart failure, transplantation and mechanical support at University of Louisville, are fueling hope that more patients' hearts can recover sufficiently to function on their own. It would be "much better for patients to potentially do well on their own hearts again," says Dr. Birks, who is heading up the new study. With a heart transplant, there is a risk the body could reject the donated heart, for which patients must take immunosuppressant drugs. There also is a paucity of donor organs for all who need one.
Last year, 2,379 patients received a heart transplant in the U.S., according to the United Network for Organ Sharing, a private nonprofit group that manages the nation's organ-transplant program. The number has remained relatively stable for several years, reflecting a plateauing in the number of donor organs available.
Jared Castaldi for The Wall Street Journal; Rob Press/Penn Medicine
Joe Bellettiere, of South Philadelphia, was born with a diseased heart muscle. An artificial heart pump, which was removed 18 months ago, helped his heart.
The new study is funded by Thoratec Corp., THOR -0.55% of Pleasanton, Calif., which makes the Heartmate II, the most popular LVAD currently on the market.
For reasons not fully understood, when an LVAD is implanted in a patient with heart failure, the enlarged heart shrinks in a process doctors call reverse remodeling and can regain at least some of its lost function. An aggressive regimen of heart-failure and other drugs contributes to the benefit.
Joe Bellettiere of South Philadelphia illustrates the potential for the approach. Four years ago, when he was 19, a diseased heart muscle that had troubled him since birth triggered two life-threatening episodes of acute heart failure that robbed him of his breath and resulted in extended hospital stays. Initially, doctors recommended a transplant. But at Hospital of the University of Pennsylvania he met Dr. Rame, who encouraged him to consider an LVAD to help his heart recover.
"Either way, I had to get open-heart surgery and both things were going to make me better," Mr. Bellettiere says. He opted for the chance to try a new idea and to avoid drugs to prevent rejection of a donor heart. The treatment included regular exercise and an aggressive regimen of medication.
His LVAD was implanted in October 2009, during which doctors also repaired a leaky valve in his heart. Nearly 18 months later, Mr. Bellettiere's heart had recovered to the point where doctors performed a second open-heart operation to "explant" the device.
The first day after his discharge two weeks later, "I walked a mile," he says. "I didn't get out of breath. It was definitely a great feeling." Now 23 and with a year-and-a-half under his belt with his recovered heart working on its own, he's planning to go back to school.
In 2012, LVADs were implanted in 2,113 U.S. patients, according to Intermacs, a federally funded registry maintained at the University of Alabama at Birmingham that accounts for most of such patients. That is up from 907 in 2009, an increase partly due to the Food and Drug Administration's decision in 2010 to allow expanded use of Thoratec's Heartmate II beyond prospective transplant patients to include long-term or permanent therapy.
Rob Press/Penn Medicine
Dr. Eduardo Rame talks to heart patient George Smart, 51, of Norristown, Pa. Tests will show if his heart can function without the aid of an implanted pump.
Still, long-term LVAD use also comes with risks, including infection and stroke. Current versions run on batteries that need to be changed and recharged frequently.
Not every patient is likely to see the heart recover with an LVAD. Patients whose heart failure is caused by a heart attack—about 60% of all cases—aren't good candidates for the strategy because damage to the heart muscle hinders its ability to regain effective pumping function. And heart failure is often accompanied by kidney problems that could undermine the ability of patients with advanced disease to tolerate the drug regimen that is used in the new LVAD study.
For most other patients, heart failure is caused by genetic anomalies, infection of the heart muscle, adverse reaction to drugs such as chemotherapy or unknown reasons. Because these patients' heart muscle haven't been deprived of blood flow—the problem with heart attacks—doctors believe there is greater potential for the underlying tissue to recover.
But Lynne Warner Stevenson, director of the cardiomyopathy and heart-failure program at Brigham and Women's Hospital in Boston, cautions that some previous studies have found a very low rate of recovery for patients taken off an LVAD. Moreover, relieving the heart of its workload, but not so much that it gets lazy and can't recover, is a challenge, says Dr. Stevenson, who isn't involved in the study.
Deciding whether a patient's heart has recovered also remains uncertain. Dr. Rame last week performed the first "turn-down" test on George Smart, a 51-year-old LVAD patient from Norristown, Pa., who could be a candidate to have the device removed. The propeller in Mr. Smart's device that takes the workload off his heart spins 9,000 to 10,000 times a minute. Dr. Rame turned it down to about 6,400 rpms, including during an exercise test, so the heart was taking on most of its normal load. Mr. Smart did well, Dr. Rame said, but will repeat the test several times before a decision is reached on removing the LVAD.
Such tests are part of the protocol for the new study, which in addition to Penn and Louisville is being conducted at Montefiore Medical Center, in New York, and University of Utah, in Salt Lake City, with others expected to be added.
It isn't known how long the heart's recovery might last. But Dr. Birks offers reason for optimism. She and her colleagues published a study last year in the Journal of Thoracic and Cardiovascular Surgery comparing 40 patients who had LVADs removed with 50 others who had transplant surgery. With a follow-up as long as seven years, survival rates were at least comparable for those living with their own hearts, she says. "You still can't predict who will and who won't recover," she says. "That's what we're trying to work out now."
Write to Ron Winslow at ron.winslow@wsj.com
Why Hospitals Want Patients to Ask Doctors, 'Have You Washed Your Hands?'
Infections picked up in hospitals, nursing homes and doctor's offices affect more than 1 million patients and are linked to nearly 100,000 deaths a year.
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Most patients wouldn't dare to ask their doctor to wash his or her hands. But with growing concerns about antibiotic-resistant germs, it's more critical than ever. WSJ's Laura Landro and Premier Safety Institute Vice President Gina Pugliese explain. (Photo: Associated Press)
It's a simple enough request, but for patients and families who feel vulnerable, scared or uncomfortable in a hospital room, the subject can be too intimidating to even bring up with a doctor or nurse: Have you washed your hands?
Hospitals are encouraging patients to be more assertive, amid growing concern about infections that are resistant to antibiotics.
Strict hand hygiene measures are the gold standard for reducing infections associated with health care. Acquired primarily in hospitals but also in nursing homes, outpatient surgery centers and even doctor's offices, they affect more than one million patients and are linked to nearly 100,000 deaths a year, according to the Centers for Disease Control and Prevention.
Centers for Disease Control
The CDC aims to engage both patients and caregivers in preventing dangerous hospital infections.
Yet despite years of efforts to educate both clinicians and patients, studies show hospital staff on average comply with hand-washing protocols, including cleansing with soap and water or alcohol-based gels, only about 50% of the time. Two new studies show patients aren't much more comfortable today than a decade ago with the idea of asking doctors and medical staff to lather up.
Hospitals have reduced certain infections over the past four years with measures such as removing unnecessary catheters and washing a patient's skin before surgery with antibacterial soap. Some have lifted hygiene compliance to nearly 100% with strict "wash in, wash out" protocols, and some have designated unidentified staffers to secretly monitor co-workers. Some hospitals link merit increases to compliance and temporarily suspend clinical privileges of doctors who ignore the rules, says Gina Pugliese, vice president of the Safety Institute at hospital purchasing alliance Premier Inc. According to a 2010 study, a disciplinary program at the University of Kentucky Medical Center in Lexington that included suspending doctors' privileges led to improved compliance rates.
More hospitals have turned to electronic sensors, thermal imaging and video cameras to monitor hand hygiene, and some are issuing badges that wirelessly record staffers' use of hand hygiene stations before entering a patient room. Some monitoring systems emphasize patient engagement and sound an electronic alert to remind patients to speak up when a staffer enters the room.
Centers for Disease Control
A CDC poster aims to raise patient awareness of the role of hand washing in preventing infection and encourages patients to speak up to hospital staffers each time they enter the room.
The CDC has provided 16,000 copies of a video, titled "Hand Hygiene Saves Lives," to be shown to patients at admission. In one scenario, a doctor comes into a room and the patient's wife says, "Doctor, I'm embarrassed to even ask you this, but would you mind cleansing your hands before you begin?" The doctor replies, "Oh, I washed them right before I came in the room." The wife says, "If you wouldn't mind, I'd like you to do it again, in front of me."
After patients at 17 hospitals run by Cincinnati-based Catholic Health Partners watched the video, there was a rise in both the proportion of patients asking staffers to wash their hands, and physicians and nurses reporting that they were asked, according to a 2010 study. "Hand hygiene is probably the most important thing health-care workers can do to protect their patients from infection," says John Jernigan, director of the CDC's hospital infection-prevention efforts who appears in the video. When patients speak up, it helps create "a culture of safety," he says.
The nonprofit Association for Professionals in Infection Control and Epidemiology is kicking off a campaign this month including posters mailed to 15,000 hospitals with tips on how patients can take an active role. It suggests asking staff about hand hygiene and requesting that hospital rooms be cleaned if they appear dirty.
"We've been focusing on intensive interventions to improve hand hygiene among health-care workers for decades, yet we've really shown very little progress," says Carol McLay, a Lexington, Ky., infection prevention consultant and chair of the committee that designed the campaign. "We are trying to empower patients and families to speak up and understand their role."
At some hospitals, posters, bedside placards and buttons for staffers say, "Ask me if I've washed my hands." Susan Coffin, a pediatric infectious disease physician at the Children's Hospital of Philadelphia, says while many efforts are made in good faith, they are "insufficient to overcome some of these barriers." She is co-author of a study, published in June in the American Journal of Infection Control, which found that 84% of parents were aware of infection risk yet only 67% would remind a health-care worker to wash their hands, most often because of concern about appearing rude or undermining authority. Yet 92% of parents said if a health-care worker invited reminders, they would be more likely to do so. The hospital is "trying to make it a more active conversation," Dr. Coffin says. Admission packets offer detailed information on hand hygiene and nurses tell families that staffers welcome questions about hand washing.
In a study published in September in the journal Infection Control and Hospital Epidemiology, one-third of patients surveyed at the University of Pittsburgh Medical Center said they observed doctors failing to wash their hands, but nearly two-thirds said nothing to their doctor about hand hygiene. Most didn't believe it was their role to do so and said they felt embarrassed or awkward and worried about reprisal.
Patients are more likely to ask nurses about hand hygiene, says Gregory Bump, associate professor of medicine. "There is something about the white-coat barrier that makes them reluctant to challenge doctors." Physicians may resist assertive patients and seem unreceptive or even hostile to a question about hand washing, he says.
Patients, instead of receiving information about infections and hand washing, would prefer having staffers wear a button or light to indicate whether his or her hands had been washed, the study also found. UPMC is developing a system to measure and track hand-washing compliance, as well as computerized verbal reminders to patients to ask the employee to clean their hands when they enter the room.
Michael Gettes, 50, has been hospitalized several times and says he has never had to remind Dr. Bump, his primary physician, to wash his hands. He has asked other hospital staffers to do so. One doctor reacted negatively. "It put our relationship on a bad footing," Mr. Gettes says. "Yes, you run the risk of upsetting someone who has been taking care of you. But it is my life. If they make a mistake I am impacted or I die."
Gail Ulager, a 72-year-old kidney transplant recipient at UPMC, says she worries about the possibility of infection because she is taking drugs that suppress her immune system to prevent rejection of her new organ. She found a way to give the message to doctors, nurses and even her dentist without seeming disrespectful. "I always tell them that the transplant center insists that everyone washes their hands" she says.
Write to Laura Landro at laura.landro@wsj.com
Science of Healing the Heart
In a Surprise, a Temporary Device Provides a Long-Term Cure
Doctors have discovered that a heart pump designed to help keep patients alive until a transplant becomes available may actually help the heart heal itself. WSJ's Larry Greenberg explains how it could bring new hope to seriously ill patients. (Photo: Getty)
A mechanical pump that was invented as a temporary life support for patients with advanced heart failure is emerging as a potential tool to help hearts heal and function for the long term on their own.
The device, called an LVAD, takes over most of the heart's main pumping function and was designed initially to enable patients to survive until a donor heart became available for transplant. But doctors have discovered to their surprise that the heart can get better on the pump. When they remove it later to perform a transplant, the heart is sometimes dramatically improved.
"An LVAD is like putting the heart on the disabled list," says Joseph Woo, surgical director of the heart transplant and LVAD program at the University of Pennsylvania in Philadelphia. As with sidelined athletes, taking the heart out of the game to ease its workload appears to enable it to recover.
Now doctors are mounting a multicenter clinical trial to see if using the left-ventricular assist device—the LVAD's full name—as a "bridge to recovery" might eventually become a viable new option for some of the thousands of patients with advanced heart failure, one of medicine's most debilitating ailments.
Congestive heart failure is characterized by an enlarged heart which loses its ability to effectively propel blood to the rest of the body. In advanced disease, fluid collects in the lungs and lower legs, leaving patients so short of breath that walking just a few steps is an ordeal. Among nearly six million Americans with heart failure, an estimated 150,000 have the disease in an advanced stage where a transplant or LVAD become potential options. Most LVAD patients are men, between the ages of 40 and 79.
Based on a small number of patients who have already tried the approach, the heart can get "almost back but not quite back to normal," says Eduardo Rame, medical director of mechanical circulatory support at Penn, a leader of the new trial.
Recent advances in LVAD technology, plus a treatment protocol successfully championed in England by Emma Birks, director of heart failure, transplantation and mechanical support at University of Louisville, are fueling hope that more patients' hearts can recover sufficiently to function on their own. It would be "much better for patients to potentially do well on their own hearts again," says Dr. Birks, who is heading up the new study. With a heart transplant, there is a risk the body could reject the donated heart, for which patients must take immunosuppressant drugs. There also is a paucity of donor organs for all who need one.
Last year, 2,379 patients received a heart transplant in the U.S., according to the United Network for Organ Sharing, a private nonprofit group that manages the nation's organ-transplant program. The number has remained relatively stable for several years, reflecting a plateauing in the number of donor organs available.
Jared Castaldi for The Wall Street Journal; Rob Press/Penn Medicine
Joe Bellettiere, of South Philadelphia, was born with a diseased heart muscle. An artificial heart pump, which was removed 18 months ago, helped his heart.
The new study is funded by Thoratec Corp., THOR -0.34% of Pleasanton, Calif., which makes the Heartmate II, the most popular LVAD currently on the market.
For reasons not fully understood, when an LVAD is implanted in a patient with heart failure, the enlarged heart shrinks in a process doctors call reverse remodeling and can regain at least some of its lost function. An aggressive regimen of heart-failure and other drugs contributes to the benefit.
Joe Bellettiere of South Philadelphia illustrates the potential for the approach. Four years ago, when he was 19, a diseased heart muscle that had troubled him since birth triggered two life-threatening episodes of acute heart failure that robbed him of his breath and resulted in extended hospital stays. Initially, doctors recommended a transplant. But at Hospital of the University of Pennsylvania he met Dr. Rame, who encouraged him to consider an LVAD to help his heart recover.
"Either way, I had to get open-heart surgery and both things were going to make me better," Mr. Bellettiere says. He opted for the chance to try a new idea and to avoid drugs to prevent rejection of a donor heart. The treatment included regular exercise and an aggressive regimen of medication.
His LVAD was implanted in October 2009, during which doctors also repaired a leaky valve in his heart. Nearly 18 months later, Mr. Bellettiere's heart had recovered to the point where doctors performed a second open-heart operation to "explant" the device.
The first day after his discharge two weeks later, "I walked a mile," he says. "I didn't get out of breath. It was definitely a great feeling." Now 23 and with a year-and-a-half under his belt with his recovered heart working on its own, he's planning to go back to school.
In 2012, LVADs were implanted in 2,113 U.S. patients, according to Intermacs, a federally funded registry maintained at the University of Alabama at Birmingham that accounts for most of such patients. That is up from 907 in 2009, an increase partly due to the Food and Drug Administration's decision in 2010 to allow expanded use of Thoratec's Heartmate II beyond prospective transplant patients to include long-term or permanent therapy.
Rob Press/Penn Medicine
Dr. Eduardo Rame talks to heart patient George Smart, 51, of Norristown, Pa. Tests will show if his heart can function without the aid of an implanted pump.
Still, long-term LVAD use also comes with risks, including infection and stroke. Current versions run on batteries that need to be changed and recharged frequently.
Not every patient is likely to see the heart recover with an LVAD. Patients whose heart failure is caused by a heart attack—about 60% of all cases—aren't good candidates for the strategy because damage to the heart muscle hinders its ability to regain effective pumping function. And heart failure is often accompanied by kidney problems that could undermine the ability of patients with advanced disease to tolerate the drug regimen that is used in the new LVAD study.
For most other patients, heart failure is caused by genetic anomalies, infection of the heart muscle, adverse reaction to drugs such as chemotherapy or unknown reasons. Because these patients' heart muscle haven't been deprived of blood flow—the problem with heart attacks—doctors believe there is greater potential for the underlying tissue to recover.
But Lynne Warner Stevenson, director of the cardiomyopathy and heart-failure program at Brigham and Women's Hospital in Boston, cautions that some previous studies have found a very low rate of recovery for patients taken off an LVAD. Moreover, relieving the heart of its workload, but not so much that it gets lazy and can't recover, is a challenge, says Dr. Stevenson, who isn't involved in the study.
Deciding whether a patient's heart has recovered also remains uncertain. Dr. Rame last week performed the first "turn-down" test on George Smart, a 51-year-old LVAD patient from Norristown, Pa., who could be a candidate to have the device removed. The propeller in Mr. Smart's device that takes the workload off his heart spins 9,000 to 10,000 times a minute. Dr. Rame turned it down to about 6,400 rpms, including during an exercise test, so the heart was taking on most of its normal load. Mr. Smart did well, Dr. Rame said, but will repeat the test several times before a decision is reached on removing the LVAD.
Such tests are part of the protocol for the new study, which in addition to Penn and Louisville is being conducted at Montefiore Medical Center, in New York, and University of Utah, in Salt Lake City, with others expected to be added.
It isn't known how long the heart's recovery might last. But Dr. Birks offers reason for optimism. She and her colleagues published a study last year in the Journal of Thoracic and Cardiovascular Surgery comparing 40 patients who had LVADs removed with 50 others who had transplant surgery. With a follow-up as long as seven years, survival rates were at least comparable for those living with their own hearts, she says. "You still can't predict who will and who won't recover," she says. "That's what we're trying to work out now."
Write to Ron Winslow at ron.winslow@wsj.com
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