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Aug. 18th, 2012 04:48 pm![[personal profile]](https://www.dreamwidth.org/img/silk/identity/user.png){kind=small}
conulyGenome Detectives Solve a Hospital’s Deadly Outbreak
There's a chart.
The ambulance sped up to the red brick federal research hospital on June 13, 2011, and paramedics rushed a gravely ill 43-year-old woman straight to intensive care. She had a rare lung disease and was gasping for breath. And, just hours before, the hospital learned she had been infected with a deadly strain of bacteria resistant to nearly all antibiotics.
The hospital employed the most stringent and severe form of isolation, but soon the bacterium, Klebsiella pneumoniae, was spreading through the hospital. Seventeen patients got it, and six of them died. Had they been infected by the woman? And, if so, how did the bacteria escape strict controls in one of the nation’s most sophisticated hospitals, the Clinical Center of the National Institutes of Health in Bethesda, Md.?
What followed was a medical detective story that involved the rare use of rapid genetic sequencing to map the entire genome of a bacterium as it spread and to use that information to detect its origins and trace its route.
“We had never done this type of research in real time,” said Julie Segre, the researcher who led the effort.
The results, published online Wednesday in the journal Science Translational Medicine, revealed a totally unexpected chain of transmission and an organism that can lurk undetected for much longer than anyone had known. The method used may eventually revolutionize how hospitals deal with hospital-acquired infections, which contribute to more than 99,000 deaths a year.
“It could transform infection control in hospitals and in the community,” said Dr. Sharon J. Peacock, a clinical microbiologist at the University of Cambridge in England, who was not involved in the study. But she added a cautionary note: The challenge now is interpretation of the genetic data. Most hospitals do not have the expertise. They need tools, perhaps Web-based, to do the data analysis. At first, the hospital was confident that it could contain bacteria that could easily kill other patients whose immune systems were weakened by disease, said Dr. Tara Palmore, deputy epidemiologist at the Clinical Center. The doctors knew the bacteria would be almost impossible to stop once they got into patients’ bloodstreams.
“It really is the proverbial superbug,” Dr. Palmore said.
So the hospital used an approach called enhanced contact isolation. The patient was kept in a single room in intensive care. Everyone who entered had to wear a mask and gloves. Every piece of equipment that touched the patient had to be disinfected. And items like blood pressure cuffs and stethoscopes that could not be disinfected were thrown away.
After 24 hours, the woman was moved to a regular private room. For her entire stay, she could walk in the hallway only if no one else was around and if she wore a gown and gloves. For physical therapy, she could use only equipment that was dedicated to her.
A month after she arrived, she was discharged. It seemed no one had picked up the bacteria. Everyone breathed a sigh of relief.
But on Aug. 5, lab technicians found the bacteria in the trachea of a man who had never been in the same area as the infected woman.
“We were worried that he could have gotten it from that first patient, but we just didn’t see how that was possible,” Dr. Palmore said. “That was when we first realized the limit of traditional culturing methods.”
The lab results could not tell the hospital whether the man had been infected by the woman or had an unrelated superbug.
But another patient tested positive for the micro-organism on Aug. 15, and another on Aug. 23. About a patient a week was turning up positive for K. pneumoniae.
Dr. Segre, a genome researcher, proposed sequencing the entire genome of the first patient’s bacteria and comparing it with the genome sequences of bacteria from other infected patients. That could enable scientists to detect minute genetic changes that were the bacterium’s fingerprints. And they could use that knowledge to track the chain of infection.
When the first bacterial genome was sequenced, in 1995, it took three years. This time, researchers did it in just a couple of days.
Sequencing revealed that all the K. pneumoniae originated from the first patient, who transmitted the bacteria from her lung and throat on three occasions.
The woman’s lung bacteria differed from those in her throat by seven DNA base pairs out of six million — a chance occurrence that allowed the researchers not only to identify her bacteria in other patients but also to know where they came from.
It showed the chain of transmission was more complex than anyone had anticipated. Patients were not infected in the order that they appeared to have been. The bacterium had smoldered in many of them, below the level of detection with the usual smears from the groin and throat.
The most surprising was Patient 4. He tested positive six weeks after the first patient left the hospital and died soon after, though not directly because of the infection. But this man had lymphoma, and it was thought that someone with a disease like that, which weakens the immune system, would have become ill within days.
“Suddenly seeing this long latency period was very worrisome,” Dr. Segre said.
The doctors were left with a mystery. How did the bacteria travel from the first patient to the others? The hospital staff had been scrupulous about hand-washing; it had isolated patients with the bacteria in a separate intensive care unit, and a staff member had been there 24 hours a day to watch as health workers and other visitors washed their hands and put on gowns and gloves. When researchers looked for the bacteria on staff members’ hands, they found none.
But they discovered the bacteria in a respirator that had been used by a patient who had the bacteria in his body but had not gotten ill. The respirator had been cleaned, but the disinfecting procedure had failed. The bacteria were also in the sink drains after the rooms had been cleaned. The hospital ended up removing plumbing to get rid of the bacteria.
“We didn’t understand the environmental stability of this organism,” Dr. Segre said.
The hospital finally controlled the outbreak by doing periodic rectal swabs of all patients and looking for the bacteria, a method that requires special equipment but that finds the bacteria even when they are undetectable in swabs from the groin and throat. The doctors also undertook the difficult task of telling patients about the outbreak, including the first woman whose infection ultimately killed six other people,
“They were understandably upset,” Dr. Palmore said. She apologized to one man.
“He in some way was still not satisfied,” Dr. Palmore said. “How could you be?”
Genes Now Tell Doctors Secrets They Can’t Utter
Dr. Arul Chinnaiyan stared at a printout of gene sequences from a man with cancer, a subject in one of his studies. There, along with the man’s cancer genes, was something unexpected — genes of the virus that causes AIDS.
It could have been a sign that the man was infected with H.I.V.; the only way to tell was further testing. But Dr. Chinnaiyan, who leads the Center for Translational Pathology at the University of Michigan, was not able to suggest that to the patient, who had donated his cells on the condition that he remain anonymous.
In laboratories around the world, genetic researchers using tools that are ever more sophisticated to peer into the DNA of cells are increasingly finding things they were not looking for, including information that could make a big difference to an anonymous donor.
The question of how, when and whether to return genetic results to study subjects or their families “is one of the thorniest current challenges in clinical research,” said Dr. Francis Collins, the director of the National Institutes of Health. “We are living in an awkward interval where our ability to capture the information often exceeds our ability to know what to do with it.”
The federal government is hurrying to develop policy options. It has made the issue a priority, holding meetings and workshops and spending millions of dollars on research on how to deal with questions unique to this new genomics era.
The quandaries arise from the conditions that medical research studies typically set out. Volunteers usually sign forms saying that they agree only to provide tissue samples, and that they will not be contacted. Only now have some studies started asking the participants whether they want to be contacted, but that leads to more questions: What sort of information should they get? What if the person dies before the study is completed?
The complications are procedural as well as ethical. Often, the research labs that make the surprise discoveries are not certified to provide clinical information to patients. The consent forms the patients signed were approved by ethics boards, which would have to approve any changes to the agreements — if the patients could even be found.
Sometimes the findings indicate that unexpected treatments might help. In a newly published federal study of 224 gene sequences of colon cancers, for example, researchers found genetic changes in 5 percent that were the same as changes in breast cancer patients whose prognosis is drastically improved with a drug, Herceptin. About 15 percent had a particular gene mutation that is common in melanoma. Once again, there is a drug, approved for melanoma, that might help. But under the rules of the study, none of the research subjects could ever know.
Other times the findings indicate that the study subjects or their relatives who might have the same genes are at risk for diseases they had not considered. For example, researchers at the Mayo Clinic in Rochester, Minn., found genes predisposing patients to melanoma in cells of people in a pancreatic cancer study — but most of those patients had died, and their consent forms did not say anything about contacting relatives.
One of the first cases came a decade ago, just as the new age of genetics was beginning. A young woman with a strong family history of breast and ovarian cancer enrolled in a study trying to find cancer genes that, when mutated, greatly increase the risk of breast cancer. But the woman, terrified by her family history, also intended to have her breasts removed prophylactically.
Her consent form said she would not be contacted by the researchers. Consent forms are typically written this way because the purpose of such studies is not to provide medical care but to gain new insights. The researchers are not the patients’ doctors.
But in this case, the researchers happened to know about the woman’s plan, and they also knew that their study indicated that she did not have her family’s breast cancer gene. They were horrified.
“We couldn’t sit back and let this woman have her healthy breasts cut off,” said Barbara B. Biesecker, the director of the genetic counseling program at the National Human Genome Research Institute, part of the National Institutes of Health. After consulting the university’s lawyer and ethics committee, the researchers decided they had to breach the consent stipulations and offer the results to the young woman and anyone else in her family who wanted to know if they were likely to have the gene mutation discovered in the study. The entire family — about a dozen people — wanted to know. One by one, they went into a room to be told their result.
“It was a heavy and intense experience,” Dr. Biesecker recalled.
Around the same time, Dr. Gail Jarvik, now a professor of medicine and genome science at the University of Washington, had a similar experience. But her story had a very different ending.
She was an investigator in a study of genes unrelated to breast cancer when the study researchers noticed that members of one family had a breast cancer gene. But because the consent form, which was not from the University of Washington, said no results would be returned, the investigators never told them, arguing that their hands were tied. The researchers said an ethics board — not they — made the rules.
Dr. Jarvik argued that they should have tried to persuade the ethics board. But, she said, “I did not hold sway.”
Such ethical quandaries grow more immediate year by year as genome sequencing gets cheaper and easier. More studies include gene sequencing and look at the entire genome instead of just one or two genes. Yet while some findings are clear-cut — a gene for colon cancer, for example, will greatly increase the disease risk in anyone who inherits it — more often the significance of a genetic change is not so clear. Or, even if it is, there is nothing to be done.
Researchers are divided on what counts as an important finding. Some say it has to suggest prevention or treatment. Others say it can suggest a clinical trial or an experimental drug. Then there is the question of what to do if the genetic findings only sometimes lead to bad outcomes and there is nothing to do to prevent them.
“If you are a Ph.D. in a lab in Oklahoma and think you made a discovery using a sample from 15 years ago from a subject in California, what exactly are you supposed to do with that?” asked Dr. Robert C. Green, an associate professor of medicine at Harvard. “Are you supposed to somehow track the sample back?”
Then there are the consent forms saying that no one would ever contact the subjects.
“If you go back to them and ask them to re-consent, you are telling them something is there,” Dr. Green said. “There is a certain kind of participant who doesn’t want to know,” he added, and if a researcher contacts study subjects, “you are kind of invalidating the contract.”
Other questions involve the lab that did the analysis. All labs providing clinical results to patients must have certification ensuring that they follow practices making it more likely that their results are accurate and reproducible. But most research labs lack this certification, and some of the latest genetic tests are so new that there are no certification standards for them.
“I find it really hard to defend the notion that we are not going to give you something back because it was not done” in a certified lab, “even though we are 99 percent certain it is correct,” Dr. Jarvik said.
Gloria M. Petersen, a genetic epidemiologist at the Mayo Clinic, and her colleagues ran into a disclosure problem in a study of genes that predispose people to pancreatic cancer. The 2,000 study patients had signed consents indicating whether they wanted to know about research findings that might be important to them. But the forms did not ask about sharing findings that might be important to their families, or about what the researchers should do if they discovered important information after the patients were dead.
Seventy-three of the study patients, almost all of whom are now dead, had one of three clinically important mutations. One predisposed them mostly to melanoma but also to pancreatic cancer. A second predisposed them primarily to breast and ovarian cancer. The third, a cystic fibrosis gene, can increase the risk of pancreatic cancer and can also be important in family planning. If a man and a woman each have this gene, they have a one-in-four chance of having a child with the disease.
When it comes to the family members, “I don’t know what my obligation is,” Dr. Petersen said. “There is an incredible burden to track down the relatives. Whose information is it, and who has a right to that information?”
Dr. Petersen, along with Barbara Koenig, a professor of medical anthropology and bioethics at the University of California, San Francisco, and Susan M. Wolf, a professor of law, medicine and public policy at the University of Minnesota, got a federal grant to study the effects of offering to return the genetic results to the families of those 73 patients. The questions involved are tricky, Dr. Koenig said. Finding patients and their families can be expensive, and labs do not have money set aside for it. How would you find them? Even if they were found, whom would you tell? What if there had been a divorce, or if family members were estranged?
My gut feeling is that there is a moral obligation to return results,” Dr. Koenig said. “But that comes at an enormous cost. If you were in a study 20 years ago, where does my obligation end?”
There's a chart.
The ambulance sped up to the red brick federal research hospital on June 13, 2011, and paramedics rushed a gravely ill 43-year-old woman straight to intensive care. She had a rare lung disease and was gasping for breath. And, just hours before, the hospital learned she had been infected with a deadly strain of bacteria resistant to nearly all antibiotics.
The hospital employed the most stringent and severe form of isolation, but soon the bacterium, Klebsiella pneumoniae, was spreading through the hospital. Seventeen patients got it, and six of them died. Had they been infected by the woman? And, if so, how did the bacteria escape strict controls in one of the nation’s most sophisticated hospitals, the Clinical Center of the National Institutes of Health in Bethesda, Md.?
What followed was a medical detective story that involved the rare use of rapid genetic sequencing to map the entire genome of a bacterium as it spread and to use that information to detect its origins and trace its route.
“We had never done this type of research in real time,” said Julie Segre, the researcher who led the effort.
The results, published online Wednesday in the journal Science Translational Medicine, revealed a totally unexpected chain of transmission and an organism that can lurk undetected for much longer than anyone had known. The method used may eventually revolutionize how hospitals deal with hospital-acquired infections, which contribute to more than 99,000 deaths a year.
“It could transform infection control in hospitals and in the community,” said Dr. Sharon J. Peacock, a clinical microbiologist at the University of Cambridge in England, who was not involved in the study. But she added a cautionary note: The challenge now is interpretation of the genetic data. Most hospitals do not have the expertise. They need tools, perhaps Web-based, to do the data analysis. At first, the hospital was confident that it could contain bacteria that could easily kill other patients whose immune systems were weakened by disease, said Dr. Tara Palmore, deputy epidemiologist at the Clinical Center. The doctors knew the bacteria would be almost impossible to stop once they got into patients’ bloodstreams.
“It really is the proverbial superbug,” Dr. Palmore said.
So the hospital used an approach called enhanced contact isolation. The patient was kept in a single room in intensive care. Everyone who entered had to wear a mask and gloves. Every piece of equipment that touched the patient had to be disinfected. And items like blood pressure cuffs and stethoscopes that could not be disinfected were thrown away.
After 24 hours, the woman was moved to a regular private room. For her entire stay, she could walk in the hallway only if no one else was around and if she wore a gown and gloves. For physical therapy, she could use only equipment that was dedicated to her.
A month after she arrived, she was discharged. It seemed no one had picked up the bacteria. Everyone breathed a sigh of relief.
But on Aug. 5, lab technicians found the bacteria in the trachea of a man who had never been in the same area as the infected woman.
“We were worried that he could have gotten it from that first patient, but we just didn’t see how that was possible,” Dr. Palmore said. “That was when we first realized the limit of traditional culturing methods.”
The lab results could not tell the hospital whether the man had been infected by the woman or had an unrelated superbug.
But another patient tested positive for the micro-organism on Aug. 15, and another on Aug. 23. About a patient a week was turning up positive for K. pneumoniae.
Dr. Segre, a genome researcher, proposed sequencing the entire genome of the first patient’s bacteria and comparing it with the genome sequences of bacteria from other infected patients. That could enable scientists to detect minute genetic changes that were the bacterium’s fingerprints. And they could use that knowledge to track the chain of infection.
When the first bacterial genome was sequenced, in 1995, it took three years. This time, researchers did it in just a couple of days.
Sequencing revealed that all the K. pneumoniae originated from the first patient, who transmitted the bacteria from her lung and throat on three occasions.
The woman’s lung bacteria differed from those in her throat by seven DNA base pairs out of six million — a chance occurrence that allowed the researchers not only to identify her bacteria in other patients but also to know where they came from.
It showed the chain of transmission was more complex than anyone had anticipated. Patients were not infected in the order that they appeared to have been. The bacterium had smoldered in many of them, below the level of detection with the usual smears from the groin and throat.
The most surprising was Patient 4. He tested positive six weeks after the first patient left the hospital and died soon after, though not directly because of the infection. But this man had lymphoma, and it was thought that someone with a disease like that, which weakens the immune system, would have become ill within days.
“Suddenly seeing this long latency period was very worrisome,” Dr. Segre said.
The doctors were left with a mystery. How did the bacteria travel from the first patient to the others? The hospital staff had been scrupulous about hand-washing; it had isolated patients with the bacteria in a separate intensive care unit, and a staff member had been there 24 hours a day to watch as health workers and other visitors washed their hands and put on gowns and gloves. When researchers looked for the bacteria on staff members’ hands, they found none.
But they discovered the bacteria in a respirator that had been used by a patient who had the bacteria in his body but had not gotten ill. The respirator had been cleaned, but the disinfecting procedure had failed. The bacteria were also in the sink drains after the rooms had been cleaned. The hospital ended up removing plumbing to get rid of the bacteria.
“We didn’t understand the environmental stability of this organism,” Dr. Segre said.
The hospital finally controlled the outbreak by doing periodic rectal swabs of all patients and looking for the bacteria, a method that requires special equipment but that finds the bacteria even when they are undetectable in swabs from the groin and throat. The doctors also undertook the difficult task of telling patients about the outbreak, including the first woman whose infection ultimately killed six other people,
“They were understandably upset,” Dr. Palmore said. She apologized to one man.
“He in some way was still not satisfied,” Dr. Palmore said. “How could you be?”
Genes Now Tell Doctors Secrets They Can’t Utter
Dr. Arul Chinnaiyan stared at a printout of gene sequences from a man with cancer, a subject in one of his studies. There, along with the man’s cancer genes, was something unexpected — genes of the virus that causes AIDS.
It could have been a sign that the man was infected with H.I.V.; the only way to tell was further testing. But Dr. Chinnaiyan, who leads the Center for Translational Pathology at the University of Michigan, was not able to suggest that to the patient, who had donated his cells on the condition that he remain anonymous.
In laboratories around the world, genetic researchers using tools that are ever more sophisticated to peer into the DNA of cells are increasingly finding things they were not looking for, including information that could make a big difference to an anonymous donor.
The question of how, when and whether to return genetic results to study subjects or their families “is one of the thorniest current challenges in clinical research,” said Dr. Francis Collins, the director of the National Institutes of Health. “We are living in an awkward interval where our ability to capture the information often exceeds our ability to know what to do with it.”
The federal government is hurrying to develop policy options. It has made the issue a priority, holding meetings and workshops and spending millions of dollars on research on how to deal with questions unique to this new genomics era.
The quandaries arise from the conditions that medical research studies typically set out. Volunteers usually sign forms saying that they agree only to provide tissue samples, and that they will not be contacted. Only now have some studies started asking the participants whether they want to be contacted, but that leads to more questions: What sort of information should they get? What if the person dies before the study is completed?
The complications are procedural as well as ethical. Often, the research labs that make the surprise discoveries are not certified to provide clinical information to patients. The consent forms the patients signed were approved by ethics boards, which would have to approve any changes to the agreements — if the patients could even be found.
Sometimes the findings indicate that unexpected treatments might help. In a newly published federal study of 224 gene sequences of colon cancers, for example, researchers found genetic changes in 5 percent that were the same as changes in breast cancer patients whose prognosis is drastically improved with a drug, Herceptin. About 15 percent had a particular gene mutation that is common in melanoma. Once again, there is a drug, approved for melanoma, that might help. But under the rules of the study, none of the research subjects could ever know.
Other times the findings indicate that the study subjects or their relatives who might have the same genes are at risk for diseases they had not considered. For example, researchers at the Mayo Clinic in Rochester, Minn., found genes predisposing patients to melanoma in cells of people in a pancreatic cancer study — but most of those patients had died, and their consent forms did not say anything about contacting relatives.
One of the first cases came a decade ago, just as the new age of genetics was beginning. A young woman with a strong family history of breast and ovarian cancer enrolled in a study trying to find cancer genes that, when mutated, greatly increase the risk of breast cancer. But the woman, terrified by her family history, also intended to have her breasts removed prophylactically.
Her consent form said she would not be contacted by the researchers. Consent forms are typically written this way because the purpose of such studies is not to provide medical care but to gain new insights. The researchers are not the patients’ doctors.
But in this case, the researchers happened to know about the woman’s plan, and they also knew that their study indicated that she did not have her family’s breast cancer gene. They were horrified.
“We couldn’t sit back and let this woman have her healthy breasts cut off,” said Barbara B. Biesecker, the director of the genetic counseling program at the National Human Genome Research Institute, part of the National Institutes of Health. After consulting the university’s lawyer and ethics committee, the researchers decided they had to breach the consent stipulations and offer the results to the young woman and anyone else in her family who wanted to know if they were likely to have the gene mutation discovered in the study. The entire family — about a dozen people — wanted to know. One by one, they went into a room to be told their result.
“It was a heavy and intense experience,” Dr. Biesecker recalled.
Around the same time, Dr. Gail Jarvik, now a professor of medicine and genome science at the University of Washington, had a similar experience. But her story had a very different ending.
She was an investigator in a study of genes unrelated to breast cancer when the study researchers noticed that members of one family had a breast cancer gene. But because the consent form, which was not from the University of Washington, said no results would be returned, the investigators never told them, arguing that their hands were tied. The researchers said an ethics board — not they — made the rules.
Dr. Jarvik argued that they should have tried to persuade the ethics board. But, she said, “I did not hold sway.”
Such ethical quandaries grow more immediate year by year as genome sequencing gets cheaper and easier. More studies include gene sequencing and look at the entire genome instead of just one or two genes. Yet while some findings are clear-cut — a gene for colon cancer, for example, will greatly increase the disease risk in anyone who inherits it — more often the significance of a genetic change is not so clear. Or, even if it is, there is nothing to be done.
Researchers are divided on what counts as an important finding. Some say it has to suggest prevention or treatment. Others say it can suggest a clinical trial or an experimental drug. Then there is the question of what to do if the genetic findings only sometimes lead to bad outcomes and there is nothing to do to prevent them.
“If you are a Ph.D. in a lab in Oklahoma and think you made a discovery using a sample from 15 years ago from a subject in California, what exactly are you supposed to do with that?” asked Dr. Robert C. Green, an associate professor of medicine at Harvard. “Are you supposed to somehow track the sample back?”
Then there are the consent forms saying that no one would ever contact the subjects.
“If you go back to them and ask them to re-consent, you are telling them something is there,” Dr. Green said. “There is a certain kind of participant who doesn’t want to know,” he added, and if a researcher contacts study subjects, “you are kind of invalidating the contract.”
Other questions involve the lab that did the analysis. All labs providing clinical results to patients must have certification ensuring that they follow practices making it more likely that their results are accurate and reproducible. But most research labs lack this certification, and some of the latest genetic tests are so new that there are no certification standards for them.
“I find it really hard to defend the notion that we are not going to give you something back because it was not done” in a certified lab, “even though we are 99 percent certain it is correct,” Dr. Jarvik said.
Gloria M. Petersen, a genetic epidemiologist at the Mayo Clinic, and her colleagues ran into a disclosure problem in a study of genes that predispose people to pancreatic cancer. The 2,000 study patients had signed consents indicating whether they wanted to know about research findings that might be important to them. But the forms did not ask about sharing findings that might be important to their families, or about what the researchers should do if they discovered important information after the patients were dead.
Seventy-three of the study patients, almost all of whom are now dead, had one of three clinically important mutations. One predisposed them mostly to melanoma but also to pancreatic cancer. A second predisposed them primarily to breast and ovarian cancer. The third, a cystic fibrosis gene, can increase the risk of pancreatic cancer and can also be important in family planning. If a man and a woman each have this gene, they have a one-in-four chance of having a child with the disease.
When it comes to the family members, “I don’t know what my obligation is,” Dr. Petersen said. “There is an incredible burden to track down the relatives. Whose information is it, and who has a right to that information?”
Dr. Petersen, along with Barbara Koenig, a professor of medical anthropology and bioethics at the University of California, San Francisco, and Susan M. Wolf, a professor of law, medicine and public policy at the University of Minnesota, got a federal grant to study the effects of offering to return the genetic results to the families of those 73 patients. The questions involved are tricky, Dr. Koenig said. Finding patients and their families can be expensive, and labs do not have money set aside for it. How would you find them? Even if they were found, whom would you tell? What if there had been a divorce, or if family members were estranged?
My gut feeling is that there is a moral obligation to return results,” Dr. Koenig said. “But that comes at an enormous cost. If you were in a study 20 years ago, where does my obligation end?”
