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Prescription for Ebola
When Ebola meets modern medicine, most patients survive.
But the Ebola epidemic in West Africa is raging far from the hospitals in Germany and the United States, where the few people infected with the virus have received prompt diagnosis and aggressive care.
Instead, patients in Liberia, Sierra Leone and Guinea are dying for lack of “staff, stuff, space and systems,” Paul Farmer told the Harvard Medical School community members who gathered to hear him talk about Ebola and global health equity.
Farmer is the Kolokotrones University Professor of Global Health and Social Medicine at Harvard and head of the HMS Department of Global Health and Social Medicine. He is also the co-founder and chief strategist of Partners In Health, whose mission is to bring the benefits of biomedical science to those most in need.
“Modern medicine and Ebola have never collided before,” he said. “What we are doing now is making them collide.”
Modern medicine means IV solutions and the nurses to deliver them, plus clinics to care for patients and systems to control spread of the infectious disease while winning the trust of the people they serve.
Farmer cast his glance around the Joseph B. Martin Center auditorium, appealing for volunteers to join the cause.
“The unswerving support of the leadership at the medical school and its affiliated hospitals has been and will be critical to turning the Ebola epidemic around,” he said.
On his trips to West Africa, he hears time and time again that the virus was spread by one person caring for another at home.
“Doctors and nurses are at high risk, but so is anyone providing care: children, relatives, neighbors, Good Samaritans,” he said. “The transmission chain of Ebola is caring.”
Hydration and electrolyte replacement are the minimum interventions required to help patients recover. During infection, Ebola patients, much like cholera patients, can lose up to 10 liters a day of fluids. There are not enough health care workers to make up the difference.
“In Liberia, a country of 4 million people, there were fewer than 50 physicians in the country working in health care delivery in the public sector before Ebola. You can imagine what it is now,” Farmer said. “I see 50 physicians on every floor of the Brigham on any given morning.”
Volunteers should be taken care of, too, he said, rather than met with threats of quarantine and stigma when they return.
Ebola’s impact on Liberia’s primary care system has been devastating and complete, he said. “If it was bad before, it’s nothing short of apocalyptic now.”
To help “our neighbors,” we need to think about building health systems. But before then, people need to trust the Ebola treatment units where they now fear they will die.
“We need to drop the mortality rate by providing quality health care,” he said.
Farmer buttressed his arguments by citing examples of work done by Partners In Health in Haiti and Rwanda.
In his introduction, Jeffrey S. Flier, HMS dean, said, “Instead of choosing between providing care and building local capacity, Paul finds a way to do both.”
In closing, Farmer reminded his audience of the medical response to people injured in the 2013 Boston Marathon bombings.
Because of staff, stuff, space and systems, he said, no one who made it alive to a Boston hospital died.
“Can we do it in West Africa?” he asked. “Of course we can.”
Over this summer and fall, enterovirus-D68 spread across the United States. This virus belongs to a virus family that is subclassified into familiar categories, including polio viruses, coxsackie A and B viruses, echoviruses and other enteroviruses.
These viruses cause a variety of illnesses, including gastrointestinal illness, rash and neurologic illnesses, such as aseptic meningitis. The respiratory tract is mildly affected.
EV-D68, however, was recognized as causing moderate to severe respiratory illness in children in the Midwest in August 2014. These affected children usually had a preexisting respiratory condition such as asthma.
Indeed, children with asthma seem to be particularly vulnerable with these children presenting symptoms such as cough, shortness of breath and difficulty breathing. Fever, which occurs in only about 30 percent of affected children, is not a major component of this illness. Thomas Bernard Kinane is an HMS associate professor of pediatrics at Massachusetts General Hospital and an international expert in pediatric respiratory conditions. Here he talks with Harvard Medicine News about EV-D68.
HMS: How concerned do people need to be about enterovirus?
KINANE: Most EV-D68 infections cause very mild symptoms, like a cough, runny nose or muscle aches. In patients with respiratory disease it can cause more serious symptoms, such as difficulty breathing or wheezing. These patients can be severely affected but almost all recover.
HMS: Who in particular might be more vulnerable or at most risk?
KINANE: Children with asthma seem to be particularly vulnerable, but asthma is not the only respiratory condition that is exacerbated by this virus. Patients with neuromuscular disease and interstitial lung disease seem to be similarly affected.
HMS: How does it differ from other more common viruses such as cold and flu?
KINANE: Enteroviruses are a different viral family from the cold (rhino) virus and the flu (influenza) virus. Enteroviruses do not usually affect the respiratory system as cold and flu viruses do. Indeed, this enterovirus is different from other enteroviruses as it seems to predominantly affect the respiratory systems.
HMS: In what sorts of ways is the biomedical research community making progress against these sorts of pathogens?
KINANE: This virus is relatively new and has only caused minor outbreaks of viral illness over the last 40 years. The medical community has focused on supportive care, which has allowed almost everyone to recover.
However, there is intense focus on another illness. Over the last two years, there was another unusual illness affecting a very small number of children. This illness causes acute muscle weakness, similar to polio. Two of these cases tested positive for EV-D68. It is difficult to know if this new condition is related to EV-D68 but is subject to intense research.
HMS: Are there more of these kinds of dangerous viruses out there in the community then there have been in the past, or are we just more aware?
KINANE: From time to time a new virus emerges; most of the viruses are variations of well-known viruses. The CDC has an excellent surveillance system. There is no reason to be concerned.
On September 30, the first case of Ebola virus disease diagnosed outside of Africa during the current outbreak was reported in Dallas, Texas. With more than 3,000 already dead and estimates that as many as 1.4 million may become infected by January, the outbreak, centered in the West African nations of Liberia and Sierra Leone, has the potential to be a massive public health crisis with lasting implications across the global community.
As members of the Harvard community respond to the epidemic, Michael VanRooyen, HMS professor of medicine at Brigham and Women’s Hospital, professor in the department of global health and population in the Harvard School of Public Health and director of the Harvard Humanitarian Initiative, highlights what we need to know now about the disease.
HMN: With news of this recent case in Texas, what do Americans need to know?
MVR: The U.S. has excellent resources to detect and manage an outbreak and to prevent epidemic spread of Ebola. U.S. hospitals are generally well prepared (or will be). I think there is still work to be done for routine questioning and screening of travelers from West Africa by airlines and travel security to identify high-risk travelers. This is the same in U.S. hospitals caring for recent travelers from Ebola-endemic areas.
HMN: What are the breakdowns in global public health that got us to this point?
MVR: Ebola is a disease of poverty. Liberia and Sierra Leone have very little true public health capacity and limited public health literacy, which makes epidemic detection, investigation and management very challenging. It is important to note, however, that early in the epidemic, organizations that were working on containing the epidemic, including Doctors Without Borders and Samaritan’s Purse, were calling for help and indicating that this was an extraordinary event with explosive potential. One breakdown in the system was the lack of ability to listen to such advice and to mobilize international resources earlier.
It was an important moment when the President declared Ebola as a national security issue and mobilized resources. There is still little understanding, however, of the economic and security threats to West Africa. The effects of Ebola will be measured not only in those infected with the virus but in the economic slowdown and collapse of the health system.
HMN: Many entities, such as the World Health Organization, are urging the global community to step up efforts, and organizations like Partners In Health are acting. But what still needs to be done that isn't being done? What can academic institutions like ours do that isn't being done yet?
MVR: Many organizations are scaling up efforts, and there are new Ebola Treatment Centers planned; most are not familiar with the management of this type of emergency, so the time to operational readiness is slow. While treatment centers are important, it is also important to note that this war will be won not in the hospital but in educating communities, increasing public awareness and advancing new models like home-based care. This is not as high profile, but public health will be the answer to stopping the epidemic.
HMN: Are there any plans yet to send people from the Harvard Humanitarian Initiative to Africa?
MVR: We are working with several NGOs and the U.N., WHO, etc., to identify personnel needs. HHI-affiliated physicians and technical experts are being deployed on behalf of their home hospitals and will work within existing NGOs. HHI is also coordinating data collection and sharing for Doctors Without Borders and others running Ebola treatment centers and assisting African leaders to advocate for logical policy and increased resources.
HMN: What lessons must the global community draw from this outbreak?
MVR: Listen to the field. As with many major humanitarian emergencies, this epidemic could have been controlled far earlier and with far fewer resources if we would have 1) understood the need to prepare for these crises, and 2) listened to field organizations who see the crisis expanding. Now we have to play catch up.
Speeding HIV Care
A new point-of-care test to measure CD4 T cells, the prime indicator of HIV disease progression, can expedite the process leading from HIV diagnosis to antiretroviral therapy (ART) and improve clinical outcomes. Now a study by Massachusetts General Hospital investigators, working in collaboration with colleagues in Mozambique and South Africa, indicates that routine use of point-of-care CD4 testing at the time of HIV diagnosis could be cost effective in countries where health care and other resources are severely limited.
Their analysis is published in the journal PLOS Medicine.
“In severely resource-limited settings, too many people learn that they have HIV but then never initiate care,” explained Emily Hyle, HMS instructor in medicine at Mass General and lead author of the paper. “Point-of-care CD4 tests can help more people reach care. But it is critical to evaluate the implementation of any technology more expensive than current care to be sure the investment is a wise one. Our mathematical model, based on the situation in Mozambique, found that point-of-care CD4 testing at the time of HIV diagnosis was very cost effective, as long as patients then have access to ART.”
In most regions of sub-Saharan Africa, when people are diagnosed with HIV the standard procedure is to send blood samples to an external laboratory for CD4 testing. Patients must then return to the clinic to learn their test results, which determine whether they meet local standards to receive ART. Additional visits are often required to educate patients on the procedures necessary for successful treatment.
Patients may have limited ability to travel back and forth to clinics that are far from their home communities and require taking a day off from work, so many of them fail to return after initial diagnosis and never receive the care they need. A point-of-care test can reveal an individual’s CD4 result the same day as the original diagnosis, allowing expedited initiation of ART for those who meet local standards.
Conducted in collaboration with the Clinton Health Access Initiative, the Mass General-led study used an established mathematical model of the natural history of HIV infection—including outcomes related to diagnosis and treatment initiation—to simulate adoption of point-of-care CD4 testing at an HIV testing and counseling clinic in Mozambique. Previous studies in that country, some conducted by co-authors of the current report, indicated that the availability of point-of-care CD testing improved patients’ linkage to continued care but did not evaluate the costs associated with the test itself and with the initiation of ART.
The current analysis revealed that the information provided by point-of-care CD4 testing would allow more patients to receive treatment sooner than if laboratory testing were used, resulting in almost one full year of additional life expectancy. With a cost-per-year-of-life-saved of $500—less than Mozambique’s per-capita GDP of $570—point-of-care testing meets standards to be considered “very cost effective.”
The authors noted that because their model used the least favorable estimates for the accuracy and costs of the point-of-care test, the actual cost effectiveness could be even greater. They also examined scenarios reflecting situations in other sub-Saharan countries, some with less stringent standards for ART eligibility and others with reduced access to care. The model indicated that point-of-care testing would have the greatest clinical impact and be most cost effective in areas with fewer opportunities for patients to reach care if care had not been started at the time of their initial diagnosis.
“Many types of point-of-care testing are of value in resource-limited settings, especially those with limited capacity for convenient or frequent clinic visits. The rapid turnaround provided by point-of-care CD4 testing can substantially improve clinical outcomes and be cost effective,” said Rochelle Walensky, HMS professor of medicine at Mass General and senior author of the report. “Further studies are needed to investigate point-of-care CD4 testing for monitoring of patients who have started on ART in order to determine whether treatment is effective or should be changed to other, more expensive options.”
Funding for this study includes National Institute of Allergy and Infectious Disease grants T32 AI 007433, R01 AI058736, R01 MH090326 and R01 AI0932690, as well as grants from the U.K. Department for International Development and the Clinton Health Access Initiative.
Adapted from a Mass General news release.
Mobilizing Against TB
Every year, more than one million people around the world die from tuberculosis, a disease that has been treatable and preventable for decades.
“Although new tools are needed, we could achieve zero deaths from TB with treatments and technologies that we’ve had since the 1980s, but to reach that goal we need to fundamentally change the way we look at the disease,” said Salmaan Keshavjee, director of the Harvard Medical School Program in Infectious Disease and Social Change and associate professor of medicine and of global health and social medicine at HMS.
“We need a road map to ensure that the medicines and methods that have already been proven to save lives make it the last mile down the road to the communities where they are needed most,” he said.
To that end, on Sept. 12 Paul Farmer, Kolokotrones University Professor at Harvard and chair of the HMS Department of Global Health and Social Medicine, and Paul Stoffels, chief scientific officer and worldwide chairman of Janssen Pharmaceuticals of Johnson & Johnson, hosted a symposium on “Rethinking the Global Response to Tuberculosis” that brought together innovative researchers and care givers to address the challenges of treating and preventing TB in new ways.
The symposium also launched a new program funded by a pledge from Janssen Pharmaceuticals to HMS that will help plot a course for improved access to TB diagnosis and treatment in some of the world’s most vulnerable communities.
While the disease has virtually vanished in the United States and Western Europe, TB is hiding in plain sight in India, China, the Russian Federation and South Africa, where nearly 60 percent of the world’s multi-drug resistant-TB cases are found. Eastern European and Central Asian countries are hot spots for the disease, accounting for nearly one-third of new infections and two-thirds of previously treated TB infections. TB is the biggest killer of people co-infected with HIV in sub-Saharan Africa and elsewhere.
“Harvard Medical School is proud to forge a new partnership with Janssen to begin to address many of the gaps in the current approach to combatting TB—developing a new roadmap for TB treatment and prevention, working in alliance with researchers and advocacy groups here and around the world to shift outcomes, hopefully in a dramatic fashion,” HMS Dean Jeffrey S. Flier said in his welcoming remarks.
Stoffels spoke about the importance of transforming the global response to tuberculosis through collaboration, stressing the importance of speeding the transition from the discovery of new science to the delivery of solutions for patients. "That requires massive partnerships," Stoffels said.
Janssen Pharmaceuticals, a company of Johnson & Johnson, developed bedaquiline, the first new medicine for TB in forty years.
Instead of funding pharmacological research or a pilot program for a new clinical model, the Janssen project will support a broad effort to promote and empower innovation and integration of effective existing TB treatments in local health systems, changes in global TB policy and the development of new community health systems needed to fight TB, with a particular focus on drug-resistant TB and TB in children.
“Stopping the spread of TB—whether in a single community or around the globe—requires strong partnerships and bold action,” said Farmer. “Many in the global health community have begun to mobilize around the goal of zero tuberculosis deaths; achieving such a vision will require a major acceleration of efforts to link service delivery, research and the training of health workers. This project is a critical next step on that path.”
Other symposium speakers outlined the importance of using a multi-disciplinary approach—understanding the disease in historical and cultural context and looking for solutions using the methodologies of microbiology, epidemiology, genetics and engineering, and about various potential methods to improve treatment and save lives.
Finding missing children
In the 1970s, global health policies were put in place that prioritized treating the most infectious cases of TB with the hope that strategic application of limited resources would stop TB in its tracks. This left many cases of TB untreated, or treated ineffectively, which helped fuel the rising pandemic of drug-resistant TB.
In addition, since TB in children rarely takes the most infectious forms of the disease, pediatric TB became an unseen epidemic.
“We have a perfect recipe for making TB in kids invisible,” said Mercedes Becerra, associate professor of global health and social medicine at HMS and author of a recent study that doubled the estimate of the global burden of TB in children.
Childhood TB looks different than TB in adults—kids often have extra-pulmonary TB that affects their bones or other body parts instead of their lungs. And the most widely used test for the disease catches fewer than one in five children sick with TB.
“We found that a million kids are falling sick with TB every single year,” Becerra said. “But TB can be prevented, and each one of those children represents a missed opportunity to stop the spread of the disease.”
Fighting drug resistance
The selective treatment policies put in place also increased the risk of developing drug resistance in the bug. Drug-resistant forms of TB also often go undetected in resource-poor settings, because lab tests for resistance are difficult to administer with limited infrastructure.
Even when drug-resistant TB can be detected, the months-long therapy necessary to effectively treat the illness requires a careful integration between hospitals, clinics and community health workers.
To overcome these challenges, Keshavjee says, the support from Janssen Pharmaceuticals will help researchers, physicians and policy makers rethink how the disease should be approached worldwide.
“This is a great opportunity to rethink our whole global strategy for TB,” said Keshavjee, who will serve as the leader of the new program.
The program will enable HMS to help set treatment targets based on sound science and accurate estimates of disease prevalence, partner with grassroots organizations in affected communities, assist low- and middle-income nations in developing their own initiatives to address this and other diseases within their borders, and monitor progress as we move toward achieving zero TB deaths, he said.
“Just as we need to translate research findings from the basic science lab bench to the hospital bedside, we also have to get better diagnostics and medicines into the communities and homes where patients live, currently beyond the reach of over-burdened health care systems,” said Keshavjee.
“Getting to zero deaths from TB may be an aspirational goal, but we should also see it as a practical task,” said Becerra. “We need to find the best way to get there before more people die unnecessarily.”
Seven Things to Know About Ebola
The death toll from the Ebola outbreak in West Africa has passed 1,000 and is still rising, according to the World Health Organization. Fear of the virus and concerns about its spread beyond Liberia, Guinea, Sierra Leone and Nigeria are also soaring.
Hospitals in the United States, including Harvard affiliates in Boston, are reminding their staffs of standard infection-control procedures in case someone infected with Ebola comes through their emergency department doors.
Sean Whelan, HMS professor of microbiology and immunobiology and an expert in virology who studies Ebola and other pathogens, talked to Harvard Medicine News about the small chance of infection in North America, the very real humanitarian crisis in West Africa and progress being made toward therapies against the deadly disease.
Here are his answers to seven questions about Ebola.
HMN: What is Ebola?
SW: The Ebola virus was discovered in 1976. It is an RNA virus with what we call a negative-sense genome, and that virus, when it infects a cell, makes more virus particles. An infection of humans by this virus causes hemorrhagic fever and massive damage to the internal organs. Basically the body goes into shock.
HMN: What can be done to prevent or treat it?
SW: There is no current vaccine or antiviral drug that is approved to treat Ebola virus infection.
Ebola certainly has been well studied by the research community, but developing a therapeutic is not something that is a priority for most pharmaceutical companies, for example.
Until the current outbreak, the total number of deaths from Ebola virus that we knew of since 1976 was about 2,000. Whilst there’s active research to study Ebola virus infection, there are a number of other infectious agents that are responsible for many more deaths per year on a global scale than Ebola.
Also, because it’s a biosafety level four virus, you can work with the complete virus only in very specialized containment facilities, including the one that’s about to finally open at Boston University.
The U.S. government, through the National Institutes of Health and through the Centers for Disease Control and Prevention, has funded lots of research on Ebola.
HMN: Should people in the U.S. be concerned?
SW: I don’t see Ebola virus becoming a significant public health problem in the U.S. Ebola is a horrible disease but you’re obviously much more likely to be exposed to Ebola virus in Africa than you are in North America. I think the challenges of being infected with a virus like Ebola are compounded because of the living conditions in West Africa versus here.
I think it’s right for people in the U.S. to be concerned about Ebola virus infection, but I think we should be concerned from a humanitarian perspective, to help combat the outbreak in West Africa. I don’t see that Ebola is going to become a public health problem in North America.
There was a story in the news about a patient at Mt. Sinai Hospital in New York who presented with vomiting and diarrhea and had just returned from West Africa and was being checked to see if they had Ebola virus. Well, it’s much more likely that they just have food poisoning of some description.
It’s an important disease and we should be vigilant and continue our efforts to try and develop therapies to combat this disease.
HMS: What might be in the pipeline?
SW: There’s a candidate vaccine that has been generated by Heinz Feldmann [chief of the laboratory of virology at the National Institute of Allergy and Infectious Disease Rocky Mountain Laboratories] that’s based on vesicular stomatitis virus (VSV).
He replaced the envelope protein of VSV with that of Ebola virus and has demonstrated that that virus will protect monkeys against a challenge with infectious Ebola. If given 48 hours post-infection along with a lethal dose of Ebola, it will protect those monkeys against disease so they recover.
There are also a number of interesting candidate antiviral therapeutics in various stages of development that treat the infection. Jim Cunningham [HMS associate professor of medicine (Microbiology and Molecular Genetics) at Brigham and Women’s Hospital] has been working on one in cell culture that remains to be proven in the context of an infectious scenario in large animal models of disease.
There is an inhibitor against the polymerase of Ebola virus that was published earlier this year by Sina Bavari’s group at USAMRIID [U.S. Army Medical Research Institute of Infectious Diseases]. That polymerase inhibitor was able to treat monkeys that were experimentally infected with Ebola. They recovered from that infection. But the toxicity of that compound isn’t fully clear.
So there are things that are in stages of development, but there’s nothing that is currently approved as a drug and has made it through a set of trials.
HMN: What about ZMapp, the experimental serum?
SW: It’s an anti-serum that is basically an antibody against Ebola virus. We’ve known for years that passive immunotherapy can protect against many diseases, so long as you get it early enough in the process of infection. This experimental antibody is apparently what the people brought back to the United States had been given. But again, this antibody hasn’t yet been approved as a licensed therapeutic.
This is one of the challenges with these types of diseases.
How do you get approval for doing a human clinical trial for an infectious agent like this?
Under these conditions where you have an infectious agent whose lethality varies, depending on the outbreak, from 50 percent up to 90 percent, then if your chance of surviving an infection is one in two, you’re probably going to be willing to take whatever you can.
HMN: Why do Ebola outbreaks flare and subside?
SW: It’s very difficult to absolutely pin down why an outbreak starts. One source of transmission to people is eating or butchering contaminated monkeys. But as to how the virus is really transmitted in nature, what’s the real reservoir for the virus? Some people argue that it’s bats.
And then the reason that the outbreaks subside is often because of the isolation of the people who are infected. People who are infected are very sick and it’s only very close contacts of these people who usually get infected by the virus. So it sort of naturally dies out.
HMN: What’s next?
SW: I’m optimistic based on the currently available data that one day there will be an effective treatment.
Then the question becomes, how do you make that available to the people most in need of this treatment? You know, the ZMapp antibody, for example, if it’s going to be an effective therapy, there has to be a way to get it to people and keep it cold and then there has to be a way to inject those people with it. And antibody-based therapies are very expensive.
From a humanitarian perspective, I think there is the will to do this.
The U.S. has invested a lot of money in trying to develop therapies and vaccines to treat this disease. There are a lot of people working on this problem and a lot has been learned in the past decade or so in particular. I think the fact that there are certain experimental therapies and a candidate vaccine already in progress is a testament to that work.
A Spoonful of Sugar?
A spoonful of sugar helps the medicine go down—and so do movie tickets, cell phone minutes and discounts on airline flights.
A private South African health plan increased patient use of preventive care such as mammograms and influenza vaccine with a program that incentivized healthy behavior using discounts on retail goods and travel. The study, which was led by researchers at Harvard Medical School and the RAND Corporation, was published today in The American Journal of Managed Care.
“Even though most people know that preventive care is important, too few people take advantage of it,” said Ateev Mehrotra, associate professor of health care policy at HMS and a hospitalist at Beth Israel Deaconess Medical Center. “Incentive plans like this try to reinforce those long-term gains with more immediate rewards.”
Encouraging the use of preventive care and other healthy behaviors among patients is a core element of efforts to improve the quality and value of health care, including the Affordable Care Act.. Learning how to encourage healthy behaviors is crucial for these efforts, and little is currently known about which incentive techniques work.
More Than A Decade
A few small-scale pilot programs and clinical trials have assessed the usefulness of incentives for efforts such as smoking cessation, but the long-term benefits of an incentive plan in real-world settings are not well understood. The plan in this study has been running for more than a decade with more than 1.5 million enrollees, providing ample data to study the impact of the plan on patient behaviors.
The incentive program is offered by Discovery Health, a private South African health plan. Over two-thirds of the health plan’s enrollees have voluntarily chosen to pay approximately $15 per month to join the program. When program participants use preventive care measures, like blood pressure, glucose and cholesterol tests, they earn points that translate into discounts on retail goods and travel.
After joining the incentive plan, patient use of preventive services rose from 3 percent to 8 percent across a variety of services, the researchers found. These findings support the idea that patient incentive programs might be a mechanism for health plans to increase rates of preventive care, the researchers said.
South African participants in private health plans are similar demographically to the overall U.S. population and have similar access to health care. Such likeness makes this study a good model for considering parallel plans here in the U.S., the researchers said. Indeed, the same South African program is now being deployed by a U.S. health plan.
The increase in healthy behaviors was significant, Mehrotra noted, but even participants in the incentive program did not take advantage of the preventive measures available to them as often as medical guidelines recommend.
“There is no silver bullet in health care,” Mehrotra said. “These types of incentive plans are not a panacea, but our findings suggest that they are a useful tool in encouraging the kinds of patient behavior that we would like to see more of.”
This study was supported by a grant from the National Institutes of Health (NIH) Common Fund (R21-HD071568-01) and a career development award from the NIH (KL2-TR000146). One co-author reports employment with Discovery Health Plan, whose data is studied in this paper.
1 Million Children Have TB
One million children suffer from tuberculosis annually. That’s twice the number previously thought to have TB and three times the number that are diagnosed every year. What’s more, researchers have also estimated that around 32,000 children suffer from multidrug-resistant tuberculosis (MDR-TB) each year.
The findings by researchers from Harvard Medical School and Brigham and Women’s Hospital were published in The Lancet on March 24.
TB is an infectious disease that typically affects the lungs and is spread from person to person through the air. According to the World Health Organization, patients in India, China, the Russian Federation and South Africa represent nearly 60 percent of the world’s MDR-TB diagnoses. Eastern European and Central Asian countries are hot spots for the disease, accounting for nearly one-third of new infections and two-thirds of previously treated TB infections. When left untreated or inadequately treated, the risk of spreading additional drug-resistant strains increases.
“Despite children comprising approximately one quarter of the world’s population, there have been no previous estimates of how many suffer from MDR-TB disease,” said Ted Cohen, HMS associate professor of medicine in Brigham and Women’s Division of Global Health Equity and co-senior author of this study. “Our estimate of the total number of new cases of childhood TB is twice that estimated by the WHO in 2011 and three times the number of child TB cases notified globally each year,” said Cohen, who is also associate professor in the Department of Epidemiology at Harvard School of Public Health.
“TB in a child is recognized as a sentinel event; it tells us about ongoing transmission and missed opportunities for prevention,” said Mercedes Becerra, associate professor of global health and social medicine at HMS and co-senior author of the study. “Improved estimates are essential so that we can begin to understand the unmet need for pediatric TB treatment.”
In order to obtain these estimates the researchers used several sources of publicly available data and devised a new method to correct for the chronic under-diagnosis that occurs in children, using conventional TB tests which were designed for and work best on adults. The researchers used two models to estimate both the regional and global annual incidence of MDR-TB in children. Their findings indicate that around 1 million children developed TB disease in 2010 and of those, 32,000 had MDR-TB.
These findings underscore the urgent need for expanded investment in the global response to TB and MDR-TB in children. “Our findings demonstrate that there is a need for improved methods for collecting data on childhood TB. A good starting place would be improved diagnostic methods for children and more systematic collection of information on how many children are suffering with this disease,” said Helen Jenkins, HMS instructor in Brigham and Women’s Division of Global Health Equity and lead statistician on the project.
The study was supported by the U.S. National Institutes of Health (U54GM088558, K01AI102944, R01AI097015), the Helmut Wolfgang Schumann Fellowship in Preventive Medicine at Harvard Medical School, the Norman E. Zinberg Fellowship at Harvard Medical School, and the Doris and Howard Hiatt Residency in Global Health Equity and Internal Medicine at the Brigham and Women’s Hospital.
Surgery Goes Global
The world’s poorest countries have more than two-thirds of the globe’s people, but less than one-quarter of the world’s surgeries, according to World Bank president Jim Yong Kim.
Saying that surgery was an “indivisible, indispensable part of health care,” Kim, who is also the former chair of the Harvard Medical School Department of Global Health and Social Medicine, welcomed commissioners, advisors and researchers to the launch of a Lancet Commission on Global Surgery in a recorded message. He said that achieving more equitable distribution of surgical care was a key part of World Bank and World Health Organization goals to achieve universal access to health care within a generation.
The Department of Global Health and Social Medicine hosted the first of three meetings of the Commission in Boston on Jan. 17. Future meetings will take place in Freetown, Sierra Leone (hosted by King’s College London), and in Dubai (hosted by the Dubai Harvard Foundation). Planning is underway for regional meetings throughout the developing world.
The Commission is charged with analyzing the current state of surgical care in low-and middle-income countries, outlining what would be needed for a properly functioning global surgical system, and identifying actions to take to improve the delivery of surgical care and metrics to evaluate progress in care delivery. Its work will be represented in a report to be published in The Lancet by the end of 2014.
During the Boston meeting, commissioners from more than 15 countries met one another and began working groups that will focus on the challenges of educating a surgical workforce in the face of global shortages of trained personnel, managing and delivering care in complex, resource-poor settings, and financing the reforms necessary to improve care delivery. The working groups will report their progress at the second meeting in May. The Commission’s report, to be published in a report in The Lancet, will be an outline for an ongoing process of improving the delivery of surgical care worldwide, commissioners said.
John Meara, HMS associate professor of Global Health and Social Medicine and associate professor of surgery at Children’s Hospital Boston, is one of three co-chairs of the commission, along with Andy Leather from Kings College London (UK) and Lars Hagander from Lund University (Sweden).
“Surgery is a partner in health care delivery,” Meara said, noting that surgical care is crucial for adequate treatment of cancer, maternal and child health, non-communicable diseases, traffic accidents and other traumas, all areas of increasing concern in the developing world.
TB's Surprising Family Tree
For years, physicians around the world have watched as strain after strain of the deadly bacteria mycobacterium tuberculosis evolves resistance to drugs.
Over the last few decades researchers have used the tools of molecular biology to identify a handful of individual mutations that allow TB to withstand many of the key therapeutics that doctors use to treat it. These genetic markers serve as clues for new drug development and as tools for diagnosing drug-resistant strains of TB. But the pace of discovery has proven too slow in the face of the complex array of rapidly mutating bacterial strains.
A new method of analyzing whole genome sequences of TB, applied to a massive set of strains of the bacteria collected from clinics around the world, has revealed 39 new genes associated with elevated drug resistance. The results were published Sept. 1, 2013 in Nature Genetics.
“We have found that more genes might be implicated in resistance than previously thought, and this means that we can start to unravel the role of these genes,” said Megan Murray, HMS professor of global health and social medicine. “This is significant because it implicates new mechanisms in the evolution of resistance that can be further studied now and raises the possibility of more specific targets for the detection of resistance through molecular methods.”
These new data suggest that acquiring resistance is a multistep process, perhaps requiring low-level resistance mutations prior to the ones that are well known. The findings also suggest that some of these new genes are involved in resistance that may confer "global" resistance traits, helping strains become resistant to a group of antibiotics rather than just one or a single class.
“Several of the genes we identified are related to the bacteria’s regulation of cell walls; since many classes of drugs target the cell walls, we speculate that changes to the structure or metabolism of the cell walls might confer resistance to a wide variety of drugs,” said first author Maha Farhat, HMS instructor in medicine and assistant physician at Massachusetts General Hospital.
“Until now, people assumed that single mutations conferred high-level resistance—a strain either had them or did not—but our results challenge that paradigm,” Murray said. “Knowing that small changes early in the evolution of resistance open the door for big changes, or that a single change is a gateway to global resistance, would be important clues in our struggle to outrace evolving drug resistance.”
Murray is part of a network of researchers and physicians working to develop a holistic, integrative approach to understanding and treating TB. In addition to her role as a researcher at HMS, she is also an associate professor of medicine at Brigham and Women’s Hospital and professor in the Department of Epidemiology in the Harvard School of Public Health (HSPH), director of research at Partners in Health and director of the HMS Global Health and Social Medicine Research Core.
“We’re not only implementing programs and documenting outcomes, we’re using our access to clinics around the world to further basic scientific research, which will ultimately help improve standards of care,” Murray said.
To find the novel drug-resistance genes, Farhat, Murray and collaborators adapted tools from evolutionary biology known as “phylogenetics.” Phylogenetics allows the study of relationships within populations of organisms. It was originally developed to trace the path of evolution and to calculate how once-related organisms diverged onto different branches of the tree of life over many tens of thousands of years.
The team adapted these tools to measure the rapid-fire evolution of drug-resistant TB in the clinic.
They examined the whole genomes of 116 newly sequenced and 7 previously sequenced strains of TB. The sample included 47 strains with various levels of resistance to a variety of anti-TB drugs, as well as a group of susceptible strains, to allow the researchers to assess the genetic diversity of TB in the wild.
The method allows researchers to focus on the moments when resistant and susceptible strains branch off from one another. This silences the background noise of random mutations that aren’t associated with resistance.
“You're tuning out all the changes that happened to their common ancestors, which allows you to look specifically at what the differences between the daughter lineages were when resistance evolved,” Farhat said.
The project used a large set of clinical strains collected from human populations rather than strains that were developed in the lab. They sampled strains from outbreaks in British Columbia, Rome, South Africa and Russia. The strains came from dozens of sites around the world, including most of the major lineages of susceptible TB currently circulating around the world. This large, diverse data set was crucial to gaining insight into how resistant strains evolve in human populations.
They also needed a community of clinicians and researchers who were prepared to work across disciplines
“Making progress on understanding and fighting complex, global diseases like TB requires a community of physicians and scientists who are not only each working in their own niches, but building a collaborative ecosystem to share data, perspectives and results in order to push the work forward,” Murray said.
One key collaboration was with Eric Rubin, HSPH professor of immunology and infectious diseases, and Karen Keiser, a graduate research fellow at HSPH. One of the new sites of resistance was found in ponA1, a gene that is important to TB cell wall function. Rubin and Keiser introduced this mutation into laboratory TB strains and found a small yet significant elevation in their levels of resistance to the TB drug rifampicin.
The small elevation in the resistance levels suggest that resistance is more complex than previously recognized and that likely multiple small mutations may act synergistically to result in full-blown resistance.
Drug resistance is a huge problem in TB, Murray said. In some settings in Eastern Europe, up to half of TB is multi-drug resistant. Extensively resistant strains have evolved that are very difficult to treat, and some strains in India and Iraq are virtually untreatable.
“We don't really understand why resistance develops so consistently,” Murray said. “This study may provide a lens that we can use to see a way to develop better diagnostics for impending resistance, or even ways to prevent it from happening.”
This study was funded by the Senior Ellison Foundation; and the Massachusetts General Hospital Division of Pulmonary and Critical Care.