Harvard Medical School scientists have found a compound that in laboratory dishes blocks the dengue virus in two ways, raising hopes for a future drug whose dual activity could suppress the otherwise likely emergence of drug resistance.
Spread by mosquitoes, dengue belongs to the same family of viruses as Zika, whose emerging strain has just been linked by the U.S. Centers for Disease Control and Prevention to severe birth defects. Like Zika, dengue virus has no antiviral drugs to prevent illness or stop its spread.
Dengue virus infects more than 300 million people a year worldwide, causing no symptoms in some people but flu-like misery or dangerous hemorrhagic fevers in others.
“Dengue’s been an understudied virus.”—Priscilla Yang
The compound found by Yang’s team, GNF-2, keeps the dengue virus from infiltrating and overwhelming cells in the body. It does this by blocking its known kinase target inside the cell and by also inhibiting a viral target found on the surface of the virus. Yang considers the discovery of GNF-2 to be serendipitous.
“We had screened a library of known kinase inhibitors and had a ‘problem compound’ where we could not explain all the antiviral activity that we were seeing based on just the effect it had on the host kinase it normally targets,” Yang said.
That instance of serendipity was followed by years of experiments in collaboration with scientists across HMS, in particular, Stephen Harrison and Nathanael Gray, both professors in the Department of Biological Chemistry and Molecular Pharmacology. The dengue work was carried out through one of three Centers for Excellence in Translational Research at HMS, a National Institutes of Health effort designed to move discoveries about emerging infections closer to clinical applications in diagnosis, treatment and prevention.
“The compound was inhibiting the virus by targeting the host kinase, but then somehow it also was binding to the surface of the virion, and then preventing entry of the virus,” Yang said. “That’s not at all what we thought we would find when we did the original kinase inhibitor screen.”
GNF-2 had surfaced in a chemical screen Yang’s lab performed in 2007, one compound among many showing some activity against dengue virus. Viruses invade host cells and replicate there, so jamming one or both processes could mean relieving the symptoms of infection and preventing transmission of the virus.
Yang said they zeroed in on host factors as antiviral targets because it seemed likely that related viruses would rely on the same or similar host factors to replicate. If they found a compound that worked against one virus, they surmised, it might work against others in the same family. Cellular kinases seemed likely to be required by the virus because they regulate most cellular processes.
Yang also hoped that finding a way to help the host cell repel the virus would overcome the virus’ ability to thwart antiviral drugs. Viruses evolve so frequently that their elements are moving targets for antiviral drugs. Tamiflu, for example, has lost much of its efficacy in the years since it was aimed against influenza, Yang said. By comparison, combination therapies, such as those used against HIV, can be successful because they fight the virus on more than one front.
In the case of dengue and other understudied and emerging viruses, resources to develop the kinds of drug combinations that have proven effective against HIV and hepatitis C virus may not be available. In these cases, a single drug that acts by targeting multiple viral processes simultaneously may provide an alternate way to suppress resistance.
“Dengue’s been an understudied virus,” Yang said. “Everything changed when the NIH made it a priority pathogen because the number of severe infections where people get very sick has been increasing. Like Zika right now or Ebola a few years back, it’s hard to predict when that will happen and where that will happen and the scale of how many people will be affected.”
This work was supported by a Harvard Medical School Faculty Development Grant, an Armenise-Harvard Junior Faculty Grant and NIH Grants R01 CA130876, R01 AI076442, R01 AI095499, R56 AI095499, U19 AI109740, U54 AI057159 and a Catalyst grant from the Harvard Clinical and Translational Science Center (NIH UL1TR001102).
More than 5 billion people worldwide lack access to essential surgical care, but an international group of surgeons, anesthesiologists, journalists, advocates and business and biotechnology leaders have outlined a plan to bring safe, affordable surgical care to the men, women and children who need it most.
“Building surgical systems that work for everyone is affordable and achievable,” said co- first author Josh Ng-Kamstra, a Paul Farmer Global Surgery Research Fellow at Harvard Medical School and a general surgery resident at the University of Toronto. “It’s also essential if we are to meet the global goals of ending poverty, improving health, ensuring gender equality and creating economic growth.”
The paper, which appears in the inaugural issue of the BMJ Global Health, outlines a series of actions that universities, hospitals, surgeons, biotech companies and the media in wealthy countries can pursue to improve access to surgery worldwide.
The effort builds on a landmark 2015 report by the Lancet Commission on Global Surgery. The commission found that nearly a third of the global disease burden can be attributed to surgically treatable conditions. For billions of people in low- and middle-income countries, a lack of infrastructure, insufficient numbers of trained surgeons and anesthesiologists, and the prohibitive costs of receiving care prevent people from receiving the care they need. The commission estimated that 143 million additional surgical procedures are needed each year to save lives and prevent disability. But the case for action isn’t just humanitarian: Investing in surgery would save developing countries approximately $12.3 trillion in lost GDP by 2030.
As Jim Yong Kim, president of the World Bank Group, said in his address to the Lancet Commission in May 2015, “The stakes are high, because failing to fix this problem will have a substantial impact on people’s lives, well-being and even their economic health going forward.”
The current publication highlights a series of actionable recommendations that those in high-income countries can take to enhance the world’s capacity to deliver surgical and anesthesia care. Specifically, the paper calls for:
- Colleges and academic medical centers to develop global partnerships for training and ongoing professional development and to support research efforts in quality, safety and outcomes measurement
- High-income country surgery and anesthesia trainees to develop long-term clinical and research relationships with colleagues in low- and middle-income countries
- Academic surgeons and journals to support research by surgeons in low- and middle-income countries and eliminate barriers to publishing and disseminating research in the communities where it was conducted
- Global health funders to aggressively invest in strengthening health systems with a specific focus on surgery as a critical component of universal health care coverage
- The biomedical devices industry to design and manufacture user-centered equipment appropriate for resource-limited environments and train health professionals and biomedical equipment technicians in low- and middle-income countries
- Press and advocacy groups to develop public support by telling the stories of those affected by surgical disease, and to independently investigate the state of surgery around the world
"The goal is universal access to safe, affordable surgical and anesthesia care when needed," said co-author John Meara, the Steven C. and Carmella R. Kletjian Professor of Global Health and Social Medicine in the field of Global Surgery and director of the Program in Global Surgery and Social Change at HMS, Plastic Surgeon-in-Chief at Boston Children's Hospital, and co-chair of the Lancet Commission on Global Surgery. "This reports demonstrates a common policy agenda between major actors and provides a road map for maximizing benefit to surgical patients worldwide."
While the authors highlight the role of individuals and institutions in wealthy nations in the current paper, they also emphasize the important role of health professionals and policymakers who live and work in low- and middle income countries, noting that unilateral action by high-income country groups without an ethos of partnership is unlikely to bring about sustainable change. Instead, the authors wrote, high-income country resources can be brought into the service of local interests, building sustainable health systems and providing a durable solution for the world’s poor.
“We’re thrilled to be launching this paper at such a crucial time for global surgery,” said Paul Farmer, Kolokotrones University Professor at HMS, co-founder of Partners In Health and a Lancet Commissioner. “We have an opportunity to turn surgery from the ‘neglected stepchild of global health’ to a centerpiece in national health systems, averting death and disability for millions.”
This story is adapted from a multi-institution news release.
An outbreak of multidrug resistant tuberculosis (MDR-TB) in Papua New Guinea may well become a replay of the disastrously delayed response to the West African Ebola pandemic, says Jennifer Furin, Harvard Medical School lecturer on global health and social medicine, in a commentary she co-authored with Helen Cox, senior lecturer in the Division of Medical Microbiology at the University of Cape Town, South Africa. The commentary was published in Lancet Respiratory Medicine on March 23 to coincide with World TB Day, which is today, March 24.
Harvard Medicine News spoke to Furin to learn more about the situation in the island province of Daru, just north of Australia in the southwestern Pacific.
HMN: What’s happening on Daru?
JF: Currently, on Daru Island in Papua New Guinea, there is a significant and ongoing outbreak of MDR-TB. It is spreading throughout the country and could possibly move to Australia.
HMN: How does it compare to other outbreaks globally?
JF: Conservative estimates show that 1 percent of the population of Daru is sick with MDR-TB. This translates to about 150 cases per year in a population of 15,000. As a point of comparison, an outbreak on nearby Chuuk Island, one that the CDC was able to get under control, had 26 cases in a population of 108,000.
In one community in South Africa, Khayelitsha, there are about 200 MDR-TB cases a year, with a population of about 400,000 and an HIV prevalence above 20 percent.
Since Daru has almost no HIV—which greatly increases the risk of contracting MDR-TB—the number of cases there is even more staggering.
HMN: How did things get so bad?
JF: A number of factors. For example, some MDR-TB patients from Papua New Guinea who had been getting treatment in Australia were sent back home—many of them to Daru—in order to give them care closer to their families.
This was well-intended, but available care was limited on Daru. Once the infection started spreading on the island, it became difficult to stop.
Because the islanders are poor, people share accommodations—often crowding 20 people into a single room. In addition, there were few diagnostic and treatment services available on the island.
Although services have improved over the years, they have not improved fast enough to keep up with the current outbreak of the disease.
Finally, international health and policy advisors to Papua New Guinea have not given the health program leaders advice that will help them to stop this outbreak.
HMN: You’ve called the outbreak a “time bomb.” Why do you use that term?
JF: Because one does not notice the full devastation of the event right away.
With TB, people can become infected with the bacterium and not become sick until months or years later.
Someone with TB can cough in a room and expel the bacterium, where it will remain infectious for hours. Hundreds of people could breathe in those infectious organisms and not know for some time that they have been infected.
Because infection is not readily apparent, TB is much more frightening than diseases we tend to hear a lot about, such as Ebola, where infection tends to lead rapidly to disease development.
But when I describe the situation as being like a time bomb, I also mean that if we act to do something now, we might be able to defuse the situation.
HMN: What would it take to stem this disease in Papua New Guinea?
JF: There needs to be a massive influx of resources—human and financial—into the country. Although the government has put together an excellent plan to stop the outbreak, it does not have the funding or the staff to put the plan into action. And it is likely that the situation on Daru Island is also happening elsewhere in the country.
Urgent action on a large scale is needed now to support the planning done by the government. These plans include active case finding, rapid diagnosis and treatment with optimal therapy and preventive measures for those who have been exposed to pathogens.
HMN: TB is a treatable disease, but it still kills more than a million people every year. What does the reaction to this outbreak say about efforts to get to zero deaths?
JF: According to the new WHO “End TB Strategy,” we are supposed to eliminate TB by 2030, which is only 14 years away. But we don’t know how to actually eliminate TB; we have tried to control only the impact the disease has on the world’s populations.
This control strategy has been highly ineffective: TB is once again the infectious disease that causes the highest mortality among adults around the world, even though it is curable.
But if we are serious about ending TB in just a decade and a half, we have to start actually eliminating it. Daru would be the ideal place to make this happen, since the number of cases is manageable and the geographic location where the cases are occurring is small.
However, so far there has been no real attempt to try to eliminate the disease on Daru. Since the global health organizations cannot even commit to eliminating MDR-TB on Daru, it is hard to believe that we will be successful in getting to zero anytime soon.
When a diamond miner named Sahr arrived at the Ebola treatment unit in Kenema, Sierra Leone, in December 2014, he saw red fences surrounding the area where people with suspected and confirmed cases of the disease were to be treated and he panicked.
The colorful barricades reminded him of the horror he experienced in 1996 as a child soldier in Sierra Leone’s civil war, when rebel fighters attached red cloths to their guns during live battles.
As terrifying as the war was, Sahr’s struggle with Ebola was even worse, he told a team of researchers who spoke with him during and following his treatment in the winter of 2014-2015. The researchers were hoping to illuminate the biological and social context of the 2013-2016 Ebola pandemic centered in West Africa.
“During the war, you could see your enemy; Ebola can’t be seen,” Sahr told them.
Sahr’s account, along with the case histories and life stories of three other Ebola survivors, is part of an ongoing research effort to make the disease visible in its full human and medical context.
The research, led by Paul Farmer, the Kolokotrones University Professor of Global Health and Social Medicine at Harvard Medical School, and Eugene Richardson, an instructor in medicine at Brigham and Women’s Hosptial, a physician and research scientist at Partners In Health in Sierra Leone and a PhD candidate in the Department of Anthropology at Stanford University.
The researchers noted that after more than 25 documented outbreaks of Ebola in Africa during the last four decades, there is still little understanding about the political, ecological and economic forces that promote—or limit—its spread.
The study, published online in the December 2015 issue of Health and Human Rights Journal, is rich in detail that highlights the interconnecting threads woven throughout the 2013-2016 outbreak which sickened more than 28,000 people and ravaged the entire region of West Africa.
The study traces the connections between the closing of schools during quarantine and the rise in teen pregnancies, the deadly toll of the disease on caregivers, and the rise in deaths from unattended childbirth and malaria.
"To understand this Ebola pandemic, or any other transnational outbreak for that matter, we have to resist the urge for simplicity,” said Farmer, who is also co-founder of Partners In Health and editor-in-chief of Health and Human Rights Journal.
“That means going beyond the perfunctory explanations afforded by individual disciplines and, importantly, listening to the stories of those most affected. You can’t build a health care system without a faithful effort to appreciate the historical, economic and social context where the work needs to be done,” Farmer said.
Partners In Health helped to build, staff and supply Ebola treatment facilities in Sierra Leone and Liberia, two of the nations hardest hit by the epidemic.
In addition to emphasizing the importance of providing aggressive supportive care to those who were already sick, Farmer also highlighted the need to integrate research programs into clinical delivery platforms. That way, efforts to care for patients can also help improve understanding of the disease, test novel diagnostic tools and measure the effectiveness of new clinical interventions.
To further deepen understanding of the disease, Farmer, Richardson and other colleagues conducted extensive interviews to track the specific course of illness and treatment of four individuals who survived infection with Ebola virus disease.
They then analyzed the case histories and life stories in context, using analytical tools from a variety of disciplines ranging from anthropology to physiology, and studied them on a variety of scales from the global to the molecular.
Previous attempts to understand the dynamics of the epidemic have tended to focus on single aspects of the disease, the researchers said, obscuring the importance of the structural, political and economic forces that contributed to it and ignoring the human rights failures that also contributed to the severity of the outbreak, many of which have deep roots in West Africa’s colonial and post-colonial international relations.
“The whole region has suffered from centuries of transhemispheric relations of inequality, of which Ebola is just one of the many deadly manifestations,” Richardson said.
Other study collaborators included Songor Koedoyoma, chief of staff of the Kono District Ebola Response Center, Mohamed Bailor Barrie, a student in the master’s program in Global Health Delivery at HMS and co-founder of Wellbody Alliance (one of PIH’s chief partners in Sierra Leone), Dan Kelly, a co-founder of Wellbody Alliance, and Yusupha Dibba, medical director of Wellbody Alliance in Koidu, Sierra Leone.
This research was conducted with support from the Abundance Foundation.
He was known as a “frequent flyer,” a regular visitor to emergency departments and urgent care clinics who consistently failed to manage his diabetes. Living in Boston, he had access to some of the best medical care anywhere, but his illness remained out of control.
Monica Bharel, Harvard Medical School instructor in medicine at Massachusetts General Hospital and commissioner of the Massachusetts Department of Public Health, was recalling a patient she met early in her career.
At first, the patient’s repeated bouts of illness mystified her, but as she learned more about the man’s life, the mystery was solved. One key issue was the fact that he was homeless.
“People’s stories matter,” Bharel said. “We know so much about the pathophysiology of diseases, but we know so much less about where a man should store his insulin when he sleeps under a bridge.”
Bharel, who went on to serve as chief medical officer for the Boston Health Care for the Homeless Program was speaking about the challenges of caring for the most vulnerable patients at a seminar hosted by the Center for Primary Care at Harvard Medical School and the HMS Department of Global Health and Social Medicine. The crowded auditorium at the Joseph B. Martin conference center was filled with clinicians, researchers, advocates and medical students.
“Caring for poor people—whether they are in another country or living within the shadows of this campus—is a challenge requiring great creativity. That’s the real work of places like HMS.” —James O'Connell
She was joined by James O'Connell, HMS assistant professor of medicine and founder and president of the Boston Health Care for the Homeless Program, and Paul Farmer, the Kolokotrones University Professor of Global Health and Social Medicine, head of the HMS Department of Global Health and Social Medicine, and founder of Partners In Health, an organization that delivers world class health care in places such as Haiti, Rwanda and Peru by collaborating with local communities and national governments.
The speakers shared stories from their work and discussed what they said were the few differences and many similarities between work in resource-limited settings internationally and work with vulnerable populations in Massachusetts.
Community Health Care
All three agreed that building personal relationships with individuals and communities is the foundation for providing excellent care.
“It’s about learning who you are serving and what they want,” O’Connell said, noting that homeless programs around the country all look different because different communities have different needs.
From Sierra Leone to Back Bay, where and how a patient lives has a huge impact on her health, the speakers said.
Bharrel noted a study that found the chances of having diabetes were more than three times higher for riders who take the MBTA to the economically challenged Dudley Square neighborhood in Boston than for the riders who take the MBTA to more affluent Arlington station. Yet the two mass transit stops are less than two miles apart.
Bharrel said non-clinical factors, including economic status, racism and lifestyle, have a much bigger impact on health in Massachusetts than clinical care.
“There are endemic health disparities that are all of our responsibility to address together,” Bharrel said. “Soaring health care costs won’t go down unless we do something about the social determinants of health.”
Farmer said that this was one difference between health care work in places like Boston and work in nations without existing health care systems, where spending on health and education are near zero.
Investing in Health
“The first thing we need to do there is let costs soar,” Farmer said, not only because money is needed to deliver better health, but because investments in health and education yield immense dividends in economic growth.
He also noted that even some countries that are struggling to build functioning health systems have managed to achieve levels of progress delivering certain kinds of care that richer nations have not been able to attain.
Rwanda has better HIV statistics than the United States—higher survival rates, lower transmission rates and greater adherence to medication plans—because they have robust systems of community health workers who can meet patients where they live and make sure their long-term medical needs are met, Farmer said.
“We can’t deliver good care for chronic illness without community health workers,” Farmer said. “But we also need hospitals. If I get hit by a car, I don’t want community based orthopedics; I want a hospital and a surgeon.”
The speakers expressed their shared feeling that the work of treating vulnerable patients was not only morally necessary but richly rewarding, providing complex medical and scientific challenges and opportunities to work with outstanding people, both within the communities served, on clinical teams, and in collaborations with researchers, educators, advocates and policy makers.
“Caring for poor people—whether they are in another country or living within the shadows of this campus—is a challenge requiring great creativity,” O’Connell said. “That’s the real work of places like HMS.”
Researchers from Harvard Medical School and Massachusetts General Hospital have completed the first stage of an important collaboration aimed at understanding the intricate variables of neuropsychiatric disease—something that currently eludes clinicians and scientists.
It contains induced pluripotent stem cells, or iPSCs, derived from skin cells taken from 100 people with neuropsychiatric diseases such as schizophrenia, bipolar disorder and major depression, and from 50 people without neuropsychiatric illness.
In addition, a detailed profile of each patient, obtained from hours of in-person assessment as well as from electronic medical records, is matched to each cell sample.
As a result, the scientific community can now for the first time access cells representing a broad swath of neuropsychiatric illness. This enables researchers to correlate molecular data with clinical information in areas such as variability of drug reactions between patients. The ultimate goal is to help treat, with greater precision, conditions that often elude effective management.
The cell collection and generation was led by investigators at Mass General, who in collaboration with Kohane and his team are working to characterize the cell lines at a molecular level. The cell repository, funded by the National Institutes of Health, is housed at Rutgers University.
“This biobank, in its current form, is only the beginning,” said Perlis, director of the MGH Psychiatry Center for Experimental Drugs and Diagnostics and HMS associate professor of psychiatry. “By next year we'll have cells from a total of four hundred patients, with additional clinical detail and additional cell types that we will share with investigators.”
A current major limitation to understanding brain diseases is the inability to access brain biopsies on living patients. As a result, researchers typically study blood cells from patients or examine post-mortem tissue. This is in stark contrast with diseases such as cancer, for which there are many existing repositories of highly characterized cells from patients.
The new biobank offers a way to push beyond this limitation.
A Big Step Forward
While the biobank is already a boon to the scientific community, researchers at MGH and the HMS Department of Biomedical Informatics will be adding additional layers of molecular data to all of the cell samples. This information will include whole genome sequencing and transcriptomic and epigenetic profiling of brain cells made from the stem cell lines.
Collaborators in the HMS Department of Neurobiology, led by Michael Greenberg, department chair and Nathan Marsh Pusey Professor of Neurobiology, will also work to examine characteristics of other types of neurons derived from these stem cells.
“This can potentially alter the entire way we look at and diagnose many neuropsychiatric conditions,” said Perlis.
“This can potentially alter the entire way we look at and diagnose many neuropsychiatric conditions,” said Perlis.
One example may be to understand how the cellular responses to medication correspond to the patient’s documented responses, comparing in vitro with in vivo. “This would be a big step forward in bringing precision medicine to psychiatry,” Perlis said.
“It’s important to recall that in the field of genomics, we didn't find interesting connections to disease until we had large enough samples to really investigate these complex conditions,” said Kohane, chair of the HMS Department of Biomedical Informatics.
“Our hypothesis is that here we will require far fewer patients," he said. "By measuring the molecular functioning of the cells of each patient rather than only their genetic risk, and combining that all that’s known of these people in terms of treatment response and cognitive function, we will discover a great deal of valuable information about these conditions.”
Added Perlis, "In the early days of genetics, there were frequent false positives because we were studying so few people. We're hoping to avoid the same problem in making cellular models, by ensuring that we have a sufficient number of cell lines to be confident in reporting differences between patient groups."
The generation of stem cell lines and characterization of patients and brain cell lines is funded jointly by the the National Institute of Mental Health, the National Human Genome Research Institute and a grant from the Centers of Excellence in Genomic Science program.
Hundreds of global experts on the science of health care delivery attended events on Oct. 25-27 at the Harvard Medical School Center for Global Health Delivery-Dubai, to discuss a plan for improving health worldwide.
HMS faculty joined leading clinicians, researchers, advocates and government representatives from Brazil, China, Dubai, India, Pakistan, Peru, Russia, South Africa and other countries discussed case studies from the vanguard of global health delivery.
“This Center is a remarkable place, where we have embarked on research and training that is moving us closer to that goal of ensuring that the fruits of modern medicine reach those who need it most,” said Salmaan Keshavjee, director of the Center and associate professor of global health and social medicine at HMS. “Our mission is scientific, but it is also profoundly moral.”
“You can take a drug all the way from the researcher’s laboratory bench to the hospital bedside, but if you can’t put it in people’s mouths, you haven’t met your goal,” Keshavjee said.
An evocative photographic exhibit featuring images by Shehzad Noorani, an award-winning documentary photographer, was on display during the events, showing the challenging social, economic and political contexts in which health care delivery must take place.
Events occurred over three days. The first event, the Center’s inaugural symposium, took place on Sunday, Oct. 25. Speakers examined care delivery gaps in the treatment of major diseases affecting the United Arab Emirates, the broader region and the world. These conditions included diabetes and obesity, surgical care, infectious disease and mental health. Speakers emphasized the importance of developing local capacity for research, systems building and care delivery. These topics are all at the core of the Center’s research and training mission.
His Excellency Humaid Al Qatami, chairman of the board and director general of the Dubai Health Authority, noted in a statement that the Center “will provide evidence-based data on which health policy and developmental programs can be based. This is vital to achieve effective outcomes and foster further development of the health sector.”
Many presenters and attendees shared that sense of the Center’s potential.
“Your activities in this region, at the intersection of Asia, Africa and the Middle East, are critically important,” said Jim Yong Kim, president of the World Bank Group in a video message. “This Center, I am sure, will play a defining role in addressing the gap in health care delivery.”
The second and third events were focused on presenting the scientific, clinical and policy case for a campaign to eradicate tuberculosis, and highlighting a new global effort underway to test that case.
On Monday morning, the Center hosted a launch event for a new series in The Lancet, which focused on charting a course to end the global epidemic of tuberculosis, a scourge that currently kills 1.5 million people every year.
On Monday afternoon and throughout the day Tuesday, the Center hosted the launch of Zero TB Cities, an ambitious program that aims to follow the course outlined in the Lancet papers to rapidly eliminate TB in municipalities around the globe.
Fighting the disease requires a comprehensive approach that includes actively identifying people with tuberculosis disease and infection, treating all forms of TB with targeted, effective therapies and addressing the many social factors that contribute to the spread of the epidemic and mortality from TB. Current policies generally advocate treating only the sickest patients, which allows the disease to continue to spread unchecked.
“There's been a breakdown somewhere,” said Pamela Das, senior executive editor at The Lancet, speaking at the launch of the Lancet series. “Here we sit today and we see what does work if we do it properly. We can't wait for global institutions … we've got to go out there and do it.”
The inaugural symposium on Sunday included a keynote address by Paul Farmer, the Kolokotrones University Professor of Global Health and Social Medicine at Harvard and head of the Department of Global Health and Social Medicine at HMS. Jim Kim and Jeffrey S. Flier, dean of HMS, also addressed the meeting by video. The Monday and Tuesday events included leading tuberculosis researchers and clinicians from around the world.
“We at Harvard Medical School are privileged to collaborate with our colleagues in Dubai in this important effort to address gaps in global health care delivery in Dubai, the region and the world,” Flier said.
“We are pleased to welcome a world-class institution—the Harvard Medical School Center for Global Health Delivery-Dubai to the Mohammed Bin Rashid Academic Medical Center, the seat of medical education and research at Dubai Healthcare City,” said Her Excellency Dr. Raja Al Gurg, vice chairperson and executive director, Dubai Healthcare City Authority, in a statement.
The Center was established in 2014. All of the events were held at the Mohammed Bin Rashid Academic Medical Center in Dubai Healthcare City, where the Center recently opened its headquarters.
The inaugural symposium took place under the patronage of His Highness Sheikh Mohammed bin Rashid Al Maktoum, vice president and prime minister of the United Arab Emirates and ruler of Dubai.
Funding for the Center is being provided by a four-year grant from the Dubai Harvard Foundation for Medical Research. The events were supported by funding to HMS from Janssen Global.
Although tuberculosis has been curable and preventable since the 1950s, more than 4,000 people each day, or 1.5 million each year, still die from this airborne disease.
A new Series in The Lancet—led by Salmaan Keshavjee, Harvard Medical School associate professor of global health and social medicine—details a scientific, therapeutic and policy plan to rapidly stop deaths from TB and change the epidemic’s course, one community at a time.
The plan does not require new breakthroughs. Instead, it requires better use of tools that already exist.
“Ending the global tuberculosis epidemic requires the urgent deployment of a comprehensive package of effective, tried and tested interventions in low-income and middle-income settings,” Keshavjee said. “Failure to seize this opportunity now will constitute both a scientific and a moral failure.”
In preparing the series, Keshavjee, his co-editors and his colleagues at HMS’ Department of Global Health and Social Medicine brought together researchers, clinicians and advocates from governmental and nongovernmental organizations, hospitals and universities around the world for a series of working meetings and conferences.
“While TB incidence rates in high-income countries are in single-digit numbers, these rates are still in the hundreds in many countries of Asia, Africa and Latin America. The drivers of TB include poverty, poor housing, under-nutrition and HIV infection, underscoring the need to address this problem holistically,” said series co-editor, Soumya Swaminathan, director-general of the Indian Council of Medical Research.
"The drivers of TB include poverty, poor housing, under-nutrition and HIV infection." — Soumya Swaminathan
The series, which will be published online in The Lancet on Oct. 26 and as a standalone booklet, will be launched at a special event at the Harvard Medical School Center for Global Health Delivery-Dubai, where Keshavjee is director.
In addition, researchers, clinicians and policymakers will also meet to launch Zero TB Cities, an initiative that will apply the principles outlined in the Lancet series in municipalities around the world to create “islands of elimination” of the disease.
According to series co-editor David Dowdy, associate professor of medicine at Johns Hopkins University, “We cannot end TB globally without ending it locally. Cities are the places to start if we are to show the world that the status quo in TB can be changed, rapidly and dramatically.”
The series includes three commentaries that place the epidemic in historical, clinical and scientific context and four papers that detail a comprehensive strategy to quickly reach zero deaths from TB and to reach 2050 elimination targets more rapidly in high-burden settings.
The Series papers also provide the scientific and social policy rationale of comprehensive disease strategy. The keys to the elimination plan include targeting hotspots of transmission; active case finding to identify infected individuals before they can transmit disease to others; and prompt and proper treatment of all forms of tuberculosis.
This comprehensive approach is a stark contrast to current piecemeal practices that often target only the sickest patients and provide incomplete therapies for those who do receive treatment. The results have yielded steady but slow improvements in death rates, combined with a worrisome increase in drug-resistant strains of the disease.
“We have to hit this bug hard, and hit quickly. Cutting transmission in the community is key to the control of any infectious disease. Many cities in the world are seeing worrying increases in transmission of drug-resistant tuberculosis. All of us are vulnerable … and therefore, we must all act,” Swaminathan said.
“Business as usual can no longer be an option for the fight against tuberculosis,” writes Senior Executive Editor Pamela Das and Editor Richard Horton of The Lancet.
“We hope this series will be a springboard that can help shift the global tuberculosis epidemic from incremental annual improvements to an accelerating global movement for tuberculosis elimination,” he said.
The commentaries and papers in the series, with authors from more than a dozen nations, reflect this collaborative international effort.
The glacially slow decline in the death rate for tuberculosis—a decrease of less than 2 percent annually—is unacceptable, the authors argue, when the means to stop the epidemic have been available for more than half a century.
“We can’t wait another two centuries for a curable and preventable disease to disappear,” Keshavjee said.
This effort was funded by support to HMS from Janssen Global.
The Series will be launched on Monday, Oct. 26, 2015 at 10 a.m. (Dubai time), at a special event at the Harvard Medical School Center for Global Health Delivery-Dubai.
For more details, please visit: http://ghd-dubai.hms.harvard.edu/TB_lancet_manuscript_launch
To learn more about The Lancet Series: www.thelancet.com/series/how-to-eliminate-tuberculosis
A new test can accurately diagnose Ebola virus disease within minutes, providing clinicians with crucial information for treating patients and containing outbreaks.
Researchers from Harvard Medical School, Partners In Health and Boston Children’s Hospital have shown that a new commercially developed rapid diagnostic test performed at bedside was as sensitive as a conventional laboratory-based method used for clinical testing during the recent outbreak in Sierra Leone. The results are published in The Lancet.
While the West African Ebola epidemic has slowed since its peak last fall, the crisis simmers on; there were still 24 confirmed cases of Ebola reported in Guinea and Sierra Leone in the week ending June 14.
To fight Ebola, the first step is to determine which patients are sick with the disease and which with other illnesses with a similar presentation. To use the currently recommended molecular approach, laboratories must be built and samples of highly infectious blood must be drawn, often with unsafe needles and syringes, and then shipped over potentially great distances at substantial risk to the health care workers involved in the process. Then, clinicians and patients must wait for results—sometimes for several days.
These obstacles and delays prevent timely diagnosis and treatment, and also result in individuals without Ebola being admitted to holding units where they may become infected with the virus, the researchers said.
“Simplifying the process and speeding up diagnosis could have a major impact,” said Nira Pollock, senior author of the paper and HMS assistant professor of medicine and pathology and associate medical director of the Infectious Diseases Diagnostic Laboratory at Boston Children’s Hospital.
As the Ebola outbreak in West Africa began to surge in 2014, Pollock and Partners In Health researcher Jana Broadhurst worked with the research core of the HMS Department of Global Health and Social Medicine to reach out to teams around the world who were developing diagnostic tools that would enable clinicians to diagnose Ebola patients quickly.
One candidate, the ReEBOV Antigen Rapid Test, developed by Corgenix, seemed like a promising tool. Working with colleagues at Partners In Health and the Ministry of Health and Sanitation in Sierra Leone, the HMS team was able to plug into an environment that allowed it to train local technicians to perform the test and help collect data for the study. The team at the Public Health England lab at Port Loko, where clinical samples were routinely sent for standard molecular diagnostic testing, were also key collaborators. Corgenix donated test kits to the HMS team.
The field trial took place at two treatment centers operated by the Ministry of Health and Sanitation of Sierra Leone and supported by PIH, where 106 patients suspected of having Ebola were tested during February 2015 using the rapid diagnostic test (performed on a fingerstick blood sample at the point of care). The patients were also tested using the standard RT-PCR (performed on plasma in the laboratory). Both rapid diagnostic tests, on whole blood, and RT-PCR, on plasma, were also performed on 284 samples in the laboratory.
The rapid diagnostic test detected all confirmed cases of Ebola that were positive by the benchmark test in both point-of-care and laboratory testing with sensitivity of 100 percent (identifying all patients with Ebola found by the benchmark method), and a specificity of 92 percent (few false positives).
Surprisingly, the study also showed that the standard RT-PCR test, under the conditions deployed in the field, was itself an imperfect reference standard.
Both tests failed to detect a small number of Ebola cases that had been detected by an alternative lab test that was more sensitive than the benchmark test but was not available for wide usage. All of the missed cases showed very low levels of virus. The authors caution that given the limitations of the performance of the benchmark RT-PCR reference test in patients with low levels of the virus, more research is needed to assess how the new rapid diagnostic test will perform in patients still in the early stages of Ebola virus disease.
The ReEBOV test uses a drop of blood from a fingerstick performed with a safety lancet, which has a spring-loaded mechanism that prevents health care workers from receiving accidental needlesticks after the blood is sampled. The ReEBOV test works similarly to a home pregnancy test: the sample is applied to a treated strip, and if the sample is positive for Ebola, a colored line appears on the strip at a specific location.
The researchers noted that it was essential to study the test in the field to see whether it worked in the challenging conditions that clinicians face in rural clinics and in Ebola treatment units in such places as Sierra Leone. For example, wearing the required personal protective equipment made it potentially difficult to read the test strip, so instead of having one clinician check results, the research team developed a method in which two clinicians checked each test, with a third stepping up in cases where the first two disagreed.
“We’re talking about a truly extreme environment here,” said study co-author Megan Murray, HMS professor of global health and social medicine and director of research at Partners In Health.
Not only were there no electronic health records, but due to strict infection control measures, researchers were not permitted to take handwritten notes out of the treatment unit.
Because the researchers had existing relationships with Partners In Health clinicians who had already built collaborative relationships with local caregivers, they were able to build on those relationships to create an integrated clinical and research team.
“This is a powerful combination,” Murray said. “To get research that provides meaningful results, researchers need connections to the communities and health systems that they're trying to understand.“
Once the researchers saw that the test was effective, they shared their findings with the Partners In Health clinical network, with other partners in Sierra Leone and West Africa, and with the other governmental and non-governmental organizations working to end the Ebola epidemic.
“That’s another advantage of working closely with clinical care delivery teams: they can help us get the word out when we find something that works,” Murray said.
Ultimately, public health and regulatory officials in each of the affected countries will decide how the test is used in clinical and surveillance efforts, taking into account guidance from WHO and FDA.
Funding for the study was provided by a gift from the Abundance Foundation (Stephen Kahn). Corgenix provided test kits for the study but did not provide any monetary support; Corgenix personnel were not involved in data acquisition or analysis.
A map can tell you where you are, and it can also help lead to where you want to be.
The findings of the landmark Lancet Commission on Global Surgery report, which includes publications in seven academic journals and a series of teaching cases, are an assessment of the current state of need for surgery worldwide in resource-poor settings. The report also outlines steps that commissioners say will lead not just toward improved access to surgery for people around the world, but toward sustainable universal health care.
On May 6, the Commission held the Boston launch of the report at Harvard Medical School. The event was focused on the contributions that care providers, academic medical centers, industry and donor organizations in the developed world can make toward these goals. A series of similar events will take place around the world.
John Meara, the HMS Steven C. and Carmella R. Kletjian Professor of Global Health and Social Medicine in the Field of Global Surgery and lead author of the report, outlined the history of the commission process and pointed the way toward the future.
“We started with a clear vision,” said Meara, who is also HMS associate professor of surgery at Boston Children’s Hospital. “Universal access to safe, affordable, surgical care and anesthesia.”
The study more than doubled previous estimates of unmet need for surgical care, finding that 5 billion people are unable to access safe, timely affordable surgery and anesthesia. This leads to 18.6 million preventable early deaths each year, surpassing the number of people who die from HIV/AIDS, malaria and tuberculosis combined. To meet these needs, researchers calculated that an additional 143 million more surgical procedures were needed annually.
As if the costs in human life and health weren’t enough, the lack of surgical access also has dire economic costs: 33 million individuals face catastrophic expenditures that will plummet them into extreme poverty if they seek surgical care, and many low- and middle-income countries are fast approaching the point where losses in productivity from people hurt or killed by lack of access to proper surgical care will cost 2 percent of GDP.
“We call it a launch for a reason. It’s not the end of the journey. We have a long way to go, and we’re going to have to work together,” Meara said.
In spite of the human and economic costs, the Commission found that surgery is not only affordable, it is actually a high return investment, saving lives and preventing economic loss that far outweighs the costs of providing necessary care.
Reaching the necessary levels of access to surgery by 2030 would require an investment of $420 billion, the commission found. That investment would save an estimated $12 trillion in lost GDP over the same period, they found. Researchers at the launch noted that these estimate make surgery a “best buy” in global health.
“We have to think in a fundamentally different way about health care and surgery’s role in it in developing countries,” Jim Yong Kim, president of the World Bank and former head of the HMS Department of Global Health and Social Medicine, said in a taped video address. Kim and others also noted that, since surgery is crucial to health, it is an essential part of economic development.
“Without surgery, sustainable economic development is a fairy tale, a laughable fiction,” said Gavin Yamey, associate professor of epidemiology and biostatics at the University of California, San Francisco School of Medicine.
Throughout the day, speakers focused on the power of collaboration and accompaniment and emphasized that surgery is an indivisible and indispensible part of health care delivery. To accomplish these goals, surgeons will need to work with educators and students, clinicians and community health workers, hospital administrators and logistics experts. Speakers also emphasized the importance of integration, collaboration, broad-scale systems development, and building local capacity through training.
Many speakers highlighted the importance of creating pathways to unleash the passion, skills and commitment of young people throughout the world who want to make a career in global surgery.
The report features several “heat maps” that plot the availability of surgery and the supply of surgical professionals by country. In his afternoon keynote address, Paul Farmer, the Kolokotrones University Professor of Global Health and Social Medicine at Harvard and head of the HMS Department of Global Health and Social Medicine, noted that the areas in the maps that indicate the greatest unmet surgical need correspond almost exactly to the countries that are undergoing what some call a “youth tsunami.”
Farmer suggested that instead of thinking of this coming wave of young people as a destructive, crashing force, we should see them as a source of enthusiasm, energy and innovation.
“We have to think of them not just as potential patients, but as future colleagues in global health and global surgery,” Farmer said.