The Brigham is home to nearly 5,000 researchers, including physician-investigators, biomedical scientists, and faculty, who publish new research papers on a range of scientific and medical subjects. Below are brief summaries of a selection of our community’s most recent work. If you have an upcoming Brigham publication, please contact bwhclinicalandresearchnews@partners.org.

How Susceptible Are Hospital Employees to Phishing Attacks?

Multicenter study finds high click rate for simulated phishing emails, potential benefit in phishing awareness training

Cybersecurity threats are a rising problem in society, especially for health care organizations. Successful attacks can jeopardize not only patient data but also patient care, leading to cancellations and disruptions in the critical services that hospitals provide. While many hospitals have taken steps to educate, inform and forewarn their employees about cybersecurity attacks, few studies have quantified how susceptible hospital employees are to phishing attacks. A new study led by investigators from Brigham and Women’s Hospital addresses these questions through a multicenter study that aggregated data from six health care institutions that ran phishing simulations over the course of seven years. The team reports a high click rate for simulated phishing but also a reduction in click rates with increasing campaigns, suggesting a potential benefit for raising awareness. The team’s findings are published in JAMA Network Open.

“Information security is increasingly important for health care organizations, and cybersecurity attacks are a major risk to a hospital’s ability to operate and deliver care,” said corresponding author William Gordon, MD, MBI, of the Brigham’s Division of General Internal Medicine and Primary Care. “But our study suggests that while the risk is high, there is an opportunity to mitigate it through training.”

Phishing attacks via email can lure individuals into disclosing sensitive personal information or clicking on links that download malicious software. Many organizations have made a concerted effort to train their employees to recognize and report these attacks by sending simulated phishing emails, ranging from office – and IT – related to personal-related correspondence, and subsequently training those who inappropriately click or enter their credentials.

Brigham investigators aggregated data from six anonymized U.S. health care institutions representing a broad spectrum of care and geography. In total, they analyzed click rates for more than 2.9 million simulated emails. The team reports that 422,052 of these emails were clicked (14.2 percent) — roughly one in every seven. However, the odds of clicking on a phishing email decreased with increasing campaigns. After institutions had run 10 or more phishing simulation campaigns, the odds went down by more than one-third.

The authors note that many factors may go into why an individual clicks on an email and that their study, which did not drill down to the level of individual employees, could not take all of these complexities into account. In addition, the study could not answer whether the improvements may be sustainable, and for how long, after a campaign ends.

“The rates that we report here are consistent with findings across other industries, where click rates can range from 13 to 49 percent, depending on the industry, but we know that in health care the stakes are high. Patient data, patient care, patient trust and financial stability may be on the line,” said Gordon. “Understanding susceptibility, but also what steps can be taken to mitigate it, are critical as cyberattacks continue to rise.”

This work was conducted with support from Harvard Catalyst/Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health award UL1 TR001102) and by financial contributions from Harvard University and its affiliated academic health care centers. A co-author of this work reports being a previous employee of Cofense.

Paper cited: Gordon, W et al. “Assessment of Employee Susceptibility to Phishing Attacks at US Health Care Institutions” JAMA Network Open DOI: 10.1001/jamanetworkopen.2019.0393

–HB

Study: Sepsis a Leading Cause of Death in U.S. Hospitals but Many Deaths May Not Be Preventable

Sepsis is a major contributor to disability, death and health care costs in the United States and worldwide. A growing recognition of the high burden of sepsis as well as media coverage of high-profile, sepsis-induced deaths have catalyzed new efforts to prevent and manage the disease. While new initiatives have been beneficial in paving the road toward better detection and treatment of sepsis, the role of sepsis in associated deaths and their preventability remain largely unknown. To address this question, a research team at Brigham and Women’s Hospital has comprehensively reviewed the characteristics and clinical management of patients who died with sepsis. The results are published in JAMA Network Open.

“It seems intuitive that all infections should be curable with antibiotics,” said Chanu Rhee, MD, MPH, lead author and critical care physician at the Brigham. “But up until now, the extent to which sepsis-related deaths might be preventable has not been studied.”

Rhee and colleagues retrospectively reviewed the medical records of patients who died in hospital or were discharged to end-of-life hospice care between January 2014 and December 2015. The study cohort consisted of 568 patients admitted across six acute-care hospitals — three academic medical centers and three community hospitals. Using a standardized form, clinicians systematically reviewed medical records for presence of sepsis, clinical comorbidities, cause of death and indications of suboptimal sepsis care. The preventability of each sepsis-associated death was then evaluated in consideration of the above factors, and the patient’s own goals of care.

The results confirmed the high prevalence of sepsis in hospital settings and its hefty contribution to mortality: sepsis was present in over 50 percent of terminal hospitalizations and was the immediate cause of death in 35 percent of all cases. However, analyses revealed that nearly 90 percent of deaths from sepsis were considered unpreventable from the standpoint of hospital-based care. Only one in eight of all sepsis-associated deaths were potentially preventable, and of these, only one in twenty-five were moderately or highly likely preventable. While there were no indications of suboptimal care in 77 percent of sepsis-associated deaths, the most common problems in the remaining cases were delays in antibiotic administration or in source control.

Why does the prevention of death from sepsis remain elusive despite high clinical awareness and delivery of care? The answer may lie in the underlying features of the patients themselves. Many patients were elderly with severe comorbidities, including cancer, chronic heart disease, and chronic lung disease. Additionally, many expressed goals of care which were not consistent with receiving aggressive treatment.  Some patients were so severely ill from their sepsis by the time they reached the hospital that nothing further could be done at that point.

“Sepsis is a leading cause of death,” said Rhee, “but since most of these deaths are occurring in very complex patients with severe comorbidities, many of them may not be preventable with better hospital-based care. For me, as a critical care physician, that resonated with what I see in my clinical practice. A lot of sepsis patients we treat are extremely sick, and even when they receive timely and optimal medical care, many do not survive. It was important for me to see that borne out of the more rigorous study we did.”

In the future, Rhee and colleagues hope to replicate their findings in different hospital settings to further the generalizability of their results. In addition, they hope to investigate whether better preventative care prior to hospitalization could help reduce the prevalence of sepsis-related deaths.

“The point of this study is not to diminish the importance of sepsis quality-improvement issues in hospitals — even one preventable death is too much,” Rhee said. “In addition, since we only reviewed medical records for patients who died, our study doesn’t highlight all the other patients with sepsis for whom timely recognition and care in the hospital actually did prevent death. One of the takeaways, however, is that further innovation in the prevention of underlying conditions might be necessary before we can see a really large reduction in sepsis mortality.”

Funding for this work was provided by the Prevention Epicenters Program of the Centers for Disease Control and Prevention (CDC) and the Agency for Healthcare Research and Quality.

Paper cited: Rhee, C et al. “Prevalence, Underlying Causes, and Preventability of Sepsis-Associated Mortality in US Acute Care Hospitals,” JAMA Network Open, DOI: 10.1001/jamanetworkopen.2018.7571

-JZ

Chest X-ray showing severe COPD. Image from Wikimedia Commons.

Expanding the Genetic Landscape for Explaining Chronic Obstructive Pulmonary Disease

Study of hundreds of thousands of people yields new clues about genetic susceptibility, diversity of COPD

Around the world, the number of people dying from chronic obstructive pulmonary disease (COPD) is rising. Ranked third as a global cause of death by the World Health Organization, COPD is a progressive lung disease that compromises a person’s ability to breathe. Cigarette smoking is the leading risk factor for COPD, but smoking does not fully account for why people develop COPD, and up to 20 percent of people with the disease have never smoked. A population-based study led by investigators from Brigham and Women’s Hospital expands the number of genetic variants associated with the risk of developing COPD, providing new insights into the disease. The team’s findings are published in Nature Genetics Feb. 25.

“We have substantially expanded what’s known about the genetics of COPD,” said corresponding author Michael Cho, MD, MPH, physician-scientist in the Channing Division of Network Medicine and the Division of Pulmonary and Critical Care Medicine at the Brigham. “What we’re presenting here isn’t merely a list of genes. We’ve uncovered pathways and groups of variants that may affect different aspects of disease presentation and progression and find overlap with asthma and pulmonary fibrosis. These insights have implications for future investigations and drug development.”

The authors note that smoking remains a critical risk factor and that most people with COPD have smoked or currently smoke cigarettes.

“We see these genetic factors as additive or interactive with environmental risk factors,” said co-author Edwin Silverman, MD, PhD, chief of the Channing Division of Network Medicine. “Complete avoidance of smoking is the most important step that people can take to reduce their risk of COPD, but we know that there is this additional layer of susceptibility. Understanding variable susceptibility could help us diagnose patients more accurately, provide more accurate prognosis and come up with better treatments.”

To conduct a genome-wide association study (GWAS), the investigators examined data from 257,811 individuals from 25 studies, including from the International COPD Genetics Consortium and UK Biobank. The team identified 82 loci — genetic locations — significantly associated with risk of COPD. Previous reports of 22 loci explained about 12 percent of the genetic risk of COPD. The 82 loci now explain about 17.5 percent.

In addition to the GWAS, the team also sought to determine which tissues and cell types were enriched for genetic variants of COPD. Not surprisingly, they saw the most significant enrichment in lung tissue, including endothelial cells and alveolar cells, but also found enrichment in smooth muscle from the gastrointestinal tract — likely because similar data from smooth muscle in lung is not available.

The team performed further analysis to identify candidate target genes, genetic pathways and potential drug targets. In addition, the investigators found overlapping loci for asthma and pulmonary fibrosis, two other lung diseases, increasing the number of overlaps for fibrosis and finding the first genome-wide evidence for specific regions shared with asthma.

Their findings also support a role for early life events in the risk of COPD.

“Questions about the role of early life events that may influence initial lung function and patterns of growth have been on the minds of COPD researchers for years,” said co-author Brian Hobbs, MD, MMSc, a physician-scientist in the Channing Division of Network Medicine and the Division of Pulmonary and Critical Care Medicine at the Brigham. “Our work opens the door to addressing some of those questions on the population level.”

The team notes that the work sets the stage for further investigation and analysis of candidate genes in preclinical models. And while the population-based study has many strengths, it is limited to the use of a simple definition for COPD, which is a complex and diverse disease, and by a population that is predominantly of European ancestry. A new initiative sponsored by the National Heart, Lung, and Blood Institute, known as the Trans-Omics for Precision Medicine (TOPMed) program, is underway to specifically address such limitations.

“COPD is a global health problem and we’ll need a population that represents global, racial diversity to better understand its genetic underpinnings,” said Cho.

Funding for this work was provided by the Prince Mahidol Award Youth Program Scholarship, the NHLBI (R01HL084323, R01HL113264, R01HL089856, P01HL105339, K08HL136928, R01HL113264, R01HL137927, P01HL114501, and P01HL132825), the Parker B. Francis Research Opportunity Award, and the UK Biobank Resource.

Paper cited: Sakornsakolpat, P et al. “Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations” Nature Genetics DOI: 10.1038/s41588-018-0342-2

-HB

Food allergy–defined as any reported allergy to eggs, dairy, wheat, soy, fish, shellfish, fruits, or nuts or other food products–was linked to flare ups of MS. Image from Wikimedia Commons.

Food Allergies and Multiple Sclerosis: Study Reveals a New Link

Brigham investigators find that MS patients with food allergies had a higher rate of MS disease activity

Like many other medical conditions, the mechanism of multiple sclerosis (MS) remains an enigma — a puzzle composed of complex genetic and environmental factors. A key piece to this puzzle is the immune system, which is also responsible for regulating many other physiological (and pathological) phenomena — including allergies. Although previous studies investigating the association between MS and allergies have yielded mixed results, a research team at Brigham and Women’s Hospital sought to uncover the putative link in a new way. Investigating the correlation between allergy and inflammatory disease activity, the team found new evidence connecting food allergies and relapses of multiple sclerosis. The results are published in the Journal of Neurology, Neurosurgery & Psychiatry.

“Some multiple sclerosis patients with significant allergies would complain of frequent relapses associated with their allergic episodes,” said Tanuja Chitnis, MD, senior author and a neurologist at the Partners MS Center at the Brigham. “We felt that the most likely mechanism associated with allergy and its influence on MS would be related to inflammatory activity.”

Accordingly, Chitnis and colleagues set out to investigate the association between inflammatory disease activity and allergy history in a subset of patients enrolled in a large study known as the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women’s Hospital (CLIMB). A total of 1,349 study participants completed a self-administered questionnaire outlining food, environmental and/or drug allergies. Disease activity was assessed through evaluating the cumulative number of attacks over disease course, and new gadolinium (Gad)-enhancing lesions, as detected by MRI.

Interestingly, only participants in the food allergy group demonstrated a significantly higher rate of cumulative attacks and increased likelihood of new Gad-lesions compared to participants with no reported food allergies. This effect remained significant even when adjusted for potential confounders such as sex, age at symptom onset, and disease category. No significant effects were observed for the environmental and drug allergy groups after adjusted analyses.

This association between food allergy and MS disease activity highlights an important role for a potential player in immunity and inflammation — the gut. “It is interesting that this association was only found with food allergies and not other types of allergies, which might have been expected had this solely been an immune deviation issue,” said Chitnis. “The presence of food allergies and mechanisms related to food allergies may increase relapse rate and inflammatory activity in MS patients. There may be a common mechanism here, or other mechanisms which may induce MS relapses in a predisposed host.”

Currently, Chitnis and colleagues are working to further uncover these mechanisms of immune dysregulation in allergy and delineate how such dysregulation impacts MS inflammatory activity. Given the correlative nature of this study, the researchers are careful to highlight the limited clinical actionability of their findings. However, Chitnis is optimistic about the potential translational significance of the work and highlights the importance of addressing food allergies in MS patient care.

“There has long been a hypothesis of the gut being related to the immune system, and this really points to a stronger association than previously understood,” Chitnis said. “This research opens up a new way of thinking about the immune mechanisms in MS.”

Funding for this work was provided by Merck Serono and the National MS Society Nancy Davis Center Without Walls.

Paper cited: Fakih, R et al. “Food allergies are associated with increased disease activity in multiple sclerosis,” Journal of Neurology, Neurosurgery & Psychiatry, DOI: 10.1136/jnnp-2018- 319301

-JZ