Archive for April 2016
By: Keith Jacobs, Ph.D.
Zika is the newest international viral outbreak alarming physicians, researchers and the general public. The virus, which is related to dengue, yellow fever, and West Nile viruses, was first isolated in 1947 from a rhesus monkey in the Zika forest of Uganda. Very limited research was performed on the virus over the next several decades. Of the limited work that was done – including one researcher even injecting himself (under the generic description of a “human volunteer”) and several others documenting their symptoms from accidental exposure – none of it was able to shed any light on the true nature of the virus. Due to its relative obscurity and mild symptoms, there was not any interest in even studying Zika.
Times have certainly changed, however, as Zika has now been declared a “public health emergency of international concern” by the World Health Organization (WHO) in the wake of a 2015 outbreak in Brazil. Zika is transmitted through the Aedes aegypti mosquito which is endemic to South America, however strong evidence suggests that Zika may be sexually transmitted as well. While mosquitos carrying Zika have not been found in the US, over 300 Americans have contracted Zika through either travel or sexual contact with a partner who has traveled to regions where Zika is endemic. The majority of adult patients infected with Zika fail to show any symptoms, with the minority who do only exhibiting mild, general maladies such as aches, fever and rash (with no deaths reported).
While Zika infection is not a concern for adults, Brazilian physicians have noticed a stark increase in cases on microencephaly (small heads/brains) in newborns concurrent with the recent epidemic. Zika virus has also been found in the brains of affected fetuses. These correlations did not provide enough evidence however to definitively state that Zika infection was causing these deformities. A careful assessment of the reported cases cited in Brazil indicates that the recent increased incidence of microencephaly may be at least partially due to awareness bias and a lack of standardized criteria for defining deformations. In other words, physicians may be simply observing what they are already looking for based off the initial reported correlation.
As the Zika story began to spread, an alternative explanation for the explosion of microencephaly surfaced. A group of Argentinian doctors argued that it is not the Zika virus but instead the larvicide pyriproxyfen that is responsible for the increased risk of microencephaly. Ironically, pyriproxyfen is added to water in order to control the spread of the very mosquito that carries Zika and other viruses. This report cited a recommendation by the nonprofit Brazilian public health organization the Brazilian Association for Collective Health (BACH) that criticized the use of pyroxifen and warned against its potential environmental and neurotoxic effects. To add to the controversy, pyriproxyfen is manufactured by a Japanese company that is very loosely connected to the agricultural corporation Monsanto, a popular enemy of environmentalists due to its corporate practices concerning the sale of genetically modified crops. Following these assertions, BACH curiously backed off their initial claims and decried the misinterpretation of their statement. In addition to the increasingly strong data connecting Zika infection with fetal brain abnormalities, there is no evidence to support a link between microencephaly and larvicides, and these claims have been disparaged by numerous authorities including the Brazil Ministry of Health:
“Unlike the relationship between the Zika virus and microcephaly, which has had its confirmation attested in tests that indicated the presence of the virus in samples of blood, tissue and amniotic fluid, the association between the use of pyriproxyfen and microcephaly has no scientific basis.”
A case study reported in late March provided the strongest connection to date between maternal Zika infection and fetal brain abnormalities. A woman was infected with Zika 11 weeks into her pregnancy, after which uterine imaging demonstrated a progressive reduction in fetal head size and eventually abnormal gross morphology of the brain. The pregnancy was eventually terminated, and autopsy confirmed large viral loads in the fetal brain and placenta with lower amounts present in other fetal tissues as well. Zika also remained present in the mother for up to 10 weeks following infection. Finally, on April 13th the Centers for Disease Control (CDC) officially declared that the preponderance of evidence supports a causal link relationship between Zika and birth defects.
Prior to this case, physicians believed that Zika only remained active in the body for a week following infection. Likely due to this study, the Centers for Disease Control now recommends that women wait at least 8 weeks after exhibiting symptoms before trying to conceive, or up to 6 months when a male sexual partner has contracted the disease. The absence of any strong symptoms in adults along with the long duration required for viral clearance may thus contribute to Zika’s danger, as pregnant and soon-to-be-pregnant women may be infected without having any knowledge of their exposure. The true risk of Zika, its potential effect on fetal neural development, can therefore be a hidden danger.
While severe birth defects are the most common and perhaps the most threatening aspect of Zika infection, the dangers of Zika are not restricted to pregnant women. Recently, more severe consequences of Zika exposure have been identified in adults. A study published in late February identified a causal link between Zika infection and diagnosis with Guillain-Barré Syndrome. Guillain-Barré syndrome is an auto-immune neurological disease that affects the peripheral (external from brain/spinal cord) nervous system, resulting in potentially severe muscle weakness. Guillain-Barré is often preceded by infection, especially from viral pathogens such as the related dengue fever virus. Systemic infection with these viruses induces an overactive immune system leading to persistent inflammation, and Zika likely acts through this same mechanism.
By leaving its host alive and utilizing abundant mosquitos as a carrier, Zika is likely more contagious than Ebola (which only spreads through direct contact between bodily fluids). The virus therefore has the potential to spread rapidly over a wide range, and without overt visible symptoms it may be difficult to track its true reach. In contrast with Ebola however, where local African culture and poor infrastructure promoted the spread of the disease, the Americas have much better public health resources and preparation. Additionally, a great deal of research is already underway working towards both improved understanding and treatment of Zika. Published studies have described the cell biology of Zika infection, the Food and Drug Administration in the US is reviewing diagnostic tests, and international efforts have already made progress on a vaccine. While the Zika outbreak is somewhat under control, the virus is not likely to go away any time soon. Hopefully the sum of these efforts will neutralize Zika before it becomes an even more significant international public health issue.
By: Megan Roberts, Ph.D.
In January 2014, President Obama announced the Precision Medicine Initiative (PMI), the goal of which is to transform treatment and prevention from a “one size fits all” approach into an increasingly tailored approach that accounts for an individual’s genes, environment and lifestyle. While bipartisan support and PMI leadership have propelled the initiative forward, some public health researchers have voiced skepticism over whether precision medicine will improve public health. Some have even called precision medicine “a distraction from the goal of producing a healthier population.” These arguments often point to the need for public health researchers to address social determinants of health to improve overall public health, and reduce health disparities in a country that spends more on health care, but endures worse health outcomes compared to other developed countries. Furthermore, by definition, public health refers to the prevention of disease and the promotion of health among populations as a whole, which seems antithetical to the “precision medicine” paradigm, with its focus on individual-level nuances. By focusing on individual health, there is a fear that we will we lose sight of public health’s goal to improve the health of our whole population, particularly underserved groups. This begs the question: is there a place for precision medicine in public health?
While aspects of the PMI are transformative (e.g., the MATCH trial and the PMI cohort), precision medicine principles are foundational for current prevention and treatment practices. While we might immediately think “genetics” when we hear “precision medicine,” the precision medicine approach is actually much broader than only focusing on genetics, by also incorporating an individual’s environment and lifestyle for both disease prevention and treatment. Since the early 1990s, a large body of evidence has demonstrated that the effects of public health interventions are often moderated by individual level characteristics, including biological, environmental and lifestyle factors. Often, tailored approaches addressing these moderators are more effective than non-tailored approaches. As such, to move public health research forward, we must consider the interactions between individual level factors and public health strategies. This paradigm reflects the same thinking behind precision medicine, and aligns with conceptual frameworks that drive public health research and practice.
Precision medicine is already incorporated into current disease prevention strategies. Increasingly, cancer-screening programs tailor prevention strategies through targeted, risk-based screening. In a health care system with finite public health resources, targeting cancer prevention efforts to those who will receive the greatest benefit is critical. For example, breast MRI is a highly sensitive breast cancer-screening tool; however, the test has high rates of false positive results. As such, the benefits of breast MRI only outweigh the harms for women who are at high risk for breast cancer. In order to identify women who are at high risk, researchers have developed risk-based models that incorporate individual level risk factors, as well as genetic tests to identify genetic mutations that confer an increased cancer risk. For those at significantly higher risk of breast cancer, clinical guidelines recommend MRI screening, as breast MRI is cost-effective and improves health outcomes in this setting. A risk-based approach is also used in lung and cervical cancer screening. Specifically, lung cancer screening tailors on factors including smoking history, and HPV vaccination tailors on high-risk populations, including men who have sex with men and those with HIV. Precision medicine approaches for screening demonstrate an important application of precision medicine in public health, and have led to effective prevention strategies for high-risk groups.
In addition to prevention, linking individuals to high quality care remains a tenet of public health. Improved understanding of the genetic basis for disease has improved treatment strategies, particularly in cancer care. Today, high quality cancer care relies on targeting treatment using genetic tumor markers. Breast cancer, once viewed as a single disease, is now known to be multiple subtypes of breast cancer that can be distinguished by tumor genetics. Conversely, other studies have uncovered similarities between tumors that originate in different organ sites. For example, one study has found that lung squamous cell carcinoma, head and neck, and a subset of bladder cancers cluster by gene expression patterns, meaning these cancers all have genetic similarities. As such, therapeutics that target specific tumor markers have been developed. There are drugs on the market that target tumor markers that occur in multiple tumor sites, such that a lung cancer patient may receive the same drug as a pancreatic cancer patient who has a similar genetic mutation. This treatment demonstrates a shift toward considering cancer according to a tumor’s genetics rather than by a tumor’s organ site. Precision medicine programs have emerged that use this cancer treatment approach , and the MATCH trial—a component of the PMI—will elucidate the effectiveness of this approach. Similar precision medicine approaches could potentially be extended to other disease areas in the future.
Overall, the use of individualized information in research, prevention and treatment is neither new nor incongruous with the goals of public health. “Precision” public health researchers must ensure that precision medicine is equally accessible to all patients, with a strong focus on dissemination and implementation research around precision medicine approaches. While the PMI and public health priorities may not always mirror one another, to pit public health against precision medicine is a mistake. Public health and precision medicine can synergize towards common goals of disease prevention and control. Precision medicine has helped researchers and clinicians identify important interactions between individual-level factors and life-saving prevention and treatment strategies. Research findings through the PMI will only further this progress and improve population health.