diff --git a/build/assets/custom-dictionary.txt b/build/assets/custom-dictionary.txt index 3469b0ceb..9e76a7a61 100644 --- a/build/assets/custom-dictionary.txt +++ b/build/assets/custom-dictionary.txt @@ -722,6 +722,7 @@ Zydus aadattoli acceptor acetylcysteine +acknowledgement acknowledgements adamlmaclean adaptor @@ -743,10 +744,12 @@ alavendelm albuminuria aldosterone alfa +allostatic alphaviruses aminotransferases amongst amplicon +amygdala analytes anaphylaxis angiotensin @@ -902,6 +905,7 @@ doi downregulated downregulates dperrin +dqkn dsRNA ductal durations @@ -916,6 +920,7 @@ ebm ebolavirus ebselen ebselen's +ecosocial ectodomain effector eicosanoids @@ -947,6 +952,7 @@ estesevimab estradiol et etesevimab +etiologically exogenously exonuclease expiratory @@ -1030,6 +1036,7 @@ hyperinflammation hypoalbuminemia hypogammaglobulinemia hypoproteinemia +hypothalamic hypoxia iCre icosapent @@ -1078,11 +1085,13 @@ intercellular intercorrelated interferometry interferons +intergenerational interleukins interlobular intermolecular interpretability interpretable +interrelatedness interspaced interventional intracellular @@ -1110,6 +1119,7 @@ jinhui johnbarton jpbarton kDa +ketoacidosis kevinsunofficial kilobases kilodalton @@ -1126,6 +1136,7 @@ leukomonocyte leukotriene ligand likhithakolla +limbic lipoic lipopolysaccharide littermates @@ -1153,6 +1164,7 @@ maEBOV macrolide macrolides macromolecules +maladaptive mangul manubot manufacturability @@ -1379,7 +1391,9 @@ reactogenicity recombinant recombinantly recombinase +recontextualize reexposure +reflectance remdesivir remediating renin @@ -1444,6 +1458,7 @@ sociocultural Soumita soumitagh spectrometry +spectrophotometry spirulan splenic ssRNA diff --git a/content/40.inequality.md b/content/40.inequality.md index 4edff7963..eae6098c0 100644 --- a/content/40.inequality.md +++ b/content/40.inequality.md @@ -1,67 +1,125 @@ -## Social Factors Influencing COVID-19 Exposure and Outcomes - -### Social Factors Influencing COVID-19 Outcomes - -In addition to understanding the fundamental biology of the SARS-CoV-2 virus and COVID-19, it is critical to consider how the broader environment can influence both COVID-19 outcomes and efforts to develop and implement treatments for the disease. -The evidence clearly indicates that social environmental factors are critical determinants of individuals' and communities' risks related to COVID-19. -There are distinct components to COVID-19 susceptibility, and an individual's risk can be elevated at one or all stages from exposure to recovery/mortality: an individual may be more likely to be exposed to the virus, more likely to get infected once exposed, more likely to have serious complications once infected, and be less likely to receive adequate care once they are seriously ill. -The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age [@doi:10.1001/jamanetworkopen.2020.18039] underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups. -Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables [@doi:10.1001/jamanetworkopen.2020.18039]. -Here, we outline a few systemic reasons that may exacerbate the COVID-19 pandemic in communities of color. - -### Factors Observed to be Associated with Susceptibility +## Social Factors Associated with COVID-19 Exposure and Outcomes and their Biological Repercussions + +### Abstract + +### Importance + +### Introduction + +_Severe acute respiratory syndrome-related coronavirus 2_ (SARS-CoV-2) virus has become a serious worldwide threat since late 2019. +The scientific community has responded by rapidly collecting information and conducting research about the SARS-CoV-2 virus and the associated illness, novel coronavirus disease 2019 (COVID-19). +The biology of the SARS-CoV-2 virus provides important insight into the spread of the COVID-19 pandemic and the disease's effect on the human body [@individual-pathogenesis]. +Similarly, a thorough understanding of the biology of the human host is also critical to understanding the clinical manifestations of the disease. +A complete perspective on this disease therefore also requires considering factors that shape variation in human biology, including the environmental factors that are known to influence COVID-19 outcomes. + +During the pandemic, a number of risk factors have been associated with COVID-19 +These include health conditions such as obesity, diabetes mellitus, and heart disease [@url:https://www.mayoclinic.org/diseases-conditions/coronavirus/symptoms-causes/syc-20479963; @doi:10.1016/j.jinf.2020.04.021]. +An observed association among racial and ethnic background and COVID-19 outcomes has also led to racial and ethnic minorities frequently being included on the list of groups with increased susceptibility (e.g., [@url:https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/index.html]). +However, it is well documented that these health conditions occur at higher rates in communities of color. +Additionally, social factors such as poverty, housing instability, pollution, and incarceration are likely to play a role in driving discrepancies among racial and ethnic groups and COVID-19 outcomes. +Such social factors have become determinants of individual- and community-level risks related to COVID-19 and are therefore also a critical component of any analysis of COVID-19 pathology. + + +Here, we argue that social, economic, and environmental factors shape an individual's biology in ways that intersect with the pathology of COVID-19. +In particular, the social factors associated with COVID-19 drive chronic stress, which can in turn alter an individual's biology in ways that are likely to make them more susceptible to COVID-19. +Because the sources of chronic stress that are most commonly associated with COVID-19 susceptibility are promoted by systemic racism, we argue that it is the experience of racism, not an individual's ancestry, that is associated with more severe outcomes of COVID-19. +While some efforts have been made to acknowledge ethnicity and race as correlates of social and environmental influences (e.g., [@url:https://www.cdc.gov/coronavirus/2019-ncov/downloads/covid-data/hospitalization-death-by-race-ethnicity.pdf]), rarely is the potential biological basis for these connections explored. +Therefore, COVID-19 risk must be considered in the context of not only social and environmental but also biological mechanisms through which systemic racism can drive the heavy toll of the pandemic on communities of color. + +In this review, we seek to contextualize the social factors associated with COVID-19 severity and to explore how the biological implications of chronic stress intersect with the pathogenesis of SARS-CoV-2. +First, we outline the potential biological basis of several risk factors that have been identified for COVID-19. +While the term risk factors implies that they themselves predispose an individual to increased susceptibility of infection and more severe COVID-19 outcomes, we argue that this is a more nuanced question where the interrelatedness of these factors and their association with poverty and racism must be considered. +Next, we discuss how the conditions presented by systematic discrimination may predispose some individuals both to exposure to SARS-CoV-2 and to more severe outcomes of the disease it causes. +Many of the social factors associated with the negative physiological consequences of chronic stress (known as "allostatic load") are also correlated with the likelihood that an individual will be exposed to SARS-CoV-2 in the first place. +Finally, we address the relationship between allostatic load and COVID-19 on a functional biological level. +Severe COVID-19 outcomes are known to be driven by systemic inflammation, which is in turn exacerbated by chronic social stressors. +Through this review, the goal is to contextualize the symptoms associated with COVID-19 in the embodiment framework, examine how some proposed therapeutics intersect with the biology of chronic stress, and persuade the reader that diversity in scientific research and scientific researchers is critical to developing robust strategy for mitigating the damage of COVID-19 in society as a whole. +No biological analysis of the impact of COVID-19 can be complete without acknowledgement of the social factors that shape its outcomes. +This review thus serves to recontextualize the rest of this special issue within the context of embodiment and chronic stress. + +### Embodiment as a Framework for Understanding COVID-19 + +The idea that experience can shape an individual's biology is a principle known as embodiment [@doi:10.1136/jech.2004.024562]. +This paradigm contextualizes individual behaviors, environmental exposures, or other lifestyle factors in a broader social context [@doi:10.1136/jech.2004.024562]. +In particular, it offers the advantage of disentangling related, but etiologically distinct, factors such as race and racism. +In cases where ancestry is correlated with environmental exposures, for example, embodiment provides a framework to determine whether the correlation is driven by discriminatory social beliefs that are themselves correlated with ancestry [@doi:10.1136/jech.2004.024562]. +For example, one analysis [@doi:10.2105/AJPH.2005.065615] examined cardiac health in Puerto Rico in an embodiment framework by comparing social perceptions about skin color with the actual physical properties (i.e., reflectance spectrophotometry) of skin within different communities. +This study revealed that it was the perception of someone's skin color, not its physical properties, that was associated with blood pressure [@doi:10.2105/AJPH.2005.065615]. +These analyses illuminate the fact that most studies that identify race as a risk factor fail to consider the correlated variable of racism (see [@doi:10.1002/ajpa.20983]). + +Embodiment emerged in an ecosocial and epidemiological context [@doi:10.1136/jech.2004.024562], but it is also fundamentally linked to biology. +Stress, though an adaptive response to a perceived threat, harbors a maladaptive component: the same chemicals and hormones that promote survival of an acute threat have detrimental physiological effects when an individual remains in an aroused state (i.e., stressed) over time [@doi:10.1111/j.1749-6632.1999.tb08103.x]. +The negative effects of chronic stress are known as allostatic load [@doi:10.1111/j.1749-6632.1998.tb09546.x]. +The well-documented health risks associated with allostatic load are etiologically linked to the stress response itself via the limbic-hypothalamic-pituitary-adrenal axis. +For example, glucocorticoids, whose levels fluctuate with stress, influence the risk of sepsis [@doi:10.1016/j.molmed.2007.05.003], and hyperactivity of the amygdala combined with metabolic shifts and inflammation may promote development of atherosclerosis, cardiovascular disease, rheumatoid arthritis, hypertension, and diabetes [@doi:10.1016/j.physbeh.2011.08.019; @doi:10/dqkn6t; @doi:10.1073/pnas.081072698; @doi:10.1001/archinte.1997.00440400111013; @doi:10.1093/rheumatology/38.11.1050]. +Additionally, chronic stress may expedite physical and mental decline associated with age [@doi:10.1176/appi.ajp.2009.09040461; @doi:10.1001/archinte.1997.00440400111013]. +Other health conditions, such as hypertension, obesity, and cancer have also been linked to allostatic load [@doi:10.1001/archinte.1997.00440400111013; @doi:10.1073/pnas.081072698]. +These health disparities render chronic stress a risk factor on a biological level. +Additionally, the list of risks associated with allostatic load closely echoes the list of comorbidities associated with more severe COVID-19 outcomes. + +### COVID-19 "Risk Factors" As COVID-19 has spread into communities around the globe, it has become clear that the risks associated with this disease are not equally shared by all individuals or all communities. -Significant disparities in outcomes have led to interest in the demographic, biomedical, and social factors that influence COVID-19 severity. -Untangling the factors influencing COVID-19 susceptibility is a complex undertaking. -Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy [@doi:10.1056/nejmoa2002032; @doi:10.1001/jama.2020.2648; @doi:10.1001/jama.2020.4031]. +Significant disparities in outcomes have led to interest in the demographic, biomedical, and social factors associated with COVID-19 severity. +Untangling the factors that influence COVID-19 outcomes is a complex undertaking. +Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Italy and Wuhan, China [@doi:10.1056/nejmoa2002032; @doi:10.1001/jama.2020.2648; @doi:10.1001/jama.2020.4031]. However, hospitalization rates vary by location [@doi:10.15585/mmwr.mm6915e3]. This variation may be influenced by demographic (e.g., average age in the area), medical (e.g., the prevalence of comorbid conditions such as diabetes), and social (e.g., income or healthcare availability) factors that vary geographically. -Additionally, some of the same factors may influence an individual's probability of exposure to SARS-CoV-2, their risk of developing a more serious case of COVID-19 that would require hospitalization, and their access to medical support. As a result, quantifying or comparing susceptibility among individuals, communities, or other groups requires consideration of a number of complex phenomena that intersect across many disciplines of research. -In this section, the term "risk factor" is used to refer to variables that are statistically associated with more severe COVID-19 outcomes. +Importantly, discriminatory racial attitudes and other sources of social stratification are also likely to vary geographically. +Thus, in this section, the term "risk factors" is used to identify variables that are statistically associated with more severe COVID-19 outcomes. Some are intrinsic characteristics that have been observed to carry an association with variation in outcomes, whereas others may be more functionally linked to the pathophysiology of COVID-19. +These variables will then be contextualized into a broader social and biological framework below. #### Patient Traits Associated with Increased Risk Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age (typically defined as 60 or older, with the greatest risk among those 85 and older [@url:https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/older-adults.html]). In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization [@doi:10.1377/hlthaff.2020.00598; @doi:10.15585/mmwr.mm6925e1]. A retrospective study of hospitalized Chinese patients [@doi:10/ggnxb3] found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity [@doi:10.1073/pnas.2004911117]. -The CFR for adults over 80 has been estimated upwards of 14% or even 20% [@doi:10.1111/jgs.16472]. +The case fatality rate (CFR) for adults over 80 has been estimated upwards of 14% or even 20% [@doi:10.1111/jgs.16472]. Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death [@doi:10.1136/bmj.m1985; @doi:10.1186/s13293-020-00304-9; @url:https://globalhealth5050.org/the-sex-gender-and-covid-19-project/]. Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death [@doi:10.1186/s13293-020-00304-9], although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions [@doi:10.1371/journal.ppat.1008570]. -In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio [@doi:10.1186/s13293-020-00304-9]. +In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio with age [@doi:10.1186/s13293-020-00304-9]. Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 [@url:https://globalhealth5050.org/the-sex-gender-and-covid-19-project/]. -There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort [@doi:10.1371/journal.ppat.1008520]. +There also may be a compounding effect of advanced age and male sex, with differences of time to recovery that are worst for males over 60 years old relative to female members of their age cohort [@doi:10.1371/journal.ppat.1008520]. +Social factors may also influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks [@doi:10.1093/qjmed/hcaa136], and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) [@doi:10.1186/s13293-020-00304-9] among men and women. -Both of these risk factors can be approached through the lens of biology. +Both of these risk factors can be interpreted through the lens of biology. The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes [@doi:10.1111/jgs.16472]. -Several hypotheses have been proposed to account for differences in severity between males and females. +For individuals experiencing chronic stress over the course of their lifetime due to factors such as racism or poverty, the prevalence of these conditions would likely be even higher [@doi:10.1176/appi.ajp.2009.09040461; @doi:10.1001/archinte.1997.00440400111013; @doi:10.1073/pnas.081072698]. +Greater severity of illness with advanced age is typical of many infectious diseases, and therefore this association is not unexpected [@doi:10.1086/313792]. +As for the association of sex with COVID-19 severity, several hypotheses have been proposed. For example, some evidence suggests that female sex hormones may be protective [@doi:10.1186/s13293-020-00304-9; @doi:10.1371/journal.ppat.1008570]. -ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol [@doi:10.1186/2042-6410-1-6; @doi:10.1371/journal.ppat.1008570]. -Other work in mice has shown an inverse association between mortality due to SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone [@doi:10.1371/journal.ppat.1008570]. -Similarly, evidence suggests that similar patterns might be found in other tissues. -A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis showed than female patients, although this pattern was not found in controls [@doi:10.1186/s13293-020-00304-9]. -Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the Renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 [@doi:10.1186/s13293-020-00304-9]. -Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females [@doi:10.1371/journal.ppat.1008570; @doi:10.1186/2042-6410-1-6]. +Expression of angiotensin converting enzyme 2 (ACE2), the enzyme used by the SARS-CoV-2 virus to enter host cells, in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol [@doi:10.1186/2042-6410-1-6; @doi:10.1371/journal.ppat.1008570]. +Other work in mice has shown an inverse association between mortality due to the closely related virus SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone [@doi:10.1371/journal.ppat.1008570]. +Evidence also suggests that similar patterns might be found in other tissues. +A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis than female patients, although this pattern was not found in controls [@doi:10.1186/s13293-020-00304-9]. +Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 [@doi:10.1186/s13293-020-00304-9]. +Several components of the immune response, including the inflammatory response, may also differ in intensity and timing between males and females [@doi:10.1371/journal.ppat.1008570; @doi:10.1186/2042-6410-1-6]. This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males [@doi:10.1371/journal.ppat.1008570]. Sex steroids can also bind to immune cell receptors to influence cytokine production [@doi:10.1186/s13293-020-00304-9]. -Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks [@doi:10.1093/qjmed/hcaa136], and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) [@doi:10.1186/s13293-020-00304-9] among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk [@url:https://escholarship.org/uc/item/55t297mc].) +Thus, both age and sex are thought to have some intrinsic relationship to risk, but also to be correlated with social factors contributing to risk, although it should be noted that both transgender men and women are suspected to be at heightened risk [@url:https://escholarship.org/uc/item/55t297mc]. #### Comorbid Health Conditions -A number of pre-existing or comorbid conditions have repeatedly been identified as risk factors for more severe COVID-19 outcomes. +A number of pre-existing or comorbid conditions have repeatedly been identified as risk factors associated with more severe COVID-19 outcomes. Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease [@doi:10.15585/mmwr.mm6915e3]. -Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality [@doi:10/ggnxb3], and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex [@doi:10.1136/bmj.m1985]. -Diabetes may increase the risk of lengthy hospitalization [@doi:10.1016/j.cmet.2020.04.021] or of death [@doi:10.1016/j.cmet.2020.04.021;@doi:10.1007/s00592-020-01546-0]. -[@doi:10.1111/dom.14057] and [@doi:10.1152/ajpendo.00124.2020] discuss possible ways in which COVID-19 and diabetes may interact. +Higher sequential organ failure assessment (SOFA) scores have been associated with a higher probability of mortality [@doi:10/ggnxb3], and comorbid conditions such as cardiovascular and lung diseases as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex [@doi:10.1136/bmj.m1985]. +SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for sepsis-related organ failure assessment [@doi:10.1007/BF01709751; @doi:10.1001/jama.2016.0287]; sepsis is a common immediate cause of death among COVID-19 patients [@doi:10.1101/2020.06.15.20131540; @doi:10.1371/journal.pone.0235458]. +Diabetes may increase the duration of hospitalization [@doi:10.1016/j.cmet.2020.04.021] and the risk of death [@doi:10.1016/j.cmet.2020.04.021;@doi:10.1007/s00592-020-01546-0]. Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 [@doi:10.1016/j.metabol.2020.154262; @doi:10.1101/2020.04.23.20076042]. -Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear [@doi:10.1016/j.medj.2020.06.005]. -Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom [@doi:10.1136/bmj.m1985]. -It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally [@doi:10.1073/pnas.2008760117]. -Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities [@doi:10.1111/jgs.16472; @url:https://www.who.int/publications/i/item/report-of-the-who-china-joint-mission-on-coronavirus-disease-2019-(covid-19)]. +Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) of COVID-19 patients in the United Kingdom [@doi:10.1136/bmj.m1985]. + +These health conditions affect biology in ways that are thought to overlap with the pathogenesis of COVID-19. +Analyses investigating possible functional relationships between diabetes and COVID-19 have revealed that _ACE2_ expression may be elevated in individuals with diabetes mellitus [@doi:10.2337/dc20-0643] and that ketoacidosis, a metabolic disorder typically associated with diabetes, is observed in COVID-19 patients with and without diabetes [@doi:10.1111/dom.14057]. +These findings suggest that the pathology of diabetes may overlap with the pathology of COVID-19 [@doi:10.1152/ajpendo.00124.2020]. +Although a clear functional connection between obesity and COVID-19 outcomes is not yet established [@doi:10.1016/j.medj.2020.06.005], obesity is correlated with other comorbid conditions such as hypertension, diabetes, and pulmonary disease, as well as to chronic inflammation [@doi:10.1007/s11695-020-04677-z]. +Structural racism has been proposed as a driver of both obesity and severe impacts of COVID-19 [@doi:10.1016/j.cmet.2021.01.010]. +Dementia and other forms of cognitive decline are thought to be functionally related to diabetes [@doi:10/c3tm55], and both cancer and dementia are related to chronic inflammation [@doi:10.1038/nature01322; @doi:10.1186/s13195-015-0117-2]. + +It should be noted that such comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally [@doi:10.1073/pnas.2008760117]. +Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities [@doi:10.1111/jgs.16472; @WHO-China-report-2020-02-28]. Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population [@doi:10.1073/pnas.2008760117]. -However, other associations may exist, such as patients with sepsis having higher SOFA scores -- in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment [@doi:10.1007/BF01709751; @doi:10.1001/jama.2016.0287]. Additionally, certain conditions are likely to be more prevalent under or exacerbated by social conditions, especially poverty, as is discussed further below. #### Ancestry @@ -73,24 +131,27 @@ In addition to Black Americans, disproportionate harm and mortality from COVID-1 In Brazil, indigenous communities likewise carry an increased burden of COVID-19 [@doi:10.1126/science.abc0073]. In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 [@doi:10.1038/s41586-020-2521-4]. -From a genetic standpoint, it is highly unlikely that ancestry itself predisposes individuals to contracting COVID-19 or to experiencing severe COVID-19 outcomes. -Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent [@doi:10.1038/ng1438]. +From a genetic standpoint, it is highly unlikely that ancestry itself predisposes individuals from these diverse groups to experiencing severe COVID-19 outcomes. +Human genetic diversity varies over a geographic continuum, and that most human genetic variation is associated with the African continent [@doi:10.1038/ng1438]. African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans [@doi:10.1146/annurev.genom.9.081307.164258]. -Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity [@doi:10.1126/science.abd4842]. -The possibility for genetic variants that confer some risk or some protection remains possible, but has not been widely explored, especially at a global level. -Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients [@doi:10.1093/infdis/jiaa224]. +Therefore, the idea that African ancestry (at the continental level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity [@doi:10.1126/science.abd4842]. +The possibility for genetic variants that confer some risk or some protection remains possible, but has not been widely explored, especially on a global scale. +Research in Beijing of a small number (n=80) of hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients [@doi:10.1093/infdis/jiaa224]. Genetic factors may also play a role in the risk of respiratory failure for COVID-19 [@doi:10.1056/NEJMoa2020283; @doi:10.1093/gerona/glaa131; @doi:10.1101/2020.06.16.155101]. -However, genetic variants associated with outcomes within ancestral groups are far less surprising than genetic variants explaining outcomes between groups. -Alleles in _ACE2_ and _TMPRSS2_ have been identified that vary in frequency among ancestral groups [@doi:10.1186/s12916-020-01673-z], but whether these variants are associated with COVID-19 susceptibility has not been explored. +However, genetic variants associated with outcomes within ancestral groups are far more common than genetic variants explaining outcomes between groups. +Alleles in _ACE2_ and transmembrane protease serine protease-2, which is involved in proteolytic priming of SARS-CoV-2 for cell entry [@individual-pathogenesis], have been identified to vary in frequency among ancestral groups [@doi:10.1186/s12916-020-01673-z], but whether these variants are associated with COVID-19 susceptibility has not been explored. Instead, examining patterns of COVID-19 susceptibility on a global scale that suggest that social factors are of primary importance in predicting mortality. -Reports from several sub-Saharan African countries have indicated that the effects of the COVID-19 pandemic have been less severe than expected based on the outbreaks in China and Italy. -In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 [@doi:10.1101/2020.07.27.20162693]. -This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases [@doi:10.1101/2020.07.27.20162693]. -Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted [@doi:10.1101/2020.07.30.20164970]. -While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places [@doi:10.1126/science.369.6505.756], these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent. -Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location [@url:https://www.ifs.org.uk/inequality/chapter/are-some-ethnic-groups-more-vulnerable-to-covid-19-than-others/]. -Furthermore, the groups in the United States and United Kingdom that have been identified as carrying elevated COVID-19 burden, namely Black American, indigenous American, and Black and South Asian British, are quite distinct in their position on the human ancestral tree. +Reports from several sub-Saharan African countries during 2020 indicated that the effects of the COVID-19 pandemic were less severe than anticipated based on the outbreaks in China and Italy. +In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies between April and June 2020 were consistent with approximately 5% of Kenyan adults having recovered from COVID-19 [@doi:10.1126/science.abe1916]. +This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which by the median date of sampling was 71 out of 2093 known cases [@doi:10.1101/2020.07.27.20162693]. +Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up to eight times lower than models had predicted [@doi:10.1101/2020.07.30.20164970]. +While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent were explored, such as young population demographics in many places [@doi:10.1126/science.369.6505.756], these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent. +In late 2020, the continent began facing a second wave that has proven to be more deadly [@doi:10.1001/jama.2020.24288], but the initial success of many African country's management of COVID-19 still lies in stark contrast to the trends observed for populations of African descent in the United States and United Kingdom. +Additionally, while the youthfulness of many African cities may have insulated populations during the first wave, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location [@url:https://www.ifs.org.uk/inequality/chapter/are-some-ethnic-groups-more-vulnerable-to-covid-19-than-others/]. +Therefore, simple explanations such as demographics do not seem sufficient to explain the different trajectories of infection among locations. + +The groups in the United States and United Kingdom that have been identified as carrying elevated COVID-19 burden, namely Black American, indigenous American, and Black and South Asian British, are quite distinct in their position on the human ancestral tree. What is shared across these groups is instead a history of disenfranchisement under colonialism and ongoing systematic racism. A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients [@doi:10.1001/jamanetworkopen.2020.18039]. This study reported that when these factors were accounted for, the differences in mortality between Black and white patients were no longer significant. @@ -98,6 +159,12 @@ Thus, the current evidence suggests that the apparent correlations between ances ### Environmental Influences on Susceptibility +There are distinct components to COVID-19 susceptibility, and an individual's risk can be elevated at one or all stages from exposure to recovery/mortality: an individual may be more likely to be exposed to the virus, more likely to get infected once exposed, more likely to have serious complications once infected, and be less likely to receive adequate care once they are seriously ill. +The fact that one analysis found differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age [@doi:10.1001/jamanetworkopen.2020.18039] underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups. +Moreover, the Black patients analyzed in this study were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables [@doi:10.1001/jamanetworkopen.2020.18039]. +These results indicate that factors tied to socioeconomic status are likely to be fundamental to understanding COVID-19 risk. +Here, we outline a few systemic forces that may exacerbate the COVID-19 pandemic in communities of color. + #### Exposure to COVID-19 Social distancing has emerged as one of the main social policies used to manage the COVID-19 epidemic in many countries. @@ -107,6 +174,7 @@ In U.S. counties with and without stay-at-home orders, smartphone tracking indic A linear relationship was observed between counties' reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors [@doi:10.1101/2020.05.03.20084624]. Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents [@doi:10.1101/2020.05.03.20084624]. Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [@arXiv:2006.15195], as well as in a very large data set from several US cities [@doi:10.1038/s41586-020-2923-3]. + These disparities in mobility are likely to be related to the role that essential workers have played during the pandemic. Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line [@url:https://mronline.org/wp-content/uploads/2020/06/2020-04-Frontline-Workers.pdf]. Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible [@doi:10.1002/ajim.23145]. @@ -118,12 +186,12 @@ The socioeconomic and racial/ethnic gaps in who is working on the front lines of Increased risk of exposure can also arise outside the workplace. Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks [@doi:10.1001/jama.2020.11642]. -Prisons and detention centers also confer a high risk of exposure or infection [@doi:10.1001/jamainternmed.2020.1856; @doi:10.1001/jama.2020.12528]. -Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black [@url:https://www.issuelab.org/resources/695/695.pdf]. +The services provided in long-term care facilities can vary widely, with a lower quality of care frequently available to racial and ethnic minorities who need these services [@doi:10.1080/08959420.2020.1772004]. +Prisons and detention centers also confer a high risk of exposure or infection [@doi:10.1001/jamainternmed.2020.1856; @doi:10.1001/jama.2020.12528], and in the United States, incarcerated people are more likely to be male and persons of color, especially Black [@url:https://www.issuelab.org/resources/695/695.pdf]. Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds [@doi:10.1111/j.1751-9020.2010.00306.x], increasing the risk of exposure for more susceptible family members. Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure [@doi:10.1101/2020.05.03.20084624], and household crowding is associated with poverty [@doi:10.1037/12057-014]. Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism [@doi:10.7916/D8WH2W9T; @doi:10.1093/socpro/spv025], would be likely to increase household crowding and other possible sources of exposure. -As a result, facets of systemic inequality such as mass incarceration of Black Americans and poverty are likely to increase the risk of exposure outside of the workplace. +As a result, facets of systemic inequality, such as the mass incarceration of Black Americans and intergenerational poverty, are likely to increase the risk of exposure outside of the workplace. #### Severity of COVID-19 Following Exposure @@ -144,13 +212,16 @@ Furthermore, cell phone GPS data suggests that lower socioeconomic status may al Chronic inflammation is a known outcome of chronic stress (e.g., [@doi:10.1067/mai.2000.110163; @doi:10.1037/0278-6133.21.6.531; @doi:10.1037/a0025536; @doi:10.1111/j.1467-8721.2006.00450.x]). Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in [@doi:10.1038/scientificamerican1205-92]) and especially during the stress of the ongoing pandemic. -A preprint [@doi:10.1101/2020.04.05.20054502] provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates. -Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., [@doi:10.1073/pnas.1803222115]). +Environmental disparities may also influence differences in COVID-19 outcomes. +A preprint [@doi:10.1101/2020.04.05.20054502] provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates. +Although a lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., [@doi:10.1073/pnas.1803222115]). Exposure to air pollution is associated with both poverty (e.g., [@doi:10.3390/ijerph15061114]) and chronic inflammation [@doi:10.1016/j.neubiorev.2018.06.002]. Other outcomes of environmental racism, such as the proximity of abandoned uranium mines to Navajo land, can also cause respiratory illnesses and other health issues [@url:https://journalhosting.ucalgary.ca/index.php/jisd/article/view/70753/54416]. -Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency [@doi:10.1210/clinem/dgaa733]) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism [@url:https://journalhosting.ucalgary.ca/index.php/jisd/article/view/70753/54416; @doi:10.1056/NEJMp2021264]. -Taken together, the evidence suggests that low-income workers who face greater exposure to SARS-CoV-2 due to their home or work conditions are also more likely to face environmental and social stressors associated with increased inflammation, and therefore with increased risk from COVID-19. -In particular, structural racism can play an important role on disease severity after SARS-CoV-2 exposure, due to consequences of racism which include an increased likelihood of poverty and its associated food and housing instability. +Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency and other nutritional deficiencies [@individual-nutraceuticals]) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism [@url:https://journalhosting.ucalgary.ca/index.php/jisd/article/view/70753/54416; @doi:10.1056/NEJMp2021264]. + +Taken together, the evidence suggests that low-income workers who face greater exposure to SARS-CoV-2 due to their home or work conditions are also more likely to face environmental and social stressors associated with increased inflammation. +Structural racism can play a role in disease severity after SARS-CoV-2 exposure due to consequences of racism such as an increased likelihood of poverty and its associated food and housing instability. +Unsurprisingly, this convergence of factors is also associated with an increased risk of severe COVID-19 outcomes, including death. COVID-19 can thus be considered a "syndemic", or a synergistic interaction between several epidemics [@doi:10.1002/ajhb.23482]. As a result, it is not surprising that people from minoritized backgrounds and/or with certain pre-existing conditions are more likely to suffer severe effects of COVID-19, but these "risk factors" are likely to be causally linked to poverty [@doi:10.1001/jama.2020.26443]. @@ -162,15 +233,16 @@ For example, it is common to see treatment guidelines for suspected cases regard Whether and where a patient is diagnosed can depend on their access to testing, which can vary both between and within countries. In the United States, it is not always clear whether an individual will have access to free testing [@url:https://www.npr.org/sections/health-shots/2020/06/19/880543755/insurers-may-only-pay-for-coronavirus-tests-when-theyre-medically-necessary; @url:https://www.commonwealthfund.org/blog/2020/private-health-insurance-coverage-covid-19-public-health-emergency]. The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States [@doi:10.1016/j.jaad.2020.04.046]. -This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community [@doi:10.1377/hlthaff.2020.00598]. +This connection is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community [@doi:10.1377/hlthaff.2020.00598]. Any delays in treatment are a cause for concern [@doi:10.1016/j.jaad.2020.04.046], which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test [@url:https://www.hrsa.gov/coviduninsuredclaim/frequently-asked-questions]. Another important question is whether patients with moderate to severe cases are able to access hospital facilities and treatments, to the extent that they have been identified. Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country [@doi:10/ggqscd], although reported mortality is generally an estimate of CFR, which is dependent on rates of testing. Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources [@doi:10.1038/s41591-020-0823-6]. In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured [@doi:10.1016/j.jaad.2020.04.046]. -As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds [@url:https://www.census.gov/content/dam/Census/library/publications/2019/demo/p60-267.pdf]. +Black Americans, certain Asian American, Native Hawaiian and Pacific Islander subgroups, and Hispanic Americans of all races are much less likely to have health insurance than people from non-Hispanic white backgrounds [@url:https://www.census.gov/content/dam/Census/library/publications/2019/demo/p60-267.pdf; @doi:10.1377/hlthaff.2019.01394; @doi:10.1001/jamainternmed.2018.1476]. Therefore, access to diagnostics and care prior to the development of severe COVID-19 is likely to vary depending on socioeconomic and social factors, many of which overlap with the risks of exposure and of developing more severe COVID-19 symptoms. + This discrepancy ties into concerns about broad infrastructural challenges imposed by COVID-19. A major concern in many countries has been the saturation of healthcare systems due to the volume of COVID-19 hospitalizations (e.g., [@doi:10.1073/pnas.2004064117]). Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients [@doi:10.19044/esj.2020.v16n21p24; @doi:10.7249/PEA228-1; @arxiv:2008.00374; @doi:10.1016/j.surg.2020.04.044]. @@ -182,31 +254,32 @@ This approach would carry its own ethical concerns, including the fact that many As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest [@doi:10.1136/medethics-2020-106460]. Allocation of interventions that may reduce suffering, including palliative care, has become critically important [@doi:10.1136/medethics-2020-106460; @doi:10.1080/15265161.2020.1788663]. The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources [@doi:10.1080/15265161.2020.1795538]. -For example, remdesivir, discussed above, is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead [@doi:10.1016/j.mayocp.2020.06.016; @doi:10.1080/15265161.2020.1795529]. +For example, for much of 2020, remdesivir was available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by the manufacturer, Gilead [@doi:10.1016/j.mayocp.2020.06.016; @doi:10.1080/15265161.2020.1795529]. +Remdesivir is now the only FDA-approved treatment for COVID-19 [@individual-pharmaceuticals]. Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them [@doi:10.1080/15265161.2020.1795529]. -Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial [@doi:10.1080/15265161.2020.1795538]. -On the other hand, given that the drug is one of the most promising treatments available for many patients, using a framework that tacitly feeds into structural biases would also be unethical. +Prioritizing marginalized groups for treatment with a drug like remdesivir would have been unethical because it would entail disproportionately exposing these groups to a therapeutic for which the benefits and risks were not yet established [@doi:10.1080/15265161.2020.1795538]. +On the other hand, given that the drug was and remains one of the most promising treatments available for many patients, using a framework that tacitly feeds into structural biases would also be unethical. At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that "prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status" [@url:https://www.cdc.gov/about/advisory/pdf/VentDocument_Release.pdf]. In many cases, experimental therapeutics are made available only through participation in clinical trials [@doi:10.1080/15265161.2020.1795541]. However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment [@doi:10.1080/15265161.2020.1795541]. As a result, the standard practice of requiring enrollment in a clinical trial in order to receive experimental treatment may also reinforce patterns established by systemic racism. - + #### Access to and Representation in Clinical Trials Experimental treatments are often made available to patients primarily or even exclusively through clinical trials. -The advantage of this approach is that clinical trials are designed to collect rigorous data about the effects of a treatment on patients. +The advantage of this approach is that clinical trials are designed to collect rigorous data about the efficacy of a treatment as well as its safety. The disadvantage is that access to clinical trials is not equal among all people who suffer from a disease. Two important considerations that can impact an individual's access to clinical trials are geography and social perceptions of clinical trials. For the first, the geographic distribution of trial recruitment efforts are typically bounded and can vary widely among difference locations, and for the second, the social context of medical interactions can impact strategies for and the success of outreach to different communities. Differential access to clinical trials raises concerns because it introduces biases that can influence scientific and medical research on therapeutics and prophylactics broadly. Concerns about bias in clinical trials need to address both trial recruitment and operation. -In the present crisis, such biases are particularly salient because COVID-19 is a disease of global concern. +In the present crisis, such biases are particularly salient because COVID-19 is a disease of global concern, and COVID-19 studies that have included worldwide populations, such as the World Health Organization's (WHO's) Solidarity trial, do not always reach the same conclusions as those conducted exclusively within western, industrialized nations (e.g., remdesivir and tocilizumab [@individual-pharmaceuticals]). Treatment is needed by people all over the world, and clinical research that characterizes treatment outcomes in a variety of populations is critically important. Global representation in clinical trials is important to ensuring that experimental treatments are available equally to COVID-19 patients who may need them. The advantage to a patient of participation in a clinical trial is that they may receive an experimental treatment they would not have been able to access otherwise. -The potential downsides of participation include that the efficacy and side effects of such treatments are often poorly characterized and that patients who enroll in clinical trials will in some cases run the risk of being assigned to a placebo condition where they do not receive the treatment but miss out on opportunities to receive other treatments. +The potential downsides of participation include that the efficacy and side effects of such treatments are often poorly characterized and that patients who enroll in clinical trials will in some cases run the risk of being assigned to a placebo condition where they do not receive the treatment and could miss out on opportunities to receive other treatments. The benefits and burdens of clinical trials therefore need to be weighed carefully to ensure that they don't reinforce existing health disparities. The WHO Director‐General Tedros Adhanom Ghebreyesus stated his condemnation of utilizing low and middle income countries as test subjects for clinical trials, yet having highly developed countries as the majority of clinical trial representation is also not the answer [@doi:10.1002/eahr.500055]. Figure @fig:ebm-map showcases two choropleths detailing COVID-19 clinical trial recruitment by country. @@ -225,23 +298,21 @@ A few different concerns arise from this skewed geographic representation in cli First, treatments such as remdesivir that are promising but primarily available to clinical trial participants are unlikely to be accessible by people in many countries. Second, it raises the concern that the findings of clinical trials will be based on participants from many of the wealthiest countries, which may lead to ambiguity in whether the findings can be extrapolated to COVID-19 patients elsewhere. Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., [@doi:10/ggq7mf], yet data like that shown in Figure @fig:ebm-map demonstrates that accessibility is likely to be a significant issue. -Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes [@doi:10.1001/jama.2020.6641]. +Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once treatments or vaccines are developed, causing unequal health outcomes [@doi:10.1001/jama.2020.6641]. Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll [@doi:10.1016/j.cdp.2005.12.001]. Thus, geography both on the global and local levels may influence when treatments and vaccines are available and who is able to access them. Efforts such as the African Union's efforts to coordinate and promote vaccine development [@doi:10/fgzk] are therefore critical to promoting equity in the COVID-19 response. - Even when patients are located within the geographic recruitment area of clinical trials, however, there can still be demographic inequalities in enrollment. When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups [@doi:10.1002/cncr.28483]. However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., [@doi:10.1001/jama.291.22.2720; @doi:10.1245/s10434-007-9500-y; @doi:10.1089/jwh.2010.2469; @doi:10.1007/s11926-018-0728-2]). -This trend is especially concerning given the disproportionate impact of COVID-19 on African-Americans. +This trend is especially concerning given the disproportionate impact of COVID-19 on Black Americans. Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients [@doi:10.1056/NEJMp2021971]. -One proposed explanation for differences among racial and ethnic groups in clinical trial enrollment refers to different experiences in healthcare settings. -While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [@doi:10.1002/cncr.28483], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare. +One proposed explanation for differences among racial and ethnic groups in clinical trial enrollment refers to different experiences among patients in healthcare settings. In the United States, many patients experience "othering" from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., [@doi:10.1207/S15327027HC1602_7]). Many studies have sought to characterize implicit biases in healthcare providers and whether they affect their perceptions or treatment of patients. -A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [@doi:10.1016/j.socscimed.2017.05.009], with similar findings reported by a second systematic review [@doi:10.1111/acem.13214]. +A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers across many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [@doi:10.1016/j.socscimed.2017.05.009], with similar findings reported by a second systematic review [@doi:10.1111/acem.13214]. However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises [@doi:10.1016/j.socscimed.2017.05.009], and other analyses suggest that physician implicit bias could impact the patient's perception of the negativity/positivity of the interaction regardless of the physician's explicit behavior towards the patient [@doi:10.1016/j.jesp.2009.11.004]. Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 [@doi:10.1542/peds.2020-003657]. Furthermore, the experience of being othered is not only expected to impact patients' trust in and comfort with their provider, but also may directly impact whether or not the patient is offered the opportunity to participate in a clinical trial at all. @@ -249,35 +320,30 @@ Some studies suggest communication between physicians and patients impacts wheth For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. [@doi:10.1002/cncr.28483]. The data indicated that the mean word count of the entire visit was 1.5 times more for white patients in comparison to Black patients. In addition, the greatest disparity between white and Black patients' experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients [@doi:10.1002/cncr.28483]. +While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [@doi:10.1002/cncr.28483], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare. The trends observed for other clinical trials raise the concern that COVID-19 clinical trial information may not be discussed as thoroughly or as often with Black patients compared to white patients. - These discrepancies are especially concerning given that many COVID-19 treatments are being or are considered being made available to patients prior to FDA approval through Emergency Use Authorizations. +These discrepancies are especially concerning given that many COVID-19 treatments are or are being considered being made available to patients prior to FDA approval through Emergency Use Authorizations. In the past, African-Americans have been over-represented relative to national demographics in use of the FDA's Exception From Informed Consent (EFIC) pathway [@doi:10.1377/hlthaff.2018.0501]. Through this pathway, people who are incapacitated can receive an experimental treatment even if they are not able to consent and there is not sufficient time to seek approval from an authorized representative. This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments [@doi:10.1067/mem.2003.17]. While the goal of EFIC approval is to provide treatment to patients who urgently need it, the combination of the ongoing legacy of racism in medicine renders this trend concerning. With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., [@url:https://www.businessinsider.com/cdc-official-considering-giving-covid-19-vaccine-most-vulnerable-first-2020-10]), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized. Making a substantial effort to run inclusive clinical trials is also important because of the possibility that racism could impact how a patient responds to a treatment. -For example, as discussed above, dexamethasone has been identified as a promising treatment for patients experiencing cytokine release syndrome, but the mechanism of action is tied to the stress response. +For example, the corticosteroid dexamethasone has been identified as a promising treatment for COVID-19 patients experiencing cytokine release syndrome [@doi:10.1056/NEJMoa2021436], but, as discussed above, the mechanism of action of a corticosteroid is tied to the stress response. A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug [@doi:10.1378/chest.127.2.571]. In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids [@doi:10.1146/annurev.physiol.67.040403.120816] and glucocorticoid receptor resistance [@doi:10.1073/pnas.1118355109]. However, it underscores the critical need for treatment guidelines to take into account differences in life experience, which would be facilitated by the recruitment of patients from a wide range of backgrounds. Attention to the social aspects of clinical trial enrollment must therefore be an essential component of the medical research community's response to COVID-19. - - -### Conclusions and Future Directions - -As the COVID-19 pandemic evolves, the scientific community's response will be critical for identifying potential pharmacological and biotechnological developments that may aid in combating the virus and the disease it causes. -However, this global crisis highlights the importance of mounting a response based on collaboration among a wide variety of disciplines. -Understanding the basic science of the virus and its pathogenesis is imperative for identifying and envisioning possible diagnostic and therapeutic approaches; understanding how social factors can influence outcomes and shape implementation of a response is critical to disseminating any scientific advancements. -Summarizing such a complex and ever-changing topic presents a number of challenges. -This review represents the effort of over 50 contributors to distill and interpret the available information. -However, this text represents a dynamic and evolving document, and we welcome continued contributions from all researchers who have insights into how these topics intersect. -A multidisciplinary perspective is critical to understanding this evolving crisis, and in this review we seek to use open science tools to coordinate a response among a variety of researchers. -We intend to publish additional updates as the situation evolves. +### Approaching COVID-19 through the Lens of Embodiment + + +### Conclusions + diff --git a/content/90.back-matter.md b/content/90.back-matter.md index d5016a86c..ef65c4a95 100644 --- a/content/90.back-matter.md +++ b/content/90.back-matter.md @@ -5,6 +5,7 @@ [@tag:Park2020_distancing]: url:https://github.com/parksw3/Korea-analysis/blob/master/v1/korea.pdf +[@WHO-China-report-2020-02-28]: https://www.who.int/publications/i/item/report-of-the-who-china-joint-mission-on-coronavirus-disease-2019-(covid-19) [@individual-pathogenesis]: arxiv:2102.01521 diff --git a/content/metadata.yaml b/content/metadata.yaml index 14bbb8829..aa9512f3a 100644 --- a/content/metadata.yaml +++ b/content/metadata.yaml @@ -1129,3 +1129,21 @@ authors: order: 7 contributions: - Writing - Review & Editing + - + github: juliettemarie0405 + name: Juliette M Rando + initials: JMR + orcid: https://orcid.org/0000-0002-1742-9255 + email: juliette.rando@gmail.com + code of conduct: + confirmed: Yes + affiliations: + - Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America + coi: + string: "None" + lastapproved: !!str 2021-03-24 + manuscripts: + inequality: + order: 0 + contributions: + - Writing - Review & Editing