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Long COVID and Medicine's Two Cultures

      Abstract

      Medicine has separated the two cultures of biological science and social science in research, even though they are intimately connected in the lives of our patients. To understand the cause, progression, and treatment of long COVID , biology and biography, the patient's lived experience, must be studied together.

      Keywords

      Clinical Significance
      • Integrating biology and medical biography is needed to understand the pathogenesis and management of long coronavirus disease 2019 (COVID-19).
      • Biography refers to the medically relevant life experiences of patients.
      • Previous research has shown that biography affects both the susceptibility to respiratory viral disease and response to vaccination.
      • Neglect of biography contributes to the two cultures in medicine that prioritizes biology over biography despite evidence that both are important.
      We do not need to use our imagination to appreciate the suffering of patients with long coronavirus disease 2019 (COVID-2019) syndrome. There are a series of brilliant reports describing what life is like for patients who experience COVID's persistent symptoms. But you won't find those reports in prestigious medical journals. To learn about the suffering of our patients with long COVID, you need to read reports in different journals: The New York Times, The New Yorker, The Atlantic. A report from a patient with long COVID appeared in the January 21, 2021 issue of The New York Times and started with the sentence, “I remember the second time I thought I would die.” The author explains that the first time was during her acute COVID-19 disease. The second time was during her long haul COVID illness.

      Holson LM. New York Times. March 23, 2021. My Long Covid Nightmare: Still Sick AFterr 6 Months.

      That is not to suggest that medical journals ignore long COVID; they just treat it differently. An example among many is a paper in the journal Nature Medicine published March 2021 titled, “Attributes and predictors of long COVID.” Table 1 from that article illustrates that the study's most compelling strengths are also its most compelling weaknesses. The predictors listed in the table are: sex, age, obesity, comorbid clinical diseases, number of symptoms in the first week of acute COVID, and visits to the hospital. Subsequent figures listed diverse clinical symptoms and used random forest regression methods to generate prediction models. The strongest predictor was increasing age, followed by the number of symptoms in the first week of the acute COVID illness.
      • Sudre CH
      • Murray B
      • Varsavsky T
      Attributes and predictors of long COVID.
      What is missing from lay magazines that include the powerful patient testimonials is the neglect of clinical biology in recounting their stories. What is missing so prominently from the medical reports is the neglect of the patients’ biography, their lived experience, both before and during their experience with COVID-19 and its sequelae. Features such as whether the patient is an essential worker or works remotely from home, whether they are socially isolated or lonely, or struggling with the stresses of job loss, financial challenge, or troubled relationships.
      • Summers-Trio P
      • Hayes-Conroy A
      • Singer B
      • Horwitz RI
      Biology, biography, and the translational gap.
      • Horwitz RI
      • Hayes-Conroy A
      • Singer BH
      Biology, social environment, and personalized medicine.
      • Lobitz G
      • Armstrong K
      • Concato J
      • Singer BH
      • Horwitz I
      The biological and biographical basis of precision medicine.
      These extremes in how long COVID is represented in popular press and scientific journals illustrate that medicine has a profound two-cultures problem involving biology and biography similar to the one that C. P. Snow described more than 60 years ago. Snow argued that the separation of science and the humanities was a hindrance to suitably addressing society's most important problems.
      • Snow CP
      1905-1980. The Two Cultures and the Scientific Revolution.
      Today, biology and biography (a patient's lived experience) hardly ever intersect in our medical science, even though they are in constant intersection in our patients’ lives. This separation is a fundamental barrier that serves as a hindrance to developing scientific research toward long COVID that is relevant both to its cause and treatment.

      Biosocial Pathogenesis

      Medicine long ago recognized that disease does not occur from biological influences alone. There is no immutable biological law that determines who will develop tuberculosis after exposure to the mycobacterium tuberculosis. Tuberculosis occurs more often in exposed people who live in conditions of poverty, residential crowding, and are poorly nourished. A strictly biological model of disease pathogenesis ignores the role of a person's life experience and is insufficient to explain why some individuals are susceptible to disease, resilient when disease occurs, and variably responsive to treatment.
      • Horwitz RI
      • Hayes-Conroy A
      • Caricchio R
      • Singer BH
      From evidence based medicine to medicine based evidence.
      Biosocial pathogenesis is a more comprehensive model that integrates a person's biology with their biography.
      • Horwitz RI
      • Singer B
      • Hayes-Conroy A
      • et al.
      Biosocial pathogenesis.
      The foundation for biosocial pathogenesis was established two decades ago when the neuroscientist, Bruce McEwen, argued that chronic stress could both damage health and contribute to disease.
      • Horwitz RI
      • Singer BH
      • Seeman TE
      Biology and lived experience in health and disease: a tribute to Bruce McEwen (1938-2020), a scientist without Silos.
      ,
      • McEwen BS
      Protective and damaging effects of stress mediators.
      In a seminal paper with Elliott Stellar, they pointed out how chronic stress has long-term adverse impact on the body and further demonstrated that individual differences in susceptibility to stress are related to individual behavioral and perceptual differences to environmental and biological challenges that result in physiological and pathological consequences.
      • McEwen BS
      • Stellar E
      Stress and the individual. Mechanisms leading to disease.
      McEwen named the condition in which chronic stress leads to disease allostatic load and intuitively described it as a process of wear and tear on physiological systems. When the cost of adaptation is too high and the ability of physiological systems to adapt to challenge is overwhelmed, allostatic overload occurs and corresponds to conditions under which disease occurs. Other biosocial pathogenesis mechanisms have also been widely studied. Variations in the microbiome that are associated with changes in diet, living arrangements, and medications contribute to disease onset and progression. Circadian rhythms are also biosocial mechanisms associated with effects on sleep and other markers of good health.
      • Horwitz RI
      • Singer B
      • Hayes-Conroy A
      • et al.
      Biosocial pathogenesis.
      Biosocial pathogenesis is a complex process requiring the interplay of both extrinsic (outside the body) and intrinsic (inside the body physically and mentally) factors. Extrinsic factors include societal issues such as the social determinants of health (ageism, sexism, and racism, as well as poverty and the burdens of economic survival in countries like the United States where wages have stagnated and benefits like health care, childcare, and parental leave are scarce). Let's briefly review the recognition of the long COVID syndrome before considering the potential role of biosocial influences in the development of long COVID.

      Long COVID Syndrome

      Long COVID syndrome is the first patient identified illness rooted in a social media network. Diana Berrent, a patient who became ill early in the epidemic (March 2020) and had persistent symptoms after the illness, initiated a Facebook group that she named Survivor Corps.

      Khullar D. The struggle to define long COVID. The New Yorker. Available at: https://www.newyorker.com/magazine/2021/09/27/the-struggle-to-define-long-covid. Accessed April 11, 2022.

      Within a week of the initial posts to Facebook the group had more than 10,000 followers and is now estimated to have about 175,000 members. Physicians and biomedical scientists acknowledge that long COVID exists, but it lives currently in the realm of description, anecdote, and speculative theory. The definitive systematic and analytical studies that are needed to expose its etiological roots are waiting to be completed.
      Long COVID (renamed postacute sequelae of COVID19, or PASC) has been recognized around the world in a subset of patients who experience acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that is followed by persistent symptoms that fail to resolve over weeks to months.
      • Logue JK
      • Franko NM
      • McCulloch DJ
      Sequelae in adults at 6 months after COVID-19 infection.
      Long COVID has been likened to other illnesses that persist in patients such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), or even chronic Lyme syndrome.
      Long COVID comes in two distinct forms. One form occurs in patients with organ damage during the acute illness, in the form of pneumonia or acute kidney injury, for example, and who have persistent symptoms related to the damaged organ.
      • Gavriatopoulou M
      • Korompoki E
      • Fotiou D
      Organ-specific manifestations of COVID-19 infection.
      The second form occurs in patients whose illness lacks organ damage and in whom the persistence of ill health is often highlighted by symptoms such as pain, fatigue, difficulty concentrating, and brain “fog.”
      • Godlee F
      Living with COVID-19.
      It is possible to have both forms of long COVID in the same patient.
      Because there are numerous competing definitions of long COVID, its prevalence is uncertain although studies estimate that persistent symptoms occur in 10%-30% of patients after acute COVID-19.
      • Logue JK
      • Franko NM
      • McCulloch DJ
      Sequelae in adults at 6 months after COVID-19 infection.
      Long COVID is diagnosed in patients with severe acute COVID-19 but also in patients whose acute illness was mild or even asymptomatic. The cause of long COVID is unknown, but speculation about the potential cause includes a number of possibilities. A recent review suggested the following biological factors: “Consequences from SARS-CoV-2 injury to one or multiple organs, persistent reservoirs of SARS-CoV-2 in certain tissues, reactivation of neurotrophic pathogens such as herpesviruses under conditions of COVID-19 immune dysregulation, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation issues, dysfunctional brainstem/vagus nerve signaling, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins.
      • Proal AD
      • VanElzakker MB
      Long COVID or post-acute sequelae of COVID-19 (PASC): an overview of biological factors that may contribute to persistent symptoms.
      What is missing from this list of potential contributors to long COVID syndrome are biographical features that may contribute to the risk of the syndromes.

      Why Biosocial Pathogenesis May Be Needed to Explain Long COVID

      Considering the extensive array of potential biological explanations for the pathogenesis of long COVID, it is important to consider whether it is necessary to propose a biosocial explanation. We argue that nearly 40 years of research linking psychosocial vulnerabilities to respiratory infectious illness and vaccine responsiveness has been ignored and that these research insights are pertinent to understanding long COVID.
      Numerous studies employed a viral challenge model to assess how social, behavioral, and psychological factors made healthy individuals vulnerable to respiratory illness after exposure. In these studies, adults were exposed to a cold or influenza virus and then monitored in quarantine for 5-6 days or until onset of respiratory disease. An increased risk of infection was observed among subjects who reported smoking and chronic psychological stress. A decreased risk of infection occurred for subjects with strong social support, higher levels of physical activity, and efficient sleep patterns.
      • Cohen S
      Psychosocial vulnerabilities to upper respiratory infectious illness: implications for susceptibility to coronavirus disease 2019 (COVID-19).
      • Cohen S
      • Doyle WJ
      • Skoner DP
      • Rabin BS
      • Gwaltney JM
      Social ties and susceptibility to the common cold.
      • Cohen S
      • Frank E
      • Doyle WJ
      • Skoner DP
      • Rabin BS
      • Gwaltney JM
      Types of stressors that increase susceptibility to the common cold in healthy adults.
      Because the identified factors amplified and attenuated risk across multiple respiratory viruses, it is likely that the social and psychological features affect the risk of COVID disease and its sequelae as well.
      Similarly, an extensive research has demonstrated that vaccine efficacy depends on both the vaccine and the vaccinated. Considerable evidence shows that stress, depression, loneliness, and poor health behaviors are associated with less robust immune responses to vaccination and that these effects are pronounced among elderly subjects. Psychological factors have also been demonstrated to alter the prevalence and severity of vaccine-related side effects.
      • Madison AA
      • Shrout MR
      • Renna ME
      • Kiecolt-Glaser JK
      Psychological and behavioral predictors of vaccine efficacy: considerations for COVID-19.
      ,
      • Glaser R
      • Kiecolt-Glaser JK
      Stress-induced immune dysfunction: implications for health.
      These findings are particularly apposite for COVID-19 in which individual-level stress has been such a feature of the pandemic. A belief that underlies many of the theories accounting for long COVID is that the disease is caused by an improperly regulated immune process. Ample evidence suggests, however, that regulation of the immune system in respiratory illness and vaccine responsiveness is also linked to psychosocial factors. Let's listen to how our patients tell their stories.

      Our Patients’ Stories

      Here are two stories from among a collection of patients with long COVID that describe the experience in patients’ own words.

      Long Covid Support. Long covid is mentally and physically very painful. It kicks back very hard if you misjudge it. Available at:https://www.longcovid.org/stories/long-covid-is-mentally-and-physically-very-painful-it-kicks-back-very-hard-if-you-misjudge-it. Accessed January 12, 2022.

      EW, 22, mental health nurse:“I . . . have largely worked throughout the pandemic, including direct care to COVID-positive patients. I got offered a COVID antibody test in June which came back positive. Then in July . . . I became very unwell quite suddenly. From going to work one week to being unable to leave my bed in crippling pain the next. . . . Nobody is taking me seriously. . . . I find it so hard that I gave my all during the first wave of the pandemic, risking my own health, and that of my family, to now have all doors closed on me when I need it the most.”
      SH, 46:“I caught COVID in early April while isolating in a lockdown bubble with my husband and teenage daughter. The COVID descent was swift and dramatic over the next few weeks. COVID was bedded in and rampaging in battle with my immune system with my body simply the passive bystander . . . continued on for weeks and weeks, peaking as a stable of symptoms with a hefty side order of pain every 5-7 days. . . . The fatigue was and is unlike anything I have ever experienced and has become a grim memento of those early months that still dictates my days. . . . My COVID morphed into Long COVID without any bump in recovery. . . . Long COVID is mentally and physically very painful.”
      The richness of these stories has not yet succeeded in changing the way we approach research into long COVID. Consider this comment from a long COVID researcher at the National Institutes of Health: “The thing that has struck me most now in a year and a half of seeing these patients and extensively testing them is that we are finding little to no abnormalities. Echocardiogram, pulmonary function tests, X-rays, brain MRIs. You name it. Laboratory markers of organ dysfunction. We're not seeing any of that. And precious little evidence of immune activation, looking at just the sort of standard markers of inflammation. I'm running out of tests to do basically.”

      Stein R. New clues to the biology of long covid are starting to emerge. Available at: https://www.npr.org/sections/health-shots/2021/11/12/1053509795/long-covid-causes-treatment-clues. Accessed January 12, 2022.

      This investigator acknowledges that other mechanisms may be at work. For instance, he notes that his team is conducting psychological testing on their study's subjects, though not because he doubts their symptoms. “It's 100% real. These people have these symptoms. Absolutely. The question is what's causing them. Anxiety can produce real symptoms.”

      Stein R. New clues to the biology of long covid are starting to emerge. Available at: https://www.npr.org/sections/health-shots/2021/11/12/1053509795/long-covid-causes-treatment-clues. Accessed January 12, 2022.

      Anxiety can produce real symptoms. Overwhelming research evidence also documents that anxiety, often a manifestation of stress, contributes to the pathogenesis of disease. The pathways through which anxiety and stress lead to disease include the example of allostatic load described previously, but also includes biographical interactions with the microbiome, epigenetics, and triggers of the immune system, as in flares of asthma or inflammatory bowel disease. (Fuller descriptions of how biography contributes broadly to disease pathogenesis have recently been published.
      • Horwitz RI
      • Singer B
      • Hayes-Conroy A
      • et al.
      Biosocial pathogenesis.
      ,
      • Horwitz RI
      • Lobitz G
      • Mawn M
      Biosocial medicine: biology, biography, and the tailored care of the patient.
      )
      Both patients highlighted their different illness profiles. In each, pain and fatigue dominate their stories. Reading many accounts of illness available online reinforces the heterogeneity of patient experience, while also reinforcing the point that the typical clinical history fails to capture what our patients feel. Even a cursory review of the stories makes it clear that research on long COVID cannot rely on widely spaced and periodic data collection because the pace of the disease is so rapid in many patients; and the usual psychometric tools we use to measure symptom status misses both the pattern and the meaning of the illness in patients.

      The Socialization of Medical Research

      The “socialization” of medical research is occurring but slowly, as the social and contextual features of a person's life, their biography, becomes integrated in studies of both biological risk for disease and treatment response. Long COVID is an opportunity to accelerate this process by designing studies that collect more data than simply immunological measures of disease, clinical symptoms, and the sociodemographic features of age, sex, race, and ethnicity. The National Academy of Medicine proposed 12 domains of information that broaden the data we obtain in our research by including financial resource strain, stress, depression, social isolation, and intimate partner violence, among others.
      • Prather AA
      • Gottlieb LM
      • Giuse NB
      National academy of medicine social and behavioral measures: associations with self-reported health.
      But even these are insufficient. We need a more inclusive set of features that include measures of work, love, meaning in life, and other crucial aspects of a life fully experienced.
      • Horwitz RI
      • Lobitz G
      • Mawn M
      Rethinking Table 1.
      Patient stories are a crucial part of the relevant medical biography. These stories should be captured in the patient's own words, and they should describe their experience as fully as possible. Embedded in these stories may be clues to illness origins as well as information that will guide our best efforts at treatment. Previously, it was fair to ask whether we could make sense of detailed narratives that created unavoidable challenges in analysis. Advances in computational science provide new tools for analysis using natural language processing that measure word frequency, recurring themes, and taxonomies to detect regularities in patient stories. Patients should be encouraged to tell their story as they experienced it with all of the affect and emotion that is evident in stories now appearing sporadically on various websites.
      We should also consider including patient stories, in their own words, as part of the patient history. These stories could be recorded and transcribed into the medical record at the time of initial patient contact with the physician. Over time, and as trust builds between doctor and patient, the patient narrative can be continually updated and parallel the updated biological and laboratory data. Not all patients will wish to add their stories in this way, and none should be required to do so.
      We need to emphasize that we cannot expect the personal details of a patient's medical biography without the trust that is foundational in the doctor patient relationship and that Arthur Kleinman has described as an ethical gift exchange.
      • Kleinman A
      Caregiving as moral experience.
      The physician provides the patient the moral gift of dedicated caregiving made concrete by the laying on of hands, empathic listening to the patient illness narrative, and moral partnership through a sustained presence with the patient throughout their illness. In return, the patient receiving this moral based care shares their story and trust as a gift to the physician. If the patient's story is to be recorded in the medical record, it must be accorded the dignity of “presence” and the responsibility to use the information in care and research consistent with the patient's informed consent.

      Socialization of Medical Practice

      Medical practice may prove more resistant to socialization than research. We make this observation from our experience as either clinicians (RIH, IS, MRC, MM, KC) or social scientists who work intimately with clinicians (BHS, AHC). Physicians are often aware of the social context of their patients’ lives, even without a systematic approach to collecting biographical information. But many physicians are necessarily pragmatic problem solvers. If time with a patient is short, or if evidence is lacking that collecting biography will affect treatment, physicians understandably focus on solvable problems.
      We know, however, that biography cannot be ignored in COVID or long COVID. Some health care workers, or teachers, or bus drivers, have no choice but to work despite the risks. Some of our patients are confused by conflicting recommendations from authorities or are distrustful of recommendations from people they do not know. Some are under stress and their judgment under stress may be impaired by circumstances. In each of these instances, medical practice and the trusting role of the physician can make a difference by empowering our patients to act in ways that mitigate their risk for COVID and long COVID and improve both their health and the health of the public.

      Conclusion

      The insights we now lack into the origins, progression, and persistence of long COVID will not come from understanding biology alone. Now is the time to end the two separate cultures of medicine that separate our science from our patients. Over the past two decades, biological science has leveraged new insights from genomics, proteomics, metabolomics, and the microbiome to enable a rich personalized medicine that emphasizes individual biological difference. Over this same period, advances in social sciences and the explosion of knowledge about social determinants of health has created the opportunity to emphasize individual biographical difference and to seize on this opportunity to fully integrate biology and biography in disease risk and treatment response. Insights from an analysis of patient stories can be linked to biology to create an integrated biosocial understanding of the disease. Just as stress and isolation made subjects more likely to become infected with respiratory viruses and less likely to develop an immune response to vaccines, biographical factors may be contributing to the risk of long COVID. We will not know unless we approach the science as one culture and not two.

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