Synergistic epidemics: how and why diseases cluster

Syndemics attempts to explain how complex arrays of forces interact to create, exacerbate and perpetuate epidemics

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“How we think about disease pathologies affects how we design policies and deliver care to those most affected by social and economic inequities,” Assistant Professor Emily Mendenhall says.

According to the medical anthropologist, our traditional way of thinking about disease, in terms of comorbidities and multimorbidities, has missed the bigger picture, fleshed out in a series of articles in The Lancet last month.

The resulting conceptual framework explains how and why diseases cluster together – and the role social, political, environmental and economic factors have in exacerbating health problems. Synergistic epidemics, known as syndemics, are the result of these problems combining and amplifying each other to create an even greater disease burden.

In her Lancet article, Professor Mendenhall explains that the syndemic concept, coined in the 1990s, has three central features:

“Syndemics involve the clustering of two or more diseases within a population; the biological, social, and psychological interaction of those diseases; and the large-scale social forces that precipitate disease clustering in the first place.”

Looking at health problems through this lens helped explain why diseases seemed to cluster in groups of people who were disproportionately affected by poverty, social exclusion, gender-based violence, climate change, displacement arising from agricultural or industrial waste or pollution, and other forms of social and environmental stress, Professor Mendenhall said.

Take one case of a Mexican immigrant woman in the US misdiagnosed with psychosis, but who was, in fact, suffering from grief.

Her admission to a psychiatric hospital for the treatment of psychosis led to rapid weight gain from psychotropic medication, which itself led to diabetes. This woman’s experience is an example of VIDDA, one of the first syndemics studied in the US. VIDDA represents the interplay between violence, immigration, depression, diabetes and abuse among Mexican immigrant women.

“VIDDA reveals how being a woman and an immigrant or migrant leads to certain patterns of exposure to structural violence, immigration-related stress, and interpersonal abuse and marginalisation within the health system,” Professor Mendenhall explained.

Research into this specific constellation of factors revealed how poverty and subjugation influenced psychological distress and diabetes, she said.

“But, also, how internalised emotion, associated with past abuses and feelings of grief and longing for family displaced by migration and documentation, can influence illness.”

What’s the point? 

Professor Merrill Singer, the anthropologist who first coined the term in the 1990s, described syndemics as a constellation of factors contributing to the health crisis.

In its beginnings, syndemics focused on poor immigrant populations in high-income countries and more broadly in low- and middle-income countries. But proponents say there are lessons for healthcare across the spectrum.

“For multiple reasons –human rights reasons, public health reasons, reasons of health equity  – the protection of vulnerable people from syndemic suffering is both an urgent need and a fundamental matter of social justice,” the authors of the Lancet editorial.

On a policy level, this approach provides new ways of conceptualising tricky and hard-to-treat health problems.

But even for an individual clinician, familiarity with syndemics could help to understand the complex range of factors impacting on a patient’s health. “Applying a syndemic approach is novel and valuable for expanding the focus from why a patient has a poor outcome (eg, dysregulated blood sugar) to what other factors are contributing,” the authors said.

In their paper in this recent Lancet series, Professor Singer and colleagues noted the challenges for individual clinicians to provide such systematic care when faced with heavy workloads, limited time and funding.

Nevertheless, being aware of various syndemic interactions could help inform and improve history-taking, physical examination, diagnoses and treatment plans, he said. “Inattentiveness to comorbidity and disease interactions might diminish the effectiveness of disease-specific treatment,” Professor Singer said.

“Similarly, inattentiveness to social problems that affect diseases alone, and together with comorbid conditions, can exacerbate adverse health outcomes.”

For example, disease characteristics might look different in the context of a syndemic. A patient who was severely immunocompromised by a HIV infection might not test positive for hepatitis C coinfection on standard blood tests because their antibody response was not high enough to be detected, he said.

The protection of vulnerable people from syndemic suffering is both an urgent need and a fundamental matter of social justice.

And Professor Singer said patients with pulmonary tuberculosis and diabetes might also face barriers to diagnosis.

Having diabetes increases the risk of contracting active tuberculosis if exposed to the bacteria, and also increases the risk of latent tuberculosis activation compared to those without diabetes.  But patients with diabetes and pulmonary tuberculosis were also more likely to have atypical radiological features, raising the risks of misdiagnosis.

Where pulmonary tuberculosis was predominantly found in the upper lobes, patients with diabetes were more likely to present with lung lesions in the lower lung than the upper, Professor Singer said.

Research also suggested that patients presenting with lesions in the lower lung were more likely to be incorrectly diagnosed with lung abscesses, pneumonia or carcinoma.

According to Professor Mendenhall, looking at this problem from only a public-health perspective “would clearly overlook the diabetes-tuberculosis syndemic because they are viewed as having distinctly different origins and disease progression”.

The syndemic effect of depression and diabetes is also gaining recognition, and is a good example of the biological interactions between conditions.

In Australia, a patient with diabetes is more than twice as likely to develop depression compared with the general population, and the effect goes both ways.

Professor Mendenhall said the conditions shared a number of biological changes, including the activation of innate immunity which leads to an inflammatory response.

Depression and diabetes are both associated with dysfunction of the hypothalamic-pituitary-adrenal axis, which plays an important role in the regulation of metabolic function, and manifests as impaired glucocorticoid sensitivity and increased inflammation, among other problems.

But there are also shared behavioural patterns such as a high junk-food diet and minimal physical activity. Many antidepressants also added to weight gain, and the growing use of second-generation antipsychotics in people with depression was a potential problem given their ties to metabolic changes, she noted.

On the flip side, alleviating a patient’s depression through interventions such as cognitive behaviour therapy also improved glycaemic control in people with diabetes and reduced risk factors for those who did not have type 2 diabetes, Professor Mendenhall wrote.

On a population-level, it was also important to understand and be able to identify syndemics when they occurred, because not doing so made it more difficult and expensive to treat the problem, Professor Singer said.

One of the earliest identified syndemics was SAVA, which Professor Singer defined as the “set of closely intertwined and mutually enhancing epidemics” of substance abuse, violence and AIDS.

In low-income, inner-city communities, these factors did not occur in isolation or simply in parallel, he argued.

A multi-year research program into HIV risk among drug users found that socio-political and economic factors were powerful in creating the conditions where HIV and other epidemic and endemic conditions occurred. Tuberculosis, sexually transmitted infections, hepatitis, cirrhosis, infant mortality, drug abuse, suicide and homicide were closely tied to the spread of AIDS, the researchers found.

And these took place in the context of high rates of unemployment, poverty, homelessness, and overcrowding to substandard nutrition, infrastructural deterioration, disruption of social support networks, and social and ethnic inequalities. In some cases, it was the same behaviour that cause the various conditions, such as risky sexual behaviour and STIs or needle sharing and infectious diseases.

But the other, less obvious, ties came from behaviours that clustered together, Professor Singer and his colleagues explained.

The reason you would find tuberculosis and cirrhosis linked with STIs and HIV infection was due to the social marginalisation, stigmatisation and limited resources characterising these groups of patients, they said.

In a 2008 book on the significance of cultural perceptions, social representations, and biopolitics, medical anthropologist Professor Mark Nichter gave an example of how this interplay occured:

“(1) poverty leads to work migration far from home; (2) loneliness, the drudgery of the job, and being paid every few weeks lends itself to binge drinking and risky sex in an environment where prostitution flourishes; (3) this leads to sexually transmitted infections such as HIV; (4) rising rates of HIV lead to corresponding rising rates of TB [tuberculosis]; (5) poor adherence to TB medications occurs after a few months of home-based treatment (when symptoms abate) among patients who return to migrant labour far from medicine distribution sites; (6) poor management of those seeking treatment for HIV and TB leads to increases in drug-resistant TB; and so on.”

Principles of syndemics

As well as explaining the interactions between various diseases, syndemic theory aims to provide researchers and clinicians with a better explanation of the circumstances in which they interact.

Professor Mendenhall outlined some of the broad situations that can contribute to syndemic situations: “For example, socioeconomic factors such as poverty, migration, discrimination, exposure to chronic and acute trauma, including violence, and drivers of social and economic marginalisation are associated with mental health, diabetes, or both.

“Trade policies that promote big food corporations, and economic or social marginalisation processes that limit primary food staples to highly processed, high-sugar, high-carbohydrate diets, create an obesogenic environment that increases risk of obesity and diabetes when combined with livelihood factors that limit opportunities for physical activity.”

Then there was chronic exposure to interpersonal violence, which affected hypothalamic-pituitary-adrenal axis processes.

Research suggested cortisol production in response to stress, which was regulated by the hypothalamic-pituitary-adrenal axis, was blunted in people who had experienced interpersonal violence. Women in violent relationships also appeared to have low morning cortisol.

This dysregulation affected metabolism, food preferences, and protection from disease.

And if it occured during childhood, there was a greater chance of physical and mental health disorders, Professor Mendenhall wrote.

“Differential clustering of risk factors, from local food practices to exposure to violence, combined with variation in access to risk reduction and protective factors, will contribute to different syndemic emergence across settings,” she said.

As well as explaining the biological and circumstantial interplays underpinning health crises, syndemic theory also provides a strategy to tackle the issues. According to Professor Mendenhall, resources should be targeted to where the social and medical conditions interact, in order to offset the burden of that interaction.

Nevertheless, this kind of approach would butt heads with “international donor politics”, which prioritises one disease over another, she said.

For example, HIV funding in low-income populations has prioritised free HIV testing and treatment and left non-communicable diseases such as diabetes and depression marginalised.

Professor Mendenhall said this could derail strategies for improved community health and fracture primary healthcare delivery in these low-income populations.

Instead, looking at these health problems through a syndemic lens would mean clusters of diseases would need to be recognised as complex and contextually situated, she said.

But as appealing as the syndemic concept is, the evidence base supporting syndemic-style, multi-armed interventions is limited.

One of the articles in the Lancet series was a systematic analysis of the literature, which found methodological gaps and limited progress in the last two decades of research.

While the theory was largely a public health one, most of the research so far had been focused on individuals instead of populations, Professor Alexander Tsai, psychiatrist at Massachusetts General Hospital, said.

He and his colleagues pointed out that while syndemic theory was often used to justify calls for broad, all-encompassing interventions, the concepts of disease interaction and mutually caused epidemics hadn’t been well established.

So far, the methodology of most research has been to explore the sum of the effect of each disease individually, meaning that interventions targeted against one aspect may be as, or more, cost-effective than a large, multifaceted one.

Regardless, a syndemics approach provides insights into the complex array of forces creating and perpetuating disease epidemics, and provides opportunities to act politically or socially to offset the damage.

As the authors of the Lancet editorial wrote, “In the pursuit of practising more socially conscious medicine, syndemics suggest that context is key.”