by PAIREDProject | Jun 23, 2023 | Autonomics, Immune
This month our manuscript “Autonomic neuropathy as a predictor of morbidity and mortality in people living with HIV: a retrospective, longitudinal cohort study” was published in Neurology Clinical Practice. The title kind of says it all, we found that autonomic neuropathy seems to be making people with HIV sick. But what is autonomic neuropathy, why are people with HIV getting it, and how is it leading to poor health outcomes?
The story starts over ten years ago. Back then, as our team was first establishing a research program in NeuroHIV, we were reading and learning as much as we could about how HIV damaged peripheral nerves leading to sensory neuropathy and its symptoms of numbness, tingling and pain in the feet. We were especially fascinated by the work of Dr. Ahmet Hoke’s lab at Johns Hopkins which showed that an HIV protein, called gp-120, generated an inflammatory response that was toxic to nerves, and that the energy-producing mitochondria were also damaged in HIV-associated sensory neuropathy. If sensory nerves were under this multipronged attack, what was happening to autonomic nerves? Autonomic nerves are very similar structurally to sensory nerves, but since they control the function of internal organs, their malfunction can cause symptoms that often go undiagnosed since they don’t sound neurologic: racing pulse, dizziness, nausea, urinary and sexual dysfunction. And it’s not just symptoms to worry about, particularly in the heart, autonomic neuropathy can have very serious consequences. People with autonomic neuropathy due to diabetes have an increased risk of arrhythmias and sudden cardiac death.
We wanted to know if autonomic neuropathy was affecting people with HIV, so we designed a simple study. We recruited a “waiting room” sample from our primary care HIV clinic. Basically anyone who wanted to participate and could do so safely was included. We did tests for autonomic and sensory neuropathy and administered questionnaires to see if patients were experiencing symptoms. We made three important discoveries:
- Autonomic neuropathy was common overall, but especially in participants with sensory neuropathy in the feet.
- Lots of patients had the symptoms listed in the autonomic symptom questionnaire, regardless of whether or not they had autonomic neuropathy, so the symptoms weren’t helpful in establishing the diagnosis.
- Participants with autonomic neuropathy were more likely to have other medical conditions in addition to HIV.
The last finding interested us especially, because it likely meant one of two things. One possibility was that the co-existing medical conditions were an additional strain on the autonomic nerves which increased the likelihood of autonomic neuropathy. However, an alternative possibility was that the autonomic neuropathy was causing other medical conditions in people living with HIV by disrupting normal organ function. This latter idea was intriguing but wasn’t provable. At that time we only had data from a single time point, with no way of knowing whether autonomic neuropathy was the chicken or the egg. Assessing causality would take time. You’d have to wait and see if patients with autonomic neuropathy ended up with worse health outcomes than could be explained by their other medical illnesses alone. If so, it would suggest that the increased risk could be attributed to autonomic neuropathy.
So we waited, almost 10 years, and then we looked into our electronic health record to see how our study participants had been doing all that time. Fortunately, most were alive and well, many still seeing the same doctors. But not all. Some had left the health system and others had experienced deteriorating health. There are lots of ways to quantify overall health; we chose an outcome based on the landmark SMART study, which led to the current practice of using antiretroviral therapy continuously without treatment interruptions. The outcome (which continuous antiretroviral therapy helped to avoid in SMART) was the occurrence of any of the following: 1) death from any cause; 2) major cardiovascular event; 3) major cerebrovascular event; 4) major new kidney disease; 5) major new liver disease. We liked that this composite outcome was broad enough to capture a potential effect of autonomic neuropathy on multiple different organ systems.
Here is the main figure from our publication which came out this month in Neurology Clinical Practice:
It shows that even after accounting for baseline health status, people living with HIV and autonomic neuropathy (shown in the lighter grey) had about three times the risk of experiencing one of the poor health outcomes. This suggests that autonomic neuropathy may be a cause of significant organ dysfunction in many people living with HIV. This is clearly worrisome, and in order to develop strategies to prevent or reverse autonomic neuropathy and its adverse impact on the body, we must first understand the underlying mechanisms. This will be challenging but essential for fulfilling our PAIRED Project mission: “to make the best use of our unique skills as neurologists and neuroscience researchers to improve the health of the members of our surrounding communities, and to make the discoveries that will lead to even better health outcomes in the future.”
by PAIREDProject | Jun 9, 2023 | Clinical trials, Pain
By Jessica Robinson-Papp, MD MS
Every Thursday afternoon, I meet with my collaborator and friend, Dr. Monica Rivera Mindt. Dr. Monica Rivera Mindt. Dr. Rivera Mindt is a community engaged researcher who has spent decades living and working in the Harlem neighborhood of New York City focusing on brain health, specifically the mechanisms underlying racial and ethnic disparities in cognitive decline. Last week we got to talking about the different ways we have engaged with communities and how successful it has been in supporting many of our studies, particularly those focused on brain health. Today it’s the norm to include people with lived experience in the design, execution, and reporting of all kinds of clinical research. But like many things that we start to take for granted, if we don’t periodically stop to reflect on why we do something, we risk losing purpose and authenticity. Following our conversation, I wanted to remind myself of the fundamental reasons for community engagement in research. Why do we think it’s a good idea and what do we know about its effects on outcomes? I also wanted to think more specifically about community engagement in the context of pain research. So I indulged myself in little reading.
I found a comprehensive chapter on ResearchGate (published in 2008) describing the evolution of Community Based Participatory Research (CBPR) titled: “The theoretical, historical, and practice roots of CBPR,” by Bonnie Duran DrPH of the University of Washington in Seattle. Dr. Duran traces the history of CBPR back to the 1940s when the term “action research” was coined to describe a self-reflective and collaborative quality improvement method. She also draws a lineage to CBPR from the social justice movements of the 1960s and 1970s which sought to reduce inequities between researchers and study participants, including providing greater access to and control over study results and their dissemination. This historical context suggests that diverse stakeholders were originally included in research both for their unique insights and also for ethical reasons.
Many years later, patient-engaged research got a boost from the Affordable Care Act (aka Obamacare) which led to the establishment of the Patient-Centered Outcomes Research Institute (PCORI) in 2010. PCORI’s mission is to “fund research that helps people make better-informed healthcare decisions based on their needs and preferences.” As a funder of research, PCORI is unique in that it requires researchers to include patient input in their research process. This was still pretty novel at the time of PCORI’s founding; a Pubmed search of the term “patient engagement” shows a inflection point right around 2010 with increasing numbers of publications in years since. Requiring patient input for studies of healthcare delivery, such as those funded by PCORI, seem like common sense. If your goal is to help a group of patients make informed choices it seems obvious that you’d need to involve those very people in your study design. But it would still be nice to prove that patient engagement improves these studies. PCORI set out to do just that in an article published in 2019. Since all PCORI studies require patient engagement, a formal comparison of studies with and without patient engagement wasn’t possible. Instead, the authors reviewed 126 articles describing PCORI-funded research and performed a qualitative analysis of text pertaining to patient engagement. They concluded that “…findings suggest that engagement contributes to research that is better aligned with patients’ and clinicians’ needs.” This is encouraging, although a cynic might wonder about the likelihood of PCORI-funded researchers including negative statements about patient engagement in their publications.
So too in the field of pain research has patient engagement become a popular idea. The International Association for the Study of Pain (IASP) published a fact sheet on the topic last year. The Helping to End Addition Long Term (HEAL) initiative, the body within the National Institutes of Health (NIH) that funds pain research has also emphasized the importance of patient engagement. But does it really make sense to seek the patient perspective in all forms of pain research?
It feels slightly scandalous to suggest, but is it possible that patient engagement has gone too far, and that by extending it past its original purpose we are diluting its power? This question may be particularly relevant to tightly regulated areas of research, such as early drug development, in which study design may be mostly dictated by budgetary limitations and the requirements of regulatory bodies such as the Food and Drug Administration (FDA). The needs of patients must still guide such research, but what if the perspective of the clinician-scientist on these needs is enough? Clinicians interact extensively with patients absorbing their perspectives over hundreds and thousands of encounters. This is effectively qualitative research, albeit informal. The idea of the clinician as patient proxy is unpleasant, it sounds authoritative and paternalistic. But is the engagement of a handful of people with lived experience really likely to be less biased, or is it just something that’s become accepted as a “best practice” without strong rationale? If it’s the latter, we should be brave and acknowledge own our own expertise as clinician-scientists, while respecting the time and wisdom of community members by engaging with them only when their input really matters and when we can engage whole-heartedly.
It’s quite likely that there will never be strong quantitative evidence that patient engagement improves research. That doesn’t mean we shouldn’t do it, rather we should strive to engage patients in research areas where common sense and the historical origins of CBPR indicate it’s important, particularly research involving ethical and/or value-based decisions.
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