Thanks to Renaissance Philanthropy for their support of my research on this topic.
Why Prodromes?
A lot of chronic diseases, particularly autoimmune and neurodegenerative disorders, develop over the course of years, as the patient transitions from “healthy” to “sick”.
This may involve the loss of neurons (as in neurodegenerative diseases like Alzheimer’s or Parkinson’s) or the loss of other kinds of cells (like the insulin-producing cells of the pancreas in type 1 diabetes). Once cells and tissues are permanently damaged or lost, it can be difficult or even impossible to return to the pre-disease state. We may use drugs to treat symptoms (such as insulin in diabetes, to substitute for the insulin the pancreas isn’t producing, or L-dopa in Parkinson’s, to substitute for the dopamine the brain isn’t producing) but true recovery from the disease isn’t tractable.
On the other hand, we might have a better chance of discovering effective treatments if we start earlier.
Often, chronic diseases have a “presymptomatic”, “preclinical”, or “prodromal” stage, when it’s too early to diagnose the full disease, but the patient may have some mild symptoms, or there may be lab findings characteristic of developing disease.
We’re already used to this in conditions like cancer (where it’s routine to operate on precancerous growths of the skin, bowel, or cervix) or heart disease (where it’s routine to give cholesterol-lowering medications based on lab findings alone, before the patient has reported any symptoms.)
Preventative therapy is even beginning to be used in some new diseases, like type 1 diabetes. T1D is an autoimmune disease that destroys the islet cells of the pancreas, and preclinical T1D can be detected by the presence of certain autoantibodies that direct the patient’s immune system to attack their own pancreas. In 2022, the first T1D-preventing drug, teplizumab, was FDA-approved for patients who have diabetes autoantibodies and abnormal blood sugar but no symptoms yet.
Prodromes and Biomarkers
What does it look like to have pre-Parkinson’s? Pre-multiple sclerosis? Pre-rheumatoid arthritis?
In many cases we don’t have a standard definition of a prodromal or preclinical phase of disease, we just know that there are certain symptoms and findings that are more likely to occur in people who go on to get a disease diagnosis.
And for pretty much all chronic diseases, we don’t have a complete mechanistic picture of how they arise and what “levers” we might have to intervene preventatively.
So one thing that can be useful is to track people who have not yet been diagnosed with disease, and measure various biomarkers, ideally at different time intervals, to see if there are key markers that predict who will get the disease.
For instance, a 2022 study on more than 20 million US military servicemembers found that the risk of developing multiple sclerosis (MS) is 32 times higher in individuals who’ve been infected with the Epstein-Barr virus (EBV).1 This is suggestive of a viral cause of the chronic disease, one of many chronic neurological disorders that have been hypothesized to have infectious origins.
Currently, MS is incurable. But if it’s caused by EBV2, then we might be able to prevent it by targeting the EBV virus or the immune response to it.
Longitudinal biobanks, like the UK Biobank or the DOD Serum Repository, are extremely valuable resources in discovering new biomarkers of disease prodromes. These institutions store biological samples (like blood, serum, cerebrospinal fluid, or others) from many individuals, often sampled several times from each individual. They also contain detailed medical records. So it becomes possible to look at samples from everyone who went on to get a disease diagnosis, years before they were diagnosed, and see how they compare to samples from demographically matched controls.
In other words, with biobanks, we can search for the proteomic, genomic, immunological, or infectious signature of prodromal/presymptomatic disease.
While these are observational rather than experimental studies, and thus can’t determine causality, the biomarkers they discover can be of great practical value. A good biomarker can allow early disease detection (or risk prediction). Biomarkers can suggest potential prevention strategies, though of course there’s no guarantee any given strategy will work.3 And biomarkers can also be measures of disease progression or severity, such that you can track the effectiveness of a treatment by how much it affects the biomarker. Though again, this doesn’t always work.4
Convergent Research, in its recent “Gap-Map” list of open problems in science and technology, noted in several places the need for large longitudinal studies of biomarkers potentially related to developing chronic disease:
“Longitudinal Multi-Omic Immune Profiling Across Populations”
“Large-Scale Profiling of Infection to Expose Links to Neurodegeneration”
“Multi-Disease Efficacy Testing with Standardized Biomarkers”
It may be that the only hope of intervening on many chronic, progressive diseases is preventative. In cases where we don’t yet know how to do that, we need to start studying what’s starting to get weird about the human body before a diagnosis of an incurable disease.
Below the paywall: my lit review about specific diseases and their prodromal/presymptomatic stages.