Innovations in the lab could revolutionize the diagnosis and treatment of chronic inflammatory conditions.
By Jim Poggi
A mosquito, a bee and a tick go into a bar. The bartender asks, “Can I get you a drink?” The mosquito replies, “Nope. Just here for a bite.”
We’re all familiar with insect bites and the obvious inflammation they cause. But how familiar are we with the broad and growing range of clinical conditions that are associated with inflammation that is NOT obvious?
Today, the information I’m proposing is just supposition, but much of it is based upon our evolving understanding of several clinical conditions.
Is the evidence there yet to prove that inflammation underlies an increasing number of clinical conditions? No. But many associated findings of inflammation linkages to chronic disease states are being uncovered.
Do we know if some seemingly unrelated clinical problems share the same inflammatory cause? No. But we are investigating and learning rapidly.
Let’s explore this dreamscape together, remembering that medical science advances sometimes happen slowly and over time, and sometimes advances are the result of a rapid unforeseen breakthrough. Antibiotics, X-ray technology and automation of lab testing were all advances in medical technology that would have seemed impossible just a few years before they became mainstream and changed the practice of medicine forever.
Our understanding of infectious diseases
To start with, consider the development of understanding of infectious diseases and initial screening tests to uncover them. Throughout most of human history, there was no way to understand the role of infectious agents in disease and consequently no way to diagnose them or prevent their spread. While there are writings as early as the sixth century BC proposing “seeds of disease,” these findings were not widely understood and there was no way to bridge between the academic theories of the cause of the disease to effective early diagnosis and treatment. Over the centuries, plagues came and went, resulting in serious health threats to humanity. But, until the germ theory of disease became widely accepted in the 18th century, the fact that multiple diseases were related to infectious agents such as bacteria and viruses was not mainstream medical science.
Even once the germ theory took hold and the cause of infectious diseases was apparent, there was no way to screen for infected individuals as well as carriers of disease. From the bubonic plague to Ebola, SARS and most recently COVID, infectious agents have severely impacted the health of millions with death rates ranging from 30% to over 90%.
From a lab perspective, early diagnosis of diseases, particularly tuberculosis and others caused by infectious agents, has been considered a cornerstone of rapid effective management of the patient, and a key factor in slowing or preventing the contagious agent from spreading. Fast forward to modern times and there is a substantial number of effective screening tests for infectious diseases we sell daily, including group A strep, influenza and COVID to name some of the most important ones. COVID tests went from the R&D stage to fully developed antigen, antibody and molecular tests for the RNA of the virus in a matter of months, due to the pressing need for rapid diagnosis.
At the same time, complete blood counts (CBC) provide a fast, accurate way to assess an infection and can differentiate viral versus bacterial infections. New CBC markers including monocyte distribution width and immature granulocytes provide more specific information, but more work is needed here as well. So, it is true that we now have a firm grip on how to develop tests for infectious agents.
But, most infectious agents cause acute illness, and, as we know, most of the leading causes of morbidity and mortality are due to chronic diseases, where an initial inflammatory process MAY be an underlying cause or at least a key associative factor. Other than COVID and influenza, the ten leading causes of morbidity and mortality are dominated by chronic illnesses. Where are we in the process of associating inflammatory processes with chronic diseases today? Still in the exploratory phase as I see it.
Two key tests that uncover inflammation early include erythrocyte sedimentation rate (ESR) and C- reactive protein (CRP). ESR was first used in the late 19th century but became widely adopted in the 1920s as a way to measure the disease outcome of tuberculosis by Dr. Alf Westergren. While the specific mechanism of action behind the difference in red blood cell sedimentation was largely unknown, it rapidly became clear that the rate of sedimentation correlated with the presence and severity of an inflammatory process. Increased sedimentation rates are indicative of inflammation and are still used today as an initial screening test for inflammation and an indication of an infection. However, like many non-specific biological markers, ESR has its limits. Advanced age, pregnancy, kidney and thyroid issues unrelated to an underlying infection can also cause an increase in sedimentation rate. So, while ESR has been around for quite some time and points to a general inflammatory process, it lacks the specificity to point to the location and nature of the inflammation and what is needed to cure it.
This takes us to C-reactive protein (CRP). CRP was initially discovered in the 1930s and its association to the inflammatory process was more clearly established than ESR. The cascade of immune system responses to a foreign agent (real or perceived due to an autoimmune reaction) begins with identification of the agent by the immune system and secretion of various proteins and messenger substances by white blood cells. CRP is secreted in response to these chemical messengers and eventually results in synthesis of substances that remove the foreign substance, reducing inflammation and preventing a wide scale infection.
It is important to know that CRP is secreted in response to both acute and chronic sources of inflammation. However, CRP assays by their very nature are similar to ESR in that while sensitive, they are not specific. Even the newer high sensitivity CRP assays improve sensitivity resulting in an earlier indication of an inflammation but do not improve its specificity and cannot identify precisely what is wrong and what to do about it.
Identifying triggers
Yes, I’ve thrown quite a bit more lab science at us this month. What’s the point? As I see it, there is an increasing body of knowledge that inflammation is at least associated with several chronic diseases. Inflammation is associated with such seemingly unrelated medical conditions as dental plaque, atherosclerosis, arthritis, type 2 diabetes, multiple sclerosis, and others. Inflammation persists at a relatively low level, just enough to create small and seemingly insignificant increases in CRP and ESR. So what’s the problem? The problem is the persistence of the inflammatory process and the likelihood that its persistence causes unrecognized progression of the disease.
As a result, these chronic diseases and their associated inflammation remain resident long enough to create more significant disease progression and comorbidities. As lab diagnosis has advanced over the years, giving us new tumor marker assays, next generation sequencing, cell free DNA analysis and others, we still lack inflammation assays SPECIFIC enough to clearly point out the root cause. If we can eventually learn the root cause, which is likely to identify the specific trigger in the immune system and what is causing it, we should be able to find ways to deactivate the trigger through pharmaceutical agents.
Recent examples of progress in this area include medicines for arthritis and psoriasis that selectively switch off parts of the immune system and then reduce the inflammatory process, reducing the disease progression itself. I see some of the next generation of lab tests as being developed to have the capability to identify these immune system triggers. As a specific side benefit, it is likely that we could then learn whether some of these disease processes are mediated by the same root cause, leading to more effective systemic medications to treat them.
Ultimately, I believe these advances in lab medicine could improve quality of life as well as longevity. We aren’t as far off from making substantial progress in this area as you may think. Keep an eye out for development in this area. If I am right, they are likely to make substantial improvements in diagnosis and treatment of chronic inflammatory conditions.
The tick turns to the bartender “I’m just itching to learn more about inflammation and chronic diseases. I think the three of us already know how it works in acute conditions. I think I DO need a drink. Can I get a ‘bloody appendage?’”