Inflammatory Markers 101: How To Interpret

Inflammation is a necessary and crucial response in an acute setting. However, what happens when inflammation lingers and becomes systemic in nature? Chronic inflammation can increase our risk for a wide range of diseases, including diabetes, cancer, autoimmune and cardiovascular disease. More than 50% of all deaths are estimated to be related to inflammatory conditions. In order to be proactive about disease prevention, it is important to test for signs of inflammation regularly. Here we discuss some familiar yet novel lab markers to assess for inflammation.

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What are Inflammatory Markers?

Blood tests that can measure inflammation levels in the body are known as inflammatory markers. In order to monitor inflammation in a clinically useful way, these lab tests must be valid and prognostic. It is important to note that inflammatory markers are not diagnostic and must be interpreted alongside symptoms and other lab tests and imaging. Examples of inflammatory markers include:

• C-Reactive Protein (CRP)
• Erythrocyte Sedimentation Rate (ESR or sed rate )
• Neutrophil-to-Lymphocyte Ratio (NLR)

When Should You Run Inflammatory Markers?

When the body is presented with an acute threat (bacteria, viruses, toxins, trauma, etc.), it is normal for the body to have a temporary increase in inflammatory activity. This activity is characterized by the upregulation of immune and non-immune cells that help defend the body against the threat or invader. However, it is now well-recognized that there can be chronic (or persistent) low-grade systemic inflammation in the absence of an infection or threat. Inflammation in the absence of an infection is also known as sterile inflammation. This chronic inflammation can be perpetuated by a variety of social, environmental, psychological, and lifestyle factors (i.e., air pollution, a diet rich in processed foods, or stress).

Chronic inflammation plays a major role in disease progression, so when should you test inflammatory markers? In the past 15 years, routine testing of inflammatory markers has become more common in a primary care setting. Inflammatory markers can be useful in the following conditions:

• Autoimmune conditions
• Diabetes
• Hypertension
• Obesity
• Arthritis
• Pain
• Cancer

Inflammatory markers can aid in the diagnosis of these conditions and also help monitor the progression. If you have been diagnosed with one of the conditions listed above and have recently started a treatment plan (medications, supplements, exercise, nutrition), inflammatory markers can also help track how well that treatment is working.

Inflammatory Markers 101

CRP

C-Reactive Protein (CRP) is a protein manufactured by the liver in the presence of inflammation. CRP can be a predictor of cardiovascular events and, therefore, can be used for risk stratification in this population.

What Does it Mean if CRP is High?

Elevated levels of CRP can be seen in acute or chronic infection, cardiovascular disease, autoimmune conditions, and cancers. A normal value is usually less than 3mg/L. However, some inflammatory conditions can reach above 100 mg/L. In the setting of type 2 diabetes, an elevated CRP can be associated with all-cause mortality. If CRP is elevated, your doctor should be doing a root-cause analysis to evaluate where the inflammation is coming from. For example, if you are experiencing hip pain and have an elevated CRP, you may need imaging to assess for inflammatory arthritis, synovitis, or a fracture.

ESR

Erythrocyte sedimentation rate (ESR or sed rate) is a test that looks at how quickly red blood cells (RBCs) settle to the bottom of a test tube. More inflammation in the body results in the RBCs clumping together, causing them to sink to the bottom faster.

What does it Mean if ESR is High?

The normal range of ESR varies amongst gender and labs, but typically a normal result is less than 20mm/hr. Elevated ESR can be seen in infection, cancer, thyroid conditions, and autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). ESR can be falsely elevated in pregnancy, menses, and exercise and, therefore, should be utilized alongside other diagnostic workups (labs, imaging, history taking.)

Neutrophil-to-Lymphocyte (NLR) Ratio

Many of you will be familiar with a blood test known as Complete Blood Count (or CBC). This routine blood test helps clinicians screen for anemia, infection, and some blood cancers. A CBC gives us an overview of our white blood cells and can also give us a breakdown of the five different types of white blood cells: neutrophils, lymphocytes, basophils, eosinophils, and monocytes. This simple, affordable test can be used to assess inflammation as well. The neutrophil-to-lymphocyte ratio (NLR) can be used as a marker to assess chronic inflammation. This ratio is calculated by dividing the neutrophil count by the lymphocyte count. The reason that we hone in on neutrophils and lymphocytes here is that neutrophils are an indicator of acute inflammation (innate immunity), while lymphocytes reflect a more chronic inflammation (adaptive immunity). The ratio between these two types of immune cells illuminates the balance within the immune system response. This can be especially useful in the context of autoimmunity and cancer.

What does it mean if NLR is High?

NLR is being widely used across many medical disciplines to assess inflammation and act as a prognostic marker. A normal NLR is between 1-2. Some studies suggest that the normal range is from 1-3. However, an NLR between 2-3 can serve as a warning sign for low inflammatory stress that can become chronic in nature. Table 1 highlights the range of NLR and the associated inflammatory levels.

Calculation of NLR

NLR = Absolute or % neutrophil count / Absolute or % lymphocyte count

In the context of cancer, a meta-analysis of 100 studies comprising 40,559 patients with solid tumors showed that a high NLR (NLR >4) was associated with adverse overall survival. It is established that inflammation is one of the hallmarks of cancer, and this simple biomarker can reflect the inflammatory response in the tumor microenvironment. One explanation for this is that neutrophils are known to secrete tumor growth-promoting factors and suppress the activity of immune cells such as lymphocytes and natural killer cells.

NLR can also be used to assess how well a treatment is working. Cancer patients routinely have a CBC run to screen for anemia and neutropenia during active treatment. Therefore, it is very accessible to monitor NLR in this patient population. Monitoring NLR throughout treatment may help the medical team decide to continue or stop treatment and spare unnecessary toxicity.

NLR can also be helpful outside of the oncology setting - it can be used in acute pancreatitis, cardiovascular disease, sepsis, and even COVID-19.

Integrative Medicine Treatment for Patients With High Inflammatory Markers

Diet and lifestyle can have a powerful influence on inflammation. It is key to figure out the root cause of inflammation prior to implementing the suggestions below. If there is a trigger for inflammation (pollution, food, stress, disease), this should be managed before trying to decrease inflammation naturally. Always consult with a doctor to ensure the therapies below are safe and appropriate.

• Decreasing processed foods: many processed foods contain additives that can increase inflammation in the body
• Exercise! Movement and exercise on a regular basis can improve mood and decrease inflammation.
• Green tea: green tea contains antioxidants known as polyphenols that can help reduce CRP levels.
• Fish oil: daily supplementation of omega-3 fatty acids (around 3,000mg) can affect both CRP and NLR.
• Tai chi and mindfulness: mind-body therapies can impact inflammatory and metabolic pathways.

Summary

Testing for inflammation can be helpful when diagnosing autoimmune conditions, cancer, and diabetes. We highlighted three different inflammatory markers here–CRP, ESR, and NLR. NLR is a low-cost and accessible option to assess systemic chronic inflammation. Many clinicians order CBCs routinely, and these tests cost, on average, $23 when not covered by insurance. This allows both clinicians and patients to start assessing for signs of inflammation on a regular basis.