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Top Three Differential Diagnoses For Lyme Disease: How Testing Can Help

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Top Three Differential Diagnoses For Lyme Disease: How Testing Can Help

Lyme disease can be tricky to diagnose, a challenge that becomes even more pressing when considering that the incidence of Lyme disease in the United States has nearly doubled since 1991, from 3.74 reported cases per 100,000 people to 7.21 reported cases. The disease's symptoms often mimic less severe conditions, further complicating the diagnostic process. Additionally, Lyme disease shares overlapping symptoms with several other conditions, making differentiation an important part of the diagnosis. 

In this article, we will discuss the complexities of diagnosing Lyme disease, explore its common symptoms and stages, look at differential diagnoses to consider, and examine the functional medicine labs that can aid in a more accurate and timely diagnosis.


What is Lyme Disease?

Lyme disease is a complex condition transmitted by infected black-legged ticks carrying the Borrelia burgdorferi bacteria. Initial symptoms often mimic the flu, including a distinct circular rash near the tick bite. As the disease progresses, it can lead to more severe issues like multiple rashes, swollen lymph nodes, and even specific nerve disorders.

Diagnosis can be difficult, especially since many don't remember being bitten by a tick. In regions where Lyme disease is common, healthcare providers may opt for immediate treatment based on symptoms alone to prevent further complications. Failure to treat early can result in advanced stages of the disease that may involve cardiac problems and joint issues (2,4). 

What Are The Common Symptoms of Lyme Disease?

Lyme disease is usually characterized by three stages of symptoms (4): 

Stage 1: Early Localized Disease

  • Occurs within a month of tick bite
  • Typical rash (erythema migrans) and low-grade fever
  • May include flu-like symptoms

Stage 2: Early Disseminated Disease

  • 3 to 12 weeks post-infection
  • Adds malaise, neurological and cardiac symptoms to stage 1 features
  • Joint issues resembling septic arthritis

Stage 3: Late Disseminated Disease

  • Can manifest months or years later
  • Includes arthritis, particularly in the knee
  • Neurological deficits and cognitive issues

It’s important to note that Lyme disease's symptom overlap makes it challenging to diagnose, requiring a high index of suspicion, especially in endemic areas.

How Does Someone Get Lyme Disease?

The primary mode of transmission for Lyme disease is through the bite of an infected black-legged tick. These ticks are often found in wooded and grassy areas, and they attach to the skin to feed on blood. When an infected tick latches onto a person for an extended period, usually more than 24 hours, it can transmit the Borrelia burgdorferi bacteria into the bloodstream, initiating the infection. It's important to note that not all black-legged ticks carry this bacteria and even those that do may not always transmit the disease. Consequently, tick bite prevention and prompt removal are vital steps in mitigating the risk of acquiring Lyme disease (2,4). 

Top Three Differential Diagnoses For Lyme Disease

Four of the most common diagnoses to consider when evaluating symptoms similar to Lyme disease may include:

Rheumatoid Arthritis

One differential diagnosis to consider is Rheumatoid Arthritis (RA), particularly in adults. In RA, symptoms like joint pain can mimic those of Lyme disease. However, RA commonly presents with features not typically seen in Lyme disease, such as morning stiffness and rheumatoid factor. 

Other Tick Borne-Infections

Human granulocytic anaplasmosis and Babesiosis are tick-borne illnesses that can either coexist with or mimic Lyme disease, especially in the northeastern and upper Midwest regions of the U.S., where these diseases are prevalent. Both are transmitted by the I. scapularis tick, similar to Lyme disease. Human granulocytic anaplasmosis is distinguished by elevated aminotransferase (ALT) levels and may show unique inclusion bodies in neutrophils during blood tests. On the other hand, Babesiosis is suspected when symptoms like hemolytic anemia and thrombocytopenia are observed, often confirmed through microscopic examination of blood smears to identify the parasites. 

Acute Rheumatic Fever

While less common, acute rheumatic fever can also mimic Lyme disease. This condition is usually considered in patients who present with migratory polyarthralgia and an abnormal heart rhythm indicated by an increased PR interval. However, unlike Lyme disease, acute rheumatic fever may show evidence of a preceding streptococcal infection.

Functional Medicine Labs to Help Rule In or Out Differential Diagnoses of Lyme Disease

Functional medicine labs can play a vital role in narrowing down the diagnosis when Lyme disease is suspected, particularly since its symptoms can overlap with other conditions. Here are some lab tests that could help in distinguishing Lyme disease from other potential diagnoses:

Tick-Borne Disease Panel 8 (TBD8)

The TBD8 panel is an all-encompassing diagnostic tool that screens for a multitude of tick-borne diseases, including Lyme disease, Tick-Borne Relapsing Fever, Bartonellosis, Babesiosis, Anaplasmosis (human granulocytic anaplasmosis), and Ehrlichiosis. One of its most advantageous features is its capacity to test for various conditions at once, thereby streamlining the diagnostic process. For example, if a patient presents with symptoms such as hemolytic anemia and thrombocytopenia, the panel can test for Babesiosis. Importantly, it also has the capability to identify or rule out human granulocytic anaplasmosis, as well as Lyme disease and other tick-borne illnesses with overlapping symptoms (2,4).

Rheumatoid Arthritis testing

Patients suspected of Rheumatoid Arthritis can take this test to rule out the disease. These markers are not typically elevated in Lyme disease, helping differentiate the two conditions.

CBC with Differential and Liver Panel

A Complete Blood Count with Differential (CBC w/ diff) and a hepatic panel can help to distinguish Lyme disease from other potential conditions. In addition to human granulocytic anaplasmosis, which typically shows elevated aminotransferase levels (ALT), leukopenia (low WBCs), and/or thrombocytopenia (low platelets), these tests can also assist in differentiating Babesiosis. Babesiosis often presents with hemolytic anemia and thrombocytopenia, which would appear on a CBC. On the other hand, Lyme disease usually does not influence these markers in the same way.

Anti-streptolysin O Titers

Acute Rheumatic Fever can be differentiated by elevated Anti-streptolysin O titers indicating a recent streptococcal infection, which is not a feature of Lyme disease.



In summary, diagnosing Lyme disease poses considerable challenges, especially given its rising incidence and overlapping symptoms with other conditions. The disease manifests in distinct stages and can resemble a variety of other illnesses, such as rheumatoid arthritis, human granulocytic anaplasmosis, and Babesiosis, further complicating its diagnosis. Functional medicine labs offer valuable tools like the Tick-Borne Disease Panel 8 to streamline the diagnostic process and rule out other potential conditions. Early diagnosis and treatment are key to managing Lyme disease effectively and preventing its progression to more severe stages involving cardiac and neurological issues.

The information provided is not intended to be a substitute for professional medical advice. Always consult with your doctor or other qualified healthcare provider before taking any dietary supplement or making any changes to your diet or exercise routine.
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Lab Tests in This Article

  1. Climate Change Indicators: Lyme Disease | US EPA. (2023, July 21). US EPA.
  2. A Functional Medicine Acute Lyme Disease Protocol: Testing, Diagnosing, and Treatment. (2023). Rupa Health. Retrieved September 25, 2023, from
  3. Building Natural Immunity During Flu Season. (2022). Rupa Health. Retrieved September 25, 2023, from
  4. Top Labs To Run Bi-Annually On Your Patients Who Suffer From Lyme Disease. (2023, September 19). Rupa Health.
  5. Bush, L. M., & Vazquez-Pertejo, M. T. (2023, August 29). Lyme Disease. Merck Manuals Professional Edition.
  6. Skar, G. L. (2023, May 31). Lyme Disease. StatPearls - NCBI Bookshelf.
  7. Integrative Approaches to the Testing and Treatment of Rheumatoid Arthritis: A Comprehensive Review. (n.d.). Retrieved September 25, 2023, from
  8. Acute Rheumatic Fever: Information For Clinicians | CDC. (n.d.).,infection%20involving%20multiple%20organ%20systems.
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