By Joseph Burrascano, Jr., MD

Those of us who have been immersed in the care of patients with chronic medical conditions, especially those associated with tick-borne diseases, are now confronting another illness that has both acute and chronic features—COVID-19. How do we approach our Lyme patients in the COVID-19 era? First, let’s go over some basics.

What Is Lyme Disease?

Today we have a broader definition of “Lyme disease.” We include the many common tick-borne pathogens and collectively refer to this entity as “tick-borne diseases” (TBDs)

• Borrelia: Lyme Borrelia and TBRF Borrelia
• Babesia species
• Bartonella: MANY species
• Rickettsia family: Ehrlichia, Anaplasma, RMSF, others
• Viruses
• Potentially many more…

These often coexist as co-infections. In a 2018 study at the IGeneX lab, over 10,000 patient samples were tabulated and it was found that 37.3% were positive for Babesia species, 32.1% for Lyme Borrelia, 27.7% for TBRF Borrelia, 19.1% for Bartonella, 16.7% for Anaplasma, 12.8% for Rickettsia, and 6.9% for Ehrlichia. Overall 40% had two concurrent infections, 15% had three, 4.6% had four and 0.7% had five! This is why well-informed clinicians insist upon using the newer, more broadly sensitive test methods in their evaluation of these patients.

Experimental and clinical data show that when present, co-infections can alter and blur the clinical presentation, making clinical diagnosis more difficult. Co-infections can worsen the negative impact that many of these pathogens have on the immune system; and to make matters worse, co-infected patients are more ill and are more difficult to treat.

Lyme-induced immune impairment is a well-known phenomenon. This begins six to twelve months into the infection and affects all three cell types—B, T, and NK cells. Studies done by Claude Garon and colleagues at the NIH’s Rocky Mountain Lab have shown that Borrelia will impair their function and may even kill them. Clinicians have observed that this impairment has an earlier onset and is more severe if co-infected, especially Borrelia plus Babesia.

Lyme infections also activate the inflammatory cascade. In fact, nearly all the symptoms and signs associated with these infections are manifestations of this activation. It is more severe with later, more active infections, more severe when co-infected, and clearly more severe during Herxheimer reactions. Some of the more apparent signs that Lyme has weakened the immunity include low total WBC counts, low killer cell (NK-cell) counts, decreased immunoglobulin levels (B-cell impairment) and impaired T-cell reactivity. In addition, another marker for this is persistent disease that responds poorly to meds that should work.

What are the signs that Lyme has activated the cytokines? Seemingly everything! The malaise, fatigue, aches, cognitive impairment, neuropathy, arthritis…

What Is COVID-19?

COVID-19 is the disease caused by the coronavirus SARS CoV-2. This virus is highly contagious, but not everybody gets sick. Clinical COVID-19 infections may pass through several phases: there is the initial viral phase, consisting of nonspecific viral symptoms—mostly respiratory and sometimes gastrointestinal. In many, the illness does not seem to progress from there. However, this initial phase can be followed by a hyperimmune phase—a runaway immune over-reaction resulting in a “cytokine storm.” This is then followed by a collapse of T-cell function, which renders the patient susceptible to superinfections—bacterial and mycoplasmal pneumonia, for example. Could this same immune impairment reactivate latent infections with tick-borne pathogens? This is an interesting thought, which I will address shortly.

Severe infections with the SARS CoV-2 virus are also associated with significant arterial and venous blood clots, pulmonary fibrosis, and decreased oxygen carrying capacity, plus potentially serious effects on the heart, kidneys, brain; basically, no organ is spared when this infection goes rampant. In fact, these non-viral effects are what cause the severe morbidity and mortality.

Laboratory Testing for COVID-19

PCR: The well-known swab test for COVID-19 infection consists of an RT-PCR. In this setting, this test is not only highly insensitive, its sensitivity is also time-dependent. A recent article (Ann Intern Med. doi:10.7326/M20-1495; 13 May 2020) gave these surprising (or maybe not so surprising) results:

100% false negative on day 1 of infection

67% false negative on day 4 (the day before symptom onset)

38% false negative on day of symptom onset (day 5)

20% false negative on day 8

21% false negative on day 9

66% false negative on day 21

Their conclusion: “If clinical suspicion is high, infection should not be ruled out on the basis of RT-PCR alone”

Antibody Testing in COVID-19: Typically one week after symptom onset (or roughly two weeks after exposure), IgM appears and persists for six weeks on average. IgG usually appears one to two weeks after IgM and persists for at least four months but may decline earlier in the elderly. I say “typically” and “usually” because serial antibody studies in patients with confirmed infection, shockingly, showed that a not-insignificant number of them did not make detectable antibodies at all, and in some, the antibodies declined rapidly, while in others, IgG persisted for at least nine months.

False positives can occur, possibly because almost half of common colds are due to a mild coronavirus—could this be cross reactivity? Regarding the false negatives, because of the usual tradeoff between sensitivity and specificity, labs need to turn down test sensitivity to decrease these false positives, and false negatives are the result! Craziness.

However, immunoblotting may be the answer. Now offered by the IGeneX lab, studies have shown that this test is more sensitive and more specific, no doubt because it uses specific recombinant antigens. These recombinant antigens have been designed to identify reactivity to the spike proteins (S1, S2 and Receptor Binding Domain) and the Nucleocapsid protein. The result is increased sensitivity and less unwanted cross-reactivity with other coronaviruses. In addition, immunoblots offer the ability to distinguish natural vs mRNA vaccine-induced immunity in most cases. Based on the latest proficiency testing, the sensitivity of the immunoblot is 70% for IgM and 92% for IgG; specificity is 95% for IgM and 99% for IgG.

Nevertheless, there is still the mystery of the poor responders and non-responders—those who seemingly don’t make adequate amounts of antibody. It is known that some people develop T-cell-based immunity but fail to develop a B-cell response. Therefore, a possibly more important test is to measure T-cell responsiveness to the virus. An ELISPOT (T-cell response assay) is now available, also from IGeneX, for SARS CoV-2 and promises to be an important tool for us to use. When combined with serological results, it will provide a more complete picture of where someone stands from an immunological point of view. This should really help us not only in the aftermath of a natural infection, but it should be extremely useful to track immunity post-vaccine. One other advantage is that T-cell responsiveness appears before measurable serologic responses, so T-cell testing may replace the insensitive PCR swab in certain cases.

Early Lyme vs. Early COVID-19

Not unexpectedly, there already is a published report of a patient who presented with a “summer flu” and was told he had COVID-19. Long story short—he did not have COVID-19; he had Lyme. Superficially, this is not an unreasonable scenario, therefore don’t forget to consider tick bites in the differential diagnosis. Here are some clues:

Early TBDs	Early COVID-19
Arthropod bite—often is missed	Contagious—may not be aware of exposure
Early symptoms nonspecific: headache, fatigue, body aches.	Early symptoms nonspecific: headache, fatigue, body aches.
May develop a rash	If progresses, then anosmia, respiratory symptoms and fever; may get diarrhea
Without proper treatment it becomes musculoskeletal, CNS, PNS and cardiac; migratory and cyclic	May resolve, or may progress to acute cardiopulmonary disease with severe multiorgan involvement
Testing insensitive early in illness	PCR only sensitive during early symptomatic phase
Chronic sequelae possible	Chronic sequelae possible

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