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:

Chronic Cases

Well, doesn’t this sound familiar: “Post-treatment Lyme disease syndrome” and “Post-COVID syndrome” (long haulers). If someone presents to you with a persisting multisystem illness, you may be faced with the clinical dilemma of deciding whether they have a chronic active TBD or the sequelae of a previous COVID-19 infection. And there is always the possibility that they may have both!

Symptoms common to both:

• Fatigue, headache, arthralgias, myalgias, cognitive deficits, sleep difficulties, palpitations, rapid pulse
• Sweats, chills, shortness of breath, cough, dizziness
• Conjunctivitis, GI upset, anxiety, depression

Note how I grouped these. The first set of symptoms are commonly associated with Borrelia infections, the second set with Babesiosis, and the third, Bartonella! In other words, just because someone has fatigue, shortness of breath with cough, plus GI complaints, don’t automatically conclude that COVID-19 is the cause.

Physical and lab findings can also be confusing. Here are some signs that can be common to both, but keep in mind that these may not be present in every patient:

• Fever
• False positive Anti-Nuclear Antibody
• False positive Rheumatoid Factor
• Anti-phospholipid antibodies
• Activated cytokines
• Abnormal brain scans (MRI, SPECT)
• Possible cardiac and pericardial involvement

So how does one differentiate late TBDs from late COVID-19? Again, some clues:

Chronic Lyme

• Prior history of Lyme or tick exposure
• Symptoms are migratory and cyclic—this is key
• Positive or suggestive tests for TBDs

Chronic COVID-19

• History of prior COVID-19
• Symptoms do not migrate or cycle
• End-organ damage—renal failure, hypoxia, intravascular clots. These are not generally seen as a result of TBDs.

However, a big issue is that the patient could have both! In other words, what if your patient who has had their run of TBDs and is doing well, then gets COVID-19, and now feels chronically unwell. It is possible that the physical stress on the body from this nasty virus could have allowed the TBDs to reactivate. Additionally, a component of the post-COVID syndrome can be active as well. It is our duty to be thorough in our assessment of this situation to best serve our patients.

Clinical Evaluation

Because immune dysfunction is common in this situation, a simple assessment is a reasonable starting point. Measure immunoglobulin levels (reflection of B-cell function) and a T-cell response assay (or skin anergy panel).

When testing for chronic tick-borne diseases, it is wise to use both indirect and direct tests. For example, if there is an immunoglobulin deficiency, then direct tests such as PCR and FISH may be more sensitive than serologies. By utilizing both techniques, the chance for a clinically useful result improves. When doing serologies, look for positive IgM reactivity and favor using an immunoblot for Borrelia. You may also add a T-cell response assay (ELISPOT) for a more complete picture. In addition to the direct tests (PCR and FISH), you may also add an antigen capture assay (urine and/or CSF) to maximize yield.

Next, test for the SARS CoV-2 virus and for the specific damage associated with COVID-19 that would be rare in a Lyme patient. Do a COVID-19 serology (immunoblot preferred) and an ELISPOT (T-cell response assay); consider PCR but be aware of the possibility of false positives. To check for the type of end-organ damage that makes you think of COVID-19, measure arterial oxygen level, check for scarring and fibrosis on a chest x-ray, check renal function, ferritin, etc. Also consider a pulmonary stress test because a good pulse-ox reading at rest will not help you find oxygen desaturation with activity, as is common with structural lung injuries.

Also strongly consider doing a cardiac MRI. Shockingly, at least 40% of symptomatic COVID-19 patients have varying levels of myocarditis show up on this type of scan. Cardiac MRIs can show active inflammation, edema, and scarring as well as give an accurate assessment of focal and global muscle function.

Summary

• A careful clinical history can help differentiate TBDs from COVID-19.
• Be aware of the high incidence of tick-borne co-infections! If you do not test fully, then you might miss an important pathogen.
• COVID-19 serology is important; immunoblotting is preferred to decrease false positives and false negatives; ELISPOT is now available and should be used.
• SARS CoV-2 PCR may not pick up a late infection.
• Test for conditions specific to either one to differentiate them.
• Strongly consider a cardiac MRI.
• Don’t exclude the possibility that your patient may have both!

What Happens When Your Lyme Patient Gets Exposed to COVID-19?

We know that chronic TBDs are associated with depressed immunity, so there is a valid concern for worse COVID-19 and reduced vaccine response in this population. However, there is a paradox—most patients with active Lyme seem to resist getting common colds! In fact, despite the evidence of immune impairment, there does NOT seem to be an increased susceptibility to other infections except the co-infections. So, will the same be true for resistance to COVID-19?

Well, there is good news. Many of the antibiotics used in Lyme are also antiviral—tetracyclines, macrolides and azoles. Most treatments for Babesia are antiviral—those that are based on quinine or artemesia, plus the macrolides that commonly accompany them. Azole antifungals are also antiviral, and many complementary treatments used in Lyme are antiviral and/or help the immune system. Are these antiviral qualities enough to work against SARS COV-2? Possibly. In fact, informal surveys of several Lyme-literate physicians all support the finding that COVID-19 is less common in their Lyme patients! And if they do become infected with COVID-19, their course tends to be milder.

However, most LLMDs will prescribe antivirals for these patients: hydroxychloroquine or ivermectin, plus zinc, vitamins C and D, herbal remedies, supportive measures and others.

Nevertheless, the usual COVID-19 risk factors still apply, so one must be on alert for these high-risk patients—advanced age, concurrent hypertension, diabetes, obesity, clinical immune deficiency (this is possible in very advanced Lyme), and those who may be on immune suppressive treatments.

COVID-19 in Lyme Suggestions

If your Lyme patient is on treatment and gets exposed to COVID-19, I suggest that you avoid inducing strong Herxheimers as these may weaken the host and increase the cytokine response. You may need to back off Lyme treatment a little.

Regarding supportive measures, as many of you know, I prefer to use supplements and supplement brands that are pharmaceutical grade and especially those that have been validated in published trials. This is not the time or place for unproven generics!

When supplementing, begin with broad mitochondrial support. This is vital for a healthy immune system. ATP 360 from Researched Nutritionals is what I use. Vitamins C and D and zinc are absolutely essential. Melatonin in high dose, magnesium and n-acetyl cysteine all may help to dampen the cytokine storm. Herbal anti-inflammatories such as quercetin, resveratrol, green tea, sulforaphane, etc. can be added if needed; what I have used for this is CytoQuel from Researched Nutritionals—sound formula, and its benefits have been documented in published studies. Consider artemesia as well as alpha lipoic acid for their multiple potential benefits. Glutathione may be added for detox and for antioxidant support (Tri-Fortify from Researched Nutritionals—again, published). In chronic Lyme patients especially, consider using transfer factors and medicinal mushrooms to take advantage of their ability to support NK cell function; Transfer Factor Multi-Immune from Researched Nutritionals has shown impressive results in trials. Finally, aspirin can be extremely useful due to its anti-platelet effects; it may also be antiviral.

Emphasize the benefits of a healthy diet, enforced rest and adequate sleep, and also realize that between the illnesses, lockdowns, isolation and fears, emotional support becomes vital- fears and anxieties can impair immunity and besides, who wants to be miserable? So be liberal in suggesting counseling, meditation, exercise, etc. and anything else that can help improve one’s outlook in these difficult times.

Should My TBD Patient Get the COVID-19 Vaccine?

In light of all of the above, a valid question to pose is, should a patient who has TBDs get one of the COVID-19 vaccines? After all, patients with intact immunity generally do have reactions to the vaccine, especially after the second dose, and strong reactions reportedly occur in 30%. These can consist of fever, chills, weakness, fatigue, head and body aches and injection site soreness. It has been observed that TBD patients who are currently symptomatic may react more strongly to the vaccine and in theory, could even get ADE (“antibody-dependent enhancement”)—a cytokine storm from stimulating an already activated immune system. Before we can answer this, we first have to consider the properties of the individual vaccines for COVID-19:

• mRNA vaccines induce host cells to directly create spike proteins, a process that occurs in the cytoplasm, similar to a natural SARS CoV-2 infection.
• Human adenovirus with coronavirus sequences added: these are genetically modified DNA viruses engineered to induce host cells to create spike proteins. This process begins in the cell nucleus and then moves to the cytoplasm. Adenovirsuses used to vector this include adenovirus type 5 and 26. Problem is, if we have immunity to these adenoviruses then our defenses can deactivate the vaccine before it gets a chance to work. This is especially a concern with the two-dose regimens many of these require—second dose may not be as protective as hoped.
• Chimpanzee adenovirus—same mechanism as above. A chimpanzee adenovirus was chosen because of the low likelihood that humans have immunity to this and therefore our defenses are less likely to deactivate the vaccine.
• Attenuated SARS CoV-2 coronavirus: these are made from the intact virus that has been deactivated, so immunity can develop without causing an infection in the process
• Peptide vaccine: here, the method is to insert SARS CoV-2 genes into a virus that then infects arthropod cells (a moth!!) which then produce spike-forming proteins. These proteins are assembled into spikes and are injected along with an adjuvant.

The vaccine table (below/Table 1) is for general reference.

Table 1. COVID-19 Vaccines. Note the statistics on efficacy are not comparable among individual vaccine types because the way efficacy is measured is not standardized.

Antibody-Dependent Enhancement (ADE)

ADE is a cytokine storm induced by an extreme immune reaction to antigens, and this is more likely to occur if the patient had been previously sensitized to these antigens.

Mechanism of ADE in COVID-19. With infection, neutralizing and non-neutralizing antibodies form. Neutralizing antibodies inhibit the infection and prevent the spike protein from binding to the ACE-2 receptor, thereby halting the spread of the infection. The non-neutralizing antibodies do not inhibit the spike protein, and when complexed with viral antigen will bind to macrophage receptors and allow viral entry independent of ACE-2 receptors. The macrophages activate and initiate an inflammatory cascade, and the uninhibited viral entry allows it to propagate. It has been proposed that an excess of non-neutralizing antibodies is what is responsible for ADE to occur (theory, not proven).

Can COVID-19 vaccines cause ADE? If the vaccine has predominantly spike protein as the antigen, then it is unlikely that ADE will result (mRNA vaccines and the adenovirus-vectored ones). However, vaccines made from whole, attenuated coronaviruses may be more of a risk because there are antigens in addition to the spike that we may react to. Vaccines that contain adjuvants are a theoretical concern because adjuvants are nonspecific, non-neutralizing immune stimulants.

Because some propose that previous exposure to this or a similar antigen can cause immune overstimulation, then ADE after vaccination may be more likely if there was a significant coronavirus infection in the past. This is why I and others advocate antibody and/or ELISPOT testing for the virus before giving the injection. The risk of ADE may also be increased after the second dose of vaccine or if exposed to SARS CoV-2 within 10-14 days after vaccination. All of this is conjecture only; there has not been enough experience with any of these vaccines to know if these are real risks.

TBD Patients and COVID-19 Vaccination Recommendations

• Consider testing for SARS CoV-2 antibodies by immunoblot and T-cell responsiveness by ELISPOT prior to vaccination to uncover past infection that may have been missed. If immunity is present, then defer the vaccine and retest in four to six weeks.
• Always try to prepare your patient prior to vaccination by initiating and then continuing all the needed supportive measures.
• Do not vaccinate during a TBD symptom flare—likewise may have to hold TBD treatment well before vaccination to calm a Herxheimer.
• mRNA vaccines may be safer than whole-coronavirus vaccines
• With couples, stagger vaccination schedules
• Avoid immunosuppression as it may weaken vaccine-induced immunity
• If there is a strong reaction to the first dose, then you may elect to postpone the second dose and then follow SARS CoV-2 immunity to judge if and when to give the second dose.

Conclusions

Many of us are now dealing with two complex conditions—TBDs and COVID-19. They may be difficult to differentiate in certain circumstances and both pose challenges for patient management. Now, however, better testing for TBDs and for SARS CoV-2 can be extremely helpful in guiding our patient management.

COVID-19 vaccination, while beneficial, can be difficult to tolerate in the TBD patient and require careful management pre- and post-dose. However, the risk of a short-lived vaccine reaction may far outweigh the risk of a full-blown COVID-19 infection in these patients. If the vaccine reaction was strong, one can only imagine what the real thing could be like. Finally, I urge everyone to keep track of their data and share it so we all can learn from each other.

Please stay safe!