Part 2: The New Great Imitator: Lyme Disease

Home (Main Menu)

Current serologic tests are inadequate

Longer courses of treatment with higher doses of antibiotics lead to a better outcome

Confidence in Lyme serologies when positive

Diagnostic effectiveness of the antibiotic trial

Ways to minimize problems with Lyme antibiotic trials

REFERENCES

The Chronic Fatigue and Immune Dysfunction Syndrome Chronicle

Physicians' Forum, Fall 1993

Antibiotic-Responsive Chronic Fatigue and Immune Dysfunction Syndrome or Seronegative Lyme Disease?

By Dana Wiseman, MD, Glastonbury, Connecticut

I have experienced some success in offering my Chronic Fatigue and Immune Dysfunction Syndrome patients a trial of antibiotics as if they had Lyme disease, although their Lyme serologies are negative. My practice is located in central Connecticut, so virtually all of my patients live in Lyme endemic areas. (Ed. Note-Since this report was written, it has been learned that the Lyme spirochete is present in ... 48 States.)

Risk factors for Lyme Disease exposure include: 1) time spent in highly endemic areas, especially with inadequate attention to protective clothing, insect repellents and tick checks; 2) pets allowed to go freely in and out of doors; and 3) having a household member or pet with Lyme Disease.

As more is learned about Lyme Disease some of the original "truths" have been reduced to myths. The erythema migrans rash once thought to be present in 80 percent of cases, and the most reliable indicator of early Lyme Disease, may be present in only 50-60 percent of cases.1,2

Because the rash is asymptomatic and may be located in an area which is not easily visible, this valuable finding may be missed by the patient, and never brought to the physician's attention.

Ticks do not need to be attached for days in order to transmit the disease, but actually can do so in less than 24 hours, especially if improperly removed. Squeezing the body of the tick during a removal attempt can actually force the bacteria out of the tick and into the host.

Top -- Home

Current serologic tests, even the best available ELISAs (enzyme-linked immunoabsorbent assays) and western blots, are inadequate and underdiagnose the disease (false negatives).

Seronegativity has been seen at various times in the course of infection and treatment. The ELISA and Western Blot tests measure free antibody to Borrelia burgdorferi, the spirochete bacterium responsible for Lyme Disease, but cannot measure antibody bound to antigen.

There is a lag phase (window period of apparent seronegativity) that can last up to six weeks between the time the host is infected and the time the antibody response is sufficient to result in a positive blood test.3

If treated with antibiotics early in the course of the infection, such as within the first week, the entire antibody response may be aborted and a positive blood test may never develop.4

Once treated with antibiotics after serologies have been positive (even in inadequate dosages which can cause a chronic, persistent infection), subsequent assays are sometimes negative, which leads to a false sense of security.

Lyme antibodies which are secured to their antigens in immune complexes have been seen in cases of seronegative, active Lyme Disease.2 There is currently no laboratory test that proves that a person has been cured from Lyme Disease.

NINE REASONS FOR FALSE NEGATIVE LYME DISEASE BLOOD TESTS

The Lyme Disease Foundation (LDF), in their brochure entitled "LDF Frequently Asked Questions About Lyme Disease" lists the following nine reasons for false negative Lyme disease test results.

1. Antibodies against Bb are present, but the laboratory is unable to detect them. [Borrelia burgdorferi (Bb) is the Lyme disease bacteria.]

2. Antibodies against Bb may NOT be present in detectable levels in a patient with Lyme disease because the patient is currently on, or has recently taken, antibiotics. The antibacterial effect of antibiotics can reduce the body's production of antibodies.

3. Antibodies against Bb may NOT be present in detectable levels in a patient with Lyme disease because the patient is currently on or has previously taken anti-inflammatory steroidal drugs These can suppress a person's immune system, thus reducing or preventing an antibody response.

4. Antibodies against Bb may NOT be present in detectable levels in a patient with Lyme disease because the patient's antibodies may be bound with the bacteria with not enough free antibodies available for testing.

[For this reason, some of the worst cases of Lyme disease test negative -- too much bacteria for the immune system to handle.]

5. Antibodies against Bb may NOT be present in detectable levels in a patient with Lyme disease because the patient could be immunosuppressed for a number of other reasons, and the immune system is not reacting to the bacteria.

6. Antibodies against Bb may NOT be present in detectable levels in a patient with Lyme disease because the bacteria has changed its makeup (antigenic shift) limiting recognition by the patient's immune system.

7. Antibodies against Bb may NOT be present in detectable levels in a patient with Lyme disease because the patient's immune response has not been stimulated to produce antibodies, i.e., the blood test is taken too soon after the tick-bite (8-6 weeks).

Please do not interpret this statement as implying that you should wait for a positive test to begin treatment.

8. Antibodies against Bb may NOT be present in detectable levels in a patient with Lyme disease because the laboratory has raised its cutoff too high.

9. Antibodies against Bb may NOT be present in detectable levels in a patient with Lyme disease because the patient is reacting to the Lyme bacteria, but is not producing the "right" bands to be considered positive.

Lyme Disease Foundation
1 Financial Plaza
Hartford, CT 06103
(860)525-2000
fax (860)525-TICK
Lyme Disease National Hotline (800)886-LYME
mailto:lymefnd@aol.com

Top -- Home

It is becoming clearer that longer courses of treatment with higher doses of antibiotics lead to a better outcome.5 Paradoxically, even though the organism is relatively rapid to spread systemically and into the nervous system, it is slow to multiply.6

It is this slow reproductive rate that makes the organism less susceptible to short-term antibiotic therapy, and like tuberculosis, it is more successfully treated with antibiotics given over many months of treatment.7,8

Taking the analogy with tuberculosis one step further, some physicians are using antibiotic combinations, rather than single agent therapy.9,10,11 Even in early Lyme Disease, when antibiotic treatment is most effective, longer courses with higher doses of antibiotics have been advocated.12

Indeed, anyone with prior Lyme Disease who now meets criteria for Chronic Fatigue and Immune Dysfunction Syndrome should be presumed to have persistent Lyme Disease and offered a new course of antibiotics, especially if originally treated for fewer than three weeks with either oral or intravenous antibiotics.

It is exceedingly hard to differentiate Chronic Fatigue and Immune Dysfunction Syndrome from Lyme Disease on the basis of medical history. Being in a Lyme endemic area is obviously important as are the other risk factors mentioned above.

Top -- Home

In general, Chronic Fatigue and Immune Dysfunction Syndrome patients experience a more muscular pain (myalgia), while Lyme pain is felt more in the joints (arthralgia), but there is considerable overlap and fibromyalgia syndrome has been described in both.13

True "Lyme arthritis" with red and swollen joints, although more diagnostic, is not as common as arthralgia.8 Knee pain, especially when diffuse, intermittent and associated with inactivity, and which improves rapidly after walking, seems to be highly suggestive of Lyme Disease. Other joints that get stiff and painful, even with inactivity, and are suggestive of Lyme Disease, include the hips, elbows, shoulders and fingers. As in Chronic Fatigue and Immune Dysfunction Syndrome, the pain in Lyme Disease is often migratory and asymmetric.

I have found laboratory testing to be no more helpful than personal history in differentiating Lyme Disease from Chronic Fatigue and Immune Dysfunction Syndrome. Sedimentation rates, cortisol levels and red blood cell magnesium levels have not been helpful to me.

I do have confidence in Lyme serologies when positive because the lab I use is nationally-respected in the field of Lyme testing.14 Although few of the tests that I order return positive, I do not believe I am seeing false positive results, as they correlate with the ones I would have predicted on clinical grounds and because I also do syphillis screening with each Lyme test and Western Blots on all positive ELISAs.

This confidence in positive assays is in agreement with J.J. Burrascano and in contrast to A.C. Steere, who believes that false positive Lyme tests are more common than false negatives and that the disease is overdiagnosed.15,16

Perhaps the new 2-5A synthetase and R-Nase L enzyme activity assays will prove useful in differentiating viral from antibiotic responsive diseases. These enzymes are elevated with interferon activation in Chronic Fatigue and Immune Dysfunction Syndrome, and therefore are markers for a viral etiology.

Top -- Home

DISCRIMINATING BETWEEN CHRONIC FATIGUE AND IMMUNE DYSFUNCTION SYNDROME AND LYME

A currently available and cost-effective way to discriminate between bacterial illness, such as Lyme Disease, and viral illness, as Chronic Fatigue and Immune Dysfunction Syndrome is suspected to be, is the antibiotic trial. It not only has diagnostic value, but can be therapeutic as well.

In Lyme Disease, as in syphilis, patients on antibiotics will usually have Jarisch-Herxheimer reactions; one would not expect these in a viral illness. A Herxheimer, or die-off, reaction is a worsening of symptoms that occurs when spirochete antigens are released and cause immune activation.

This immune activation is similar to the proposed mechanism for symptoms in Chronic Fatigue and Immune Dysfunction Syndrome. These symptoms include: headache, body pain, sweating, insomnia, fever, confusion; in short, a flare-up of earlier symptoms. Herxheimer reactions usually appear in the first week of taking oral antibiotics and within the first three days on intravenous antibiotics.17

They can occur for many weeks and return at any time as more organisms are killed, usually with an escalation or a change in therapy. Often, a similar phenomenon of symptom flare-up occurs every fourth week, when large numbers of organisms are dividing and therefore susceptible to the destructive action of antibiotics.17

Again, it is the release of spirochete antigens responsible for the symptom flare-up. Withholding antibiotics for two days will reduce the intensity of Herxheimer symptoms, and may be especially necessary during the fourth week of treatment.

The appearance of the Herxheimer reaction is cause for optimism, because it indicates that the organism is antibiotic-responsive and therefore drugs are available to treat the syndrome.

No drugs are currently available to cure viral Chronic Fatigue and Immune Dysfunction Syndrome. Because the Herxheimer reaction has been viewed as a necessary evil to be endured in order to rid the body of Lyme Disease, the process has been likened to an exorcism.18

I have offered antibiotic trials to over 100 patients presenting with Chronic Fatigue and Immune Dysfunction Syndrome and negative Lyme serologies. Although there were no control groups for comparison, their responses have been of three types with the third group representing nearly half:

1. No Herxheimer or other response to antibiotics given over 1 to 2 months. These patients were presumed to have a viral infection an antibiotics were stopped.

2. Apparent Herxheimer reactions, usually mild, for 1 to 2 months, but without any improvement in symptoms. In these cases, antibiotics were continued for 4 to 6 months, then discontinued when it was apparent health status had not improved.

Attempts to terminate antibiotics prior to the four month mark led to a slight relapse in some cases, so they were restarted, but no relapses occurred if antibiotics were stopped after the six month mark.

These patients were presumed to have a mixed infection. Broad spectrum antibiotics cleared the bacterial superinfection, leaving the primary viral infection.

3. Longer and more severe Herxheimer reactions with progressive improvement to a near fully-functional level. Continued medium-dose, prophylactic antibiotics helped to ensure continued success. I observed some relapses with overactivity, inadequate rest, or life stresses, but with rest and an increase in antibiotic dosages, remission followed promptly. These patients were presumed to have seronegative Lyme Disease, or a similar antibiotic-responsive illness as their primary infection.

It is undetermined whether patients in this third category have seronegative Lyme Disease, a related spirochete infection or an unrelated bacterial illness. If the patient has a past history of Lyme Disease, as evidenced by a prior positive serology, culture or documented erythema migrans, then the current illness is likely to be Lyme Disease, rather than a new illness, such as Chronic Fatigue and Immune Dysfunction Syndrome.

If Lyme serologies have always been negative and there is no history of erythema migrans, then either this patient is not infected with Borrelia burgdorferi, or the antibody response has been attenuated such that no free antibody exists. In either case we could aptly describe this disease as antibiotic responsive Chronic Fatigue and Immune Dysfunction Syndrome. If a reliable antigen detection test showed evidence of Borrelia burgdorferi, however, then a diagnosis of seronegative Lyme Disease should be entertained.

Many persons with Chronic Fatigue and Immune Dysfunction Syndrome believe that antibiotics are harmful to them and should be avoided at all costs. Clearly, high doses of antibiotics, as are needed for a Lyme trial, can lead to diarrhea and yeast overgrowth, yet these are the only untoward side effects commonly encountered. I have heard persons with Chronic Fatigue and Immune Dysfunction Syndrome say that antibiotics will worsen their symptoms.

Since one quarter of my patients had no effect whatsoever from high doses of single agent antibiotics, there is no rationale to universally avoid them. Instead, I would argue that patients who feel worse from antibiotics are having Herxheimer reactions, and this is a reason to continue, not stop them.

Top -- Home

Finally, I would like to suggest ways to minimize problems with Lyme antibiotic trials. Patients should stagger doses of acidophilus or primadophilus between their antibiotic doses to limit yeast overgrowth.

In the event of persistent vaginal yeast infection, thrush or increased intestinal gas and diarrhea, nystatin tablets or powder may be added four times daily. Alternatively, one can use ketoconazole (Nizoral), fluconazole (Diflucan) or itraconazole (Sporanox) tablets, but these are expensive and potentially hepatotoxic.

With persistent diarrhea, stools should be checked for Clostridium difficile toxin.

Initial drugs of choice are doxycycline and amoxicillin because of their lower cost. Doxycycline should be avoided in children and pregnant women, and patients taking it should be cautioned to avoid prolonged sun exposure.

RESPONSE TO ANTIBIOTICS:

Often do well on antibiotics if given concurrently with acidophilus or primadophilus, even at the higher "Lyme" dosages. May contribute to overgrowth of candida necessitating antifungal medication. If symptoms intensify on antibiotics consider the Jarisch-Herxheimer reaction and a longer antibiotic trial.

Jarisch-Herxheimer reaction often within 10 days on oral antibiotics, and much more rapid and pronounced on IV antibiotics. Symptoms are a worsening of the pretreatment ones, especially fatigue, headaches, pains and sweats. Improvement may take weeks. Relapse is common when antibiotics are discontinued.

When risk factors exist for Lyme Disease, and the clinical picture fits, a diagnostic trial of antibiotics is warranted regardless of Lyme serology status. A Herxheimer response to high dose oral antibiotics is suggestive of Lyme disease, and warrants continued aggressive antibiotic therapy.

ANTIBIOTIC TRIAL:

Doxycycline 100 mg po tid

Amoxicillin 1000 mg po tid with Probenecid 500 mg po tid

Amoxicillin 1000 mg po q6 hr

When at a plateau, replace the above with Zithromax or Biaxin, or combine any of the above regimens with one of the following:

Biaxin 500 mg 2-3 times a day

Zithromax 250 mg 1 tab a day, may alternate with 2 tabs

Erythromycin 1-2 grams a day in divided doses

Bactrim DS bid

Suprax 400 mg bid

Ceftin 500 mg bid

LIMITING YEAST OVERGROWTH:

In order to limit yeast overgrowth with antibiotic trials, give acidophilus or primadophilus 2 tabs bid between antibiotic doses. A two-drug antibiotic regimen may require antifungal therapy with Nystatin 500,000 units qid, Sporonox 100 mg 1-2 times a day or Diflucan 100 mg a day in addition to lactobacillus supplementation.

[In Lyme disease] patients on antibiotics will usually have Jarisch-Herxheimer reactions; one would not expect these in a viral illness. A Herxheimer, or die-off, reaction is a worsening of symptoms that occurs when spirochete antigens are released and cause immune activation.

This immune activation is similar to the proposed mechanism for symptoms in Chronic Fatigue and Immune Dysfunction Syndrome. ... The appearance of the Herxheimer reaction is cause for optimism, because it indicates that the organism is antibiotic-responsive and therefore drugs are available to treat the syndrome ~

Ticks do not need to be attached for days in order to transmit the disease, but actually can do so in less than 24 hours, especially if improperly removed. Squeezing the body of the tick during a removal attempt can actually force the bacteria out of the tick and into the host.

Top -- Home

REFERENCES

1. Rahn DW, Malawista SE: Lyme disease: Recommendations for diagnosis and treatment. Ann Int Med 1991;114:473.

2. Schutzer SE, Coyle PK, et al.: Sequestration of antibody to Borrelia burgdorferi in immune complexes in seronegative Lyme disease. Lancet 1990;335:312-5.

3. Schutzer, SE: Diagnosing lyme disease. Amer Fam Phys 1992; 45:2151-56.

4. Dattwyler RJ, Volkman DJ, et al.: Seronegative lyme disease: dissociation of specific T-and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med 1988; 319:1441-6.

5. Lavoie PE: Lyme disease. Conn's Current Therapy 1991;101-06.

6. Garcia-Monco JC, Villar BF, et al.: Borrelia burgdorferi in the central nervous system: experimental and clinical evidence for early invasion. J Infect Dis 1990;161:1187-93.

7. Personal communication: Sam Donta MD, 1993.

8. Personal communication: Paul Lavoie MD, 1993.

9. Personal communication: John Drulle MD, 1993.

10. Gasser R, Dusleag J: Oral treatment of late borreliosis with roxithromycin plus co-trimoxazole. Lancet 1990;336:1189-90.

11. Bozsik BP, Timmer M, et al.: Combined antibiotic treatment of lyme borreliosis. Fifth International Lyme Disease Conference 1992;Abstract 67.

12. Burrascano J: Diagnostic hints and treatment guidelines for lyme disease. Sixth edition, 1992.

13. Dinerman H, Steere AC: Lyme disease associated with fibromyalgia. Ann Int Med 1992;117:281-285.

14. Bakken LL, Case KL, et al.: Performance of 45 laboratories participating in a proficiency testing program for lyme disease serology. JAMA 1992;268:891-95.

15. Burrascano J: Managing lyme disease. Diagnostic hints and treatment guidelines for Lyme borreliosis. Eighth edition, 1993. (Ed Note- Twelfth edition, 1998 now available)

16. Steere AC, Taylor E, et al.: The overdiagnosis of Lyme disease. JAMA 1993;269:1812-1816.

17. Personal communication: Joseph Burrascano, 1993.

18. Personal communication: Thomas Forschner, MBA, CPA. 1993.

Special thanks to Martina Ziska, MD, Karen Vanderhoof-Forschner and Thomas Forschner of the Lyme Disease Foundation, Inc. for their help in researching references and to Martina Ziska, MD and Amy P. Wiseman for their help with editing.

Bug War -- Top -- Home -- What's New