Randomized, double-blind, placebo-controlled study (with a one-week washout period) where subjects receive either 3 months of tetracycline or 3 months of placebo. After the 3 month primary endpoint, in the follow-up period, patients will be assigned to the alternate treatment for 3 months with blind maintained.

There is precedent for the use of tetracycline class antibiotics as an anti-inflammatory agent in chronic illnesses including dermatologic and rheumatologic illnesses. The 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis (RA) includes long-term therapy with tetracycline in its treatment recommendations. This class of antibiotics has known anti-inflammatory effect in addition to its antimicrobial properties. Tetracyclines, in particular minocycline, have been associated with a significant improvement in disease activity in RA with no increased risk of adverse effects.

To date, no clinical trials have examined the benefit of extended duration; i.e. >4 weeks tetracycline therapy in PTLD. Concerns over side effects and the development of antibiotic-resistance and superinfections such as Clostridioides difficile have limited the use of long-term antibiotics, including tetracycline. There is a large body of literature on tetracycline and other drugs in this class regarding the drugs' anti-inflammatory properties and potential benefit in several non-infectious diseases such cerebrovascular disease, rheumatoid arthritis, and rosacea.

The investigators believe that this deserves further study. Initially, the investigators propose this pilot study to examine the feasibility and tolerability of tetracycline treatment in PTLD Secondarily, the investigators propose to assess preliminary data on the efficacy of 3 months duration tetracycline treatment in reducing PTLD symptoms at (1) the end of the three-month treatment period, and (2) rate of change during the 1st 3 months of treatment.

Lastly, as an exploration, the investigators will explore in the follow-up period the return of symptoms after the completion of the 3 month tetracycline and the effect of 3 months of tetracycline in the placebo arm.

The investigators hypothesize that a tetracycline study over a 4 year interval will be feasible to conduct and tolerable to patients. Secondarily, the investigators hypothesize that 3 months of tetracycline treatment will be associated with greater improvements in fatigue, symptom burden and functional impact than placebo. This research is important because the long-term sequelae of LD are debilitating to patients and costly to society.

Inclusion Criteria:

• ≥ 18 to 80 years of age
• Meet criteria operationalized from the Infectious Diseases Society of America (IDSA) case definition for PTLD (ref) previously treated with at least one recommended course of antibiotic therapy.
• Have persistent symptoms in at least the last month. "Currently have at least one symptom attributed to Lyme disease that a) you've experienced in the past month and b) limits your daily functioning at least half the time when its present"
• Fatigue Severity Scale survey score of at least 4.0 signifying moderate or greater severity of fatigue.
• Medical Records documented history of definite or probable Lyme disease with onset starts in the last 5 years, with symptoms developing within 1 year of Lyme onset.

Definite LD. Medical record documented history of erythema migrans or medical record documented history of a Lyme disease compatible neurologic, cardiac or musculoskeletal manifestation of Lyme disease with a confirmatory 2-tier serology, modified 2-tier serologic test, or immunoglobulin G (IgG) western blot and a lack of alternative diagnosis Probable LD. Medical record documented history of Lyme disease with atypical or nonspecific manifestations with a confirmatory 2-tier serology, modified 2-tier serologic test, or IgG western blot and a lack of alternative diagnosis.

Exclusion Criteria:

• Medications:

No antibiotics in the prior 2 months No change in medications during the prior 4 months that might have an impact on primary and secondary outcome measures. See list. No immunosuppressive medications No medications that interact with tetracycline: atovaquone, retinoid medications taken by mouth (such as acitretin, isotretinoin), strontium, digoxin, kaolin pectin, warfarin Use of prescription or over the counter (OTC) medications containing calcium (i.e. Tums)

• History of the following conditions predating the diagnosis of Lyme disease: Myalgic encephalomyelitis/chronic fatigue syndrome Fibromyalgia Autoimmune disease

• Major psychiatric conditions Bipolar disorder, delusional disorder, schizophrenia Major depression Suicidal ideation with intent during the prior 6 months
• History of the following conditions in the last 4 months Alcohol or substance abuse Cancer (other than skin) Untreated HIV/AIDS Untreated moderate to severe sleep apnea Hepatitis A, B or C Pregnancy or intent to become pregnant Breastfeeding
• BMI greater than 40
• Other conditions at the discretion of the clinician