Lyme disease is rapidly spreading and there has been a 320% increase in the number of US counties affected with Lyme disease within the past 20 years [1
], with another recent threefold increase in the number of vector-borne disease cases [2
]. Among the almost 650,000 vector-borne reported cases during a 12-year period, over 491,000 were tick-borne and over 150,000 were mosquito-borne [3
]. According to prior National Institutes of Health (NIH) studies, those patients with symptoms of chronic Lyme disease, both diagnosed and undiagnosed, are extremely ill [4
] and many are disabled and unable to work [5
Nearly one out of two adults in the United States during the past decade have been found to suffer from at least one chronic condition [6
], with estimates of US disability rates ranging from 13–19% [7
]. Some of these disabling symptoms include arthritis, pain, fatigue, and cognitive difficulties. These are hallmark symptoms of Lyme disease and associated co-infections. Since the present Lyme disease diagnostic two-tiered testing strategy used for surveillance purposes [8
] is known to have a sensitivity/specificity averaging around 56% [9
], and as per the Centers for Disease Control and Prevention (CDC), the surveillance case definitions “are not intended to be used by health care providers for making a clinical diagnosis …” [10
], approximately half of the individuals with Lyme disease may go undiagnosed. Some individuals suffering from “medically unexplained symptoms” (MUS) may therefore have contracted a tick-borne illness. Inadequate diagnostic testing for Lyme disease and associated Borrelia
species may also be contributing to this diagnostic dilemma, as discussed in detail in Precision Medicine: Retrospective Chart Review and Data Analysis of 200 Patients on Dapsone Combination Therapy for Chronic Lyme Disease/PTLDS: Part 1. There has been an expansion of other Borrelia sensu lato
species across the United States in the past decade [11
], and many of these borrelia species, including Relapsing Fever Borrelia
spp. and Borrelia miyamotoi
as well as Borrelia bissetti
, will not be found on standard two-tiered testing strategies for Lyme disease, yet they can lead to unexplained chronic illness [12
The true healthcare burden for tick-borne illness may also be unappreciated due to Lyme disease and coinfections mimicking other chronic illnesses. Five percent of the US population suffers from Chronic Fatigue Syndrome (CFS)/Myalgic Encephalomyelitis and Fibromyalgia [16
], which share the same symptoms as Lyme disease. The diagnostic criteria for these two diseases are based on symptomatology and establishing a differential diagnosis, not on specific laboratory testing. The true number of individuals with borreliosis and co-infections resulting in these chronic fatiguing, musculoskeletal illnesses with cognitive difficulties is therefore unknown. Prior reports on the role of Bartonella
species indicate, for example, that this class of bacteria can cause a broad range of rheumatologic and neurologic symptoms resembling CFS/fibromyalgia [17
Spirochetes have also been reported to be found in the brains of individuals suffering from dementia, and in the biofilms of patients suffering from Alzheimer’s disease [20
]. Multiple scientific peer-reviewed journal articles in the past two decades have implicated a possible association between bacterial and viral infections [22
] along with environmental toxins in neurodegenerative conditions, with recent healthcare estimates approximating that 46 million Americans presently suffer from pre-clinical dementia [23
]. Environmental toxins and spirochetes have both been associated with cognitive difficulties, as well as autoimmune illness, which presently affects tens of millions of Americans [24
]. The necessity of effective prevention, diagnostic, and treatment strategies for Lyme disease and associated co-infections, and the need to evaluate their role in these disorders is urgently needed based on the above statistics. Just as important, however, is the need to determine the role of overlapping infections, environmental toxins, and other etiologies increasing inflammation, resulting in diverse chronic disease manifestations. If we are to improve public health and control rising health care costs, a new paradigm to account for the rising burden of chronic illness is needed.
The etiology and treatment of chronic Lyme disease/Post Treatment Lyme Disease Syndrome (PTLDS) has been a hotly debated topic in the medical literature for the past three decades. This problem exists in part because of a lack of clear definitions. PTLDS is defined as a syndrome in patients who have been treated for an erythema migrans rash (EM) with appropriate antibiotic treatment who have “persistent or recurrent patient-reported symptoms of fatigue, musculoskeletal pain, and/or cognitive complaints with associated functional decline, and this syndrome represents a defined subset of the larger patient population with the diagnosis of chronic Lyme disease, which is less understood and well defined” [25
]. Theories of why patients remain ill generally range from autoimmune reactions post infection to tissue damage and/or persistent infection of the spirochete and/or its parts. No one model, however, has been sufficient to explain ongoing symptomatology after standard courses of antibiotics. The prevailing medical model used to describe and explain most chronic infectious disease is the “one microorganism/one disease” model based on Koch’s postulates taught in medical school. This theory was established in the late 1800s. Scientific advances since that time include significant improvements in diagnostics as well as identifying expanding tick populations with a better understanding of the tick microbiome and associated coinfections, along with identifying the role of borrelia, other intracellular bacteria (i.e., Bartonella
spp. and Mycoplasma
spp.), the gastrointestinal (G.I). microbiome, and environmental toxin exposures in autoimmune illness. The role of nutritional deficiencies, food allergies/sensitivities, leaky gut [27
], and/or sleep disorders, which can contribute to free radical/oxidative stress and further increase inflammation and symptomatology [28
], have also been identified in the recent medical literature as potential etiological causes of chronic symptoms.
All these factors can have deleterious downstream effects on the body, including, but not limited to, mitochondrial and liver dysfunction; Hypothalamic-Pituitary-Adrenal (HPA) axis and autonomic nervous system dysfunction; as well as the ability to increase neuropsychiatric symptoms and pain syndromes [40
]. The establishment of a new paradigm to account for all these factors and their roles in causing disabling symptoms after standard treatment for chronic Lyme disease/PTLDS is of vital importance based on the significant numbers of individuals contracting vector borne diseases. A data mining approach in a large cohort of symptomatic Lyme disease patients was undertaken to be able to better define the role of these multiple variables in those suffering from resistant symptoms of chronic Lyme disease/PTLDS.
In 2012, Horowitz described a multifactorial model for chronic disease known as MSIDS, or Multiple Systemic Infectious Disease Syndrome [39
]. The individual patient’s risks are evaluated during the initial evaluation as the model recognizes that a “one size fits all” approach using general medical guidelines may not account for individual differences and risk factors. The 16-point MSIDS model can efficiently screen through multifactorial etiologies contributing to chronic illness and focus on prevention (epigenetics), thus personalizing treatment. It represents a potential paradigm shift in the diagnostic and treatment approaches for chronic disease, as no one factor is assumed in advance to play a predominant role in the patient’s symptomatology. It is only after taking a detailed history, evaluating chief complaints, reviewing family, social, and environmental histories, checking a review of systems, and performing a physical examination that medical hypotheses are formed, leading to focused laboratory testing.
Factors on the 16-point MSIDS model [42
], which are then evaluated based on the history and physical examination, and can contribute to chronic disease include:
(1) Infections: Four types of infections are assessed. Some are tickborne and others may be mosquito borne, and/or transmitted by other vectors (including fleas, lice, mites, biting flies, and spider bites) or due to human to human transmission:
(a) Bacteria: i.e., Borrelia burgdorferi
[Lyme disease]; other Borrelia
species, such as Borrelia sensu lato
] and Relapsing Fever; Ehrlichia
species [Rickettsia rickettsia
(Rocky Mountain spotted fever), Coxiella burnetii
(Q fever), Rickettsia typhi
(typhus)]; Francisella tularensis
[tularemia]; and Brucella
(b) Parasites: B. microti and B. duncani [Babesiosis], other piroplasms, Toxoplasma gondii (toxoplasmosis), intestinal parasites.
(c) Viruses: Herpes simplex virus 1 (HSV1), Herpes simplex virus 2 (HSV2), Human Herpes Virus 6 (HHV-6), Epstein Barr Virus [EBV], Cytomegalovirus [CMV], Coxsackie virus, Parvovirus, West Nile virus (WNV).
(d) Candida and other fungi.
(2) Immune dysfunction
: Borrelia burgdorferi
as well as European strains, including Borrelia garinii
, have been associated with autoimmune phenomena [44
]. Autoimmune markers, including antinuclear antibodies (ANA) and rheumatoid factors (RF), were assessed, as well as Human Leukocyte Antigen (HLA) markers (DR2, DR4) and immunoglobulin deficiencies and/or subclass deficiencies [46
: Inflammatory chemokines and cytokines are produced during infection [47
]. Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP, an indirect marker of IL-6), Human Transforming Growth Factor beta 1 (TGFB1), Complement component 3a (C3a), Complement component 4a (C4a), and Vascular Endothelial Growth Factor (VEGF), an indirect marker of Bartonella
]) were gauged as markers of inflammation.
: The burden of heavy metals, including mercury, lead, arsenic, cadmium, and aluminum, were recorded [50
] as well as levels of mold toxins, including aflatoxins, trichothecenes, ochratoxins, and gliotoxins. Neurotoxins, such as quinolinic acid, may also be produced during infection [53
]. Patients with a history of multiple chemical sensitivity (MCS) and/or Parkinson’s disease were evaluated for the presence of pesticides, as well as a clinical response to intravenous and oral glutathione, which is known to play a role in chemical detoxification [55
: Foods [56
], medications, and environmental allergies were recorded. Inflammatory cytokine production, similar to those produced during a Lyme infection, may be found in those with allergic reactions. Markers, including total IgE antibody levels, IgE food allergies, evidence of gluten sensitivity or celiac disease (antigliadin antibodies, tissue transglutaminase (TTG)), and histamine levels were recorded if pruritis and/or symptoms of Mast Cell Activation Disorder were present [58
(6) Nutritional and enzyme deficiencies/functional medicine abnormalities in biochemical pathways
]: Patients with poor nutritional intake were tested for amino acid and/or fatty acid deficiencies. All patients were checked for methylenetetrahydrofolate reductase (MTHFR) gene mutations as well as mineral deficiencies, including iodine, copper, zinc, and magnesium. These minerals are essential cofactors in the biochemical pathways responsible for controlling free radical/oxidative stress, inflammation, hormone production, and detoxification.
(7) Mitochondrial dysfunction [61,62,63]
: The mitochondria are essential for energy production in the muscles, nerves, brain, liver, kidney, and heart. Mitochondrial dysfunction was defined as those who had positive responses to the following mitochondrial support supplements: NT Factors, i.e., glycosylated phospholipids, CoQ10, acetyl-l-carnitine, and d-ribose.
(8) Psychological disorders
: Neuropsychiatric symptoms may result from and/or worsen when Lyme disease and associated coinfections, such as Bartonella
spp. and Babesia
spp., are present [64
]. Common manifestations, including depression, anxiety, Obsessive Compulsive Disorder (OCD), and Post Traumatic Stress Disorder (PTSD), were recorded [66
(9) Neurological dysfunction
: An infection with Borrelia burgdorferi
and associated coinfections, including, but not limited to, other Borrelia
spp., and Mycoplasma
spp., may increase neurological dysfunction [20
]. We evaluated patients using our online symptom survey for evidence of neurological symptoms (headaches, cognitive dysfunction, as well as neuropathy). Proof of neuropathy with or without Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) were also determined by direct chart review of physical examination/electromyogram (EMG)/small fiber biopsies.
(10) Endocrine disorders [68,69,70]
: Hypothalamic-Pituitary-Axis (HPA) axis dysfunction may result from an infectious process. Evidence of thyroid, adrenal, and sex hormone dysfunction were recorded. Adrenal function was measured by blood, urine, and saliva testing [71
]. Vitamin D levels (whose ratios can be an indirect marker for the presence of intracellular infections), as well as precursors of hormones, including Dehydroepiandrosterone sulfate (DHEA-S) and pregnenolone, were also noted.
(11) Sleep disorders
]: Lyme disease is known to result in circadian rhythm disorders [74
], including delayed sleep phase syndrome (DSPS) [75
], where patients have a challenging time falling asleep and/or staying asleep. Hypersomnolence due to inflammatory cytokine production is also a known clinical manifestation [76
]. Individuals were evaluated for evidence of any sleep related disorders, including obstructive sleep apnea (OSA), restless leg syndrome (RLS), hormone imbalance (menopause, elevated adrenal function at night), benign prostatic hypertrophy (BPH), and/or medication induced sleep problems.
(12) Autonomic nervous system (ANS) dysfunction and Postural Orthostatic Tachycardia Syndrome (POTS)
]: Postural orthostatic tachycardia syndrome following Lyme disease has been reported [85
], and four principal types of neuropathy can affect the nervous system in the patient infected with Borrelia burgdorferi
. Autonomic neuropathy is a form of polyneuropathy that affects elements of the central nervous system (brain/hypothalamus and spinal cord), peripheral nervous system with its sensory motor branches, and the enteric nervous system made up of nerve fibers that go to the bladder and gastrointestinal tract (including the pancreas and gallbladder). Problems with the autonomic nervous system can result in symptoms of resistant fatigue, dizziness, low blood pressure and fainting, anxiety, palpitations, cognitive difficulties, absent or excessive sweating, problems with temperature dysregulation [86
], and problems with gastroparesis (nausea, vomiting) with or without constipation and/or bladder dysfunction. POTS is often diagnosed by a Head-up Tilt Table Test (HUT), but if such testing is not available, POTS can be diagnosed with bedside measurements of heart rate and blood pressure taken in the supine (laying down) and standing up position [87
]. In our study, we performed sitting and standing blood pressures with corresponding pulse rates at time 0 (sitting for several minutes), 3, 6, and 9 min were recorded. Mild POTS was defined as a 1–10 mm Hg drop in blood pressure (BP), and/or 1–10-point increase in heart rate after standing for 9 min; moderate POTS was defined as a 11–29 mm drop in BP, and/or 11–29-point increase in heart rate after standing for 9 min; severe POTS was defined as a 30+ increase in heart rate standing and/or drop in systolic or diastolic blood pressure by 30 mm Hg or greater, standing for 9 min. More detailed tests to evaluate the autonomic nervous system [86
], such as the Quantitative Sudomotor Axon Reflex Test (QSART), Heart Rate Response to deep breathing (HRDB), Valsalva maneuver (VM), Thermoregulatory Sweat Test (TST), Quantitative sensory testing (QST), skin biopsies evaluating the small fiber nerves, and gastric motility studies were performed in a small subset of patients with symptoms of severe autonomic neuropathy.
(13) Gastrointestinal (G.I.) disorders
]: Certain G.I. disorders may result in increased inflammation, so patients were evaluated for one or more of the following gastrointestinal complaints: Gluten sensitivity, celiac disease, colitis, Candidiasis, leaky gut, parasites, Helicobacter pylori
exposure, gastroesophageal reflux disease (GERD), and/or a history of Clostridium difficile
while on dapsone combination therapy (DDS CT). Microbiome analysis and evaluation of beneficial short chain fatty acids (SCFA), inflammation, pancreatic enzymes, and fat malabsorption was done through Genova/Metametrix when clinically indicated.
(14) Elevated liver function testing (LFT’s)
: Elevated liver functions have been associated with inflammatory cytokine production [89
], and may result from Lyme disease and associated tickborne infections, including, but not limited to, anaplasmosis, ehrlichiosis, Rocky Mountain spotted fever, babesiosis, and relapsing fever (Borrelia miyamotoi
). Other causes of elevated liver functions include alpha-1 antitrypsin deficiency, Wilson’s disease, hemochromatosis, viral and autoimmune hepatitis, gallstones, inflammatory bowel disease, connective tissue disease, congestive heart failure (right-sided), hepatic steatosis (Non Alcoholic Steatohepatitis, i.e., NASH), acute and chronic pulmonary disease, endocrine disorders, chemical and drug exposure, as well as cancer [90
]. Evidence of elevated Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), alkaline phosphatase, and total bilirubin were recorded. Patients were tested for the above liver pathologies if liver function abnormalities persisted.
(15) Pain syndromes
: Muscular, arthritic, and neuropathic pain syndromes [93
] (often migratory nature, which is one of the hallmarks of Lyme disease [96
]) along with headaches/migraines can be seen with tick-borne disorders. Evidence of these syndromes were noted. Some patients were on compounded medications for pain and inflammation, including low dose naltrexone (LDN) and glutathione.
(16) Physical Therapy
]: Many patients are deconditioned due to long-standing chronic illness. The need for physical therapy and reconditioning programs was evaluated along with their efficacy with improving fatigue, muscle strength, and coordination.
These numerous factors on the 16-point MSIDS model can be arranged into two categories (multiple causes of inflammation and the downstream effects of inflammation), which can account for persistent symptoms in tickborne and other chronic disease. The causes of inflammation include multiple infections, immune dysfunction, genetic causes of autoimmunity, imbalances of the microbiome of the gut, food allergies/sensitivities, leaky gut, mineral deficiencies and sleep disorders. There are also factors which have adverse downstream effects at both the cellular and organ systems levels, leading to resistant fatigue, pain, and neurocognitive symptoms. These would include potential downstream effects of inflammation leading to endocrine disorders (low testosterone, estradiol, and progesterone with low libido; low adrenal function; hypothyroidism), neurological and psychological dysfunction, POTS/dysautonomia, mitochondrial dysfunction, pain syndromes, liver dysfunction, and autoimmune phenomenon. Any of these chronic disease manifestations may be worsened and/or due to one or multiple factors. This is the case with autoimmune reactions, which the scientific literature has shown can be affected by exposure to borrelia and other infections [100
] (including, but not limited to, Bartonella
], environmental toxin exposure (i.e., mercury, bisphenol A, asbestos, and/or small particle pollution) [50
], imbalances in the microbiome of the gut, and/or from a genetic predisposition [103
]. We therefore collected data from an online survey, which evaluated the efficacy of dapsone combined with other antibiotics and agents that disrupt biofilm for the treatment of chronic Lyme disease/PTLDS, along with information data mined directly from 200 patient records detailing abnormalities on the MSIDS model.
In part one, we evaluated the efficacy of newer “persister” drug regimens, like dapsone combination therapy, and found this protocol decreased the severity of eight major Lyme symptoms and improved treatment outcome. We also found multiple species of intracellular bacteria, including Rickettsia, Bartonella, Mycoplasma, Chlamydia, F. tularensis, and Brucella, contributing to the burden of illness, as well as a high prevalence of Babesia complicating management, with probable geographic spread of Babesia WA1/duncani to the Northeast. Occasional reactivation of viral infections, including HHV-6, in immunocompromised individuals was also seen in a small percentage of patients.
In part two, we seek to understand how Lyme disease can affect different body systems, how abnormalities on the MSIDS model can affect chronic symptoms in those with Lyme disease and associated coinfections, as well as which combination of factors might contribute to the burden of chronic illness leading to resistant symptomatology.