Dapsone combination therapy for chronic Lyme disease/PTLD
Apr 25, 2019 17:28:42 GMT
alyeska likes this
Post by Admin/ Traveler on Apr 25, 2019 17:28:42 GMT
As most of you know, I don't use pharmaceuticals, but it's not because I don't believe in them, it's because they simply don't work, or don't work as well as herbs and other alternative medicine for me. This is MY personal choice, but it also means that I don't know a whole lot about the pharmaceutical side of treatment for these infections. But there is SOO MUCH more to effective treatment than just the actual killing of the bacteria that I can and do often help those that do use pharmaceuticals to treat these infections.
With that said, I do want to post about a new protocol that does seem to be having some success in an area that has begged for any help for a long time now - chronic Lyme disease. (Yep, I rebel against PTLD because it's NOT POST infection, it's CONTINUING infection processes that are keeping us sick - just like with ANY OTHER DISEASE).
If you are someone considering using this treatment, please do go to the link and read the FULL article.
Precision medicine: retrospective chart review and data analysis of 200 patients on dapsone combination therapy for chronic Lyme disease/post-treatment Lyme disease syndrome: part 1
Authors Horowitz RI, Freeman PR
Received 6 November 2018
Accepted for publication 17 January 2019
Published 18 February 2019 Volume 2019:12 Pages 101—119
Purpose:
We collected data from an online survey of 200 of our patients, which evaluated the efficacy of dapsone (diaminodiphenyl sulfone, ie, DDS) combined with other antibiotics and agents that disrupt biofilms for the treatment of chronic Lyme disease/post-treatment Lyme disease syndrome (PTLDS). We also collected aggregate data from direct retrospective chart review, including laboratory testing for Lyme, other infections, and associated tick-borne coinfections. This helped us to determine the frequency of exposure to other infections/coinfections among a cohort of chronically ill Lyme patients, evaluate the efficacy of newer “persister” drug regimens like DDS, and determine how other infections and tick-borne coinfections may be contributing to the burden of chronic illness leading to resistant symptomatology.
Patients and methods:
A total of 200 adult patients recruited from a specialized Lyme disease medical practice had been ill for at least 1 year. We regularly monitored laboratory values and participants’ symptom severity, and the patients completed the online symptom questionnaire both before beginning treatment and after 6 months on DDS combination therapy (DDS CT). Paired-samples t-tests and Wilcoxon signed-rank nonparametric test were performed on each of eight major Lyme symptoms, both before DDS CT and after 6 months of therapy.
Results:
DDS CT statistically improved the eight major Lyme symptoms. We found multiple species of intracellular bacteria including rickettsia, Bartonella, Mycoplasma, Chlamydia, Tularemia, and Brucella contributing to the burden of illness and a high prevalence of Babesia complicating management with probable geographic spread of Babesia WA1/duncani to the Northeast. Borrelia, Bartonella, and Mycoplasma species, as well as Babesia microti had variable manifestations and diverse seroreactivity, with evidence of persistence despite commonly prescribed courses of anti-infective therapies. Occasional reactivation of viral infections including human herpes virus 6 was also seen in immunocompromised individuals.
Conclusion: DDS CT decreased eight major Lyme symptoms severity and improved treatment outcomes among patients with chronic Lyme disease/PTLDS and associated coinfections.
(Trav here - skipping to the section called:)
Results
DDS status consisted of 53.70% currently taking DDS for at least 6 months, and 46.30% no longer taking DDS. Dosages included 25 mg (12%), 50 mg (23.5%), 75 mg (12%), and 100 mg (51.5%). DDS treatment is occasionally pulsed – instead of taking the medication daily, it can be taken 3 days a week, or every other day, and so on, depending on the severity of Herxheimer reactions with regular use. About 20.5% of participants indicated that their DDS treatment was pulsed. Reasons for stopping DDS treatment were “My symptoms improved” (N=22), “I had an adverse reaction” (N=46), and “I switched to a different protocol” (N=22).
The percent severity rating for each symptom in pre-dapsone (pre-DDS) and DDS-treated patients are available in Table 1. Thirty-five cases were missing both pre-DDS and DDS severity data or either one. These cases were removed from this table and from t-test analyses leaving symptom severity data for 165 patients.
In order to analyze this, paired-samples t-tests were performed on each symptom with pre-DDS and DDS conditions of: fatigue and/or tiredness: t(164)=10.69, P<0.001, muscle and/or joint pain: t(164)=8.13, P<0.001, headache: t(164)=5.35, P<0.001, tingling and/or numbness and/or burning of extremities: t(164)=6.71, P<0.001, sleep problems: t(164)=6.17, P<0.001, forgetfulness and/or brain fog: t(164)=9.84, P<0.001, difficulty with speech and/or writing: t(164)=8.70, P<0.001, and day sweats and/or night sweats and/or flushing: t(164)=8.36, P<0.001.
A Wilcoxon signed-rank nonparametric test (which was run due to the small range of severity ratings) showed a statistically significant change in severity ratings of the same eight symptoms for pre-DDS and DDS conditions. Results indicated that for fatigue and/or tiredness: Z=−8.624, P<0.001, muscle and/or joint pain: Z=−7.295, P<0.001, headache: Z=−5.587, P<0.001, tingling and/or numbness and/or burning of extremities: Z=–7.302, P<0.001, sleep problems: Z=−6.363, P<0.001, forgetfulness and/or brain fog: Z=–8.169, P<0.001, difficulty with speech and/or writing: Z=−7.873, P<0.001, day sweats and/or night sweats and/or flushing: Z=–8.081, P<0.001.
These results further confirm that patients had a significant change in all eight chronic Lyme symptoms (Table 1).
We used two antibiotic combinations (these were the only combinations with similar group sizes, an assumption which must be met to do statistical analyses) to evaluate which combinations were the most effective:
DDS and a tetracycline with rifampin
DDS and a tetracycline with rifampin and a cephalosporin or a macrolide
(Most people were on rifampin, having one group with rifampin and another without would have given us grossly disproportionate group sizes).
There was no significant difference between the two groups, and both groups were effective in decreasing symptomatology. Further detailed data analysis will be necessary to determine if the addition of a cephalosporin and/or a macrolide temporarily improved symptoms (we often rotate antibiotics during the clinical course based on a patient’s response).
Unpublished scientific research done by Dr Eva Sapi’s team at the University of New Haven evaluated DDS CTs in culture, and their effect on lowering Borrelia biofilm mass. These results were presented as a poster presentation at the ILADS 16th International Lyme Conference in 2016 in Boston16 and showed that DDS combined with doxycycline, rifampin and stevia was the most effective three drug/herbal biofilm combination therapy, confirmed in our clinical study. Further translational clinical research, moving from the laboratory to the bedside will be necessary however to evaluate the efficacy of one regimen over another, especially in patients with associated coinfections. We were also not able to differentiate changes in symptom outcome based on different DDS doses, due to inadequate numbers of individuals in each dosage group.
Before rating the severity of their symptoms via questionnaire, patients were asked for a pre-DDS and DDS “Percent Normal” (on a 100-point scale) apart from evaluating their eight hallmark symptoms of Lyme disease. These data come from symptom ratings collected via an online Surveymonkey.com questionnaire. Success in the DDS trial was operationally defined as improvement in percent of normal after 6 months on DDS. Failure was operationally defined as remaining the same or worsening of percentage of normal after at least 6 months of DDS CT.
A paired-samples t-test demonstrates a significant difference from pre-DDS to DDS conditions: t(180)=12.83, P<0.001 (pre-M=51.34%, DDS M=65.85%). Of 181 participants who gave both pre-DDS and DDS percentage scores, 14 participants reported feeling worse currently than they did before the DDS, 22 participants reported no difference, while all other participants (145) currently reported a higher percentage of normal. Of the 145 participants who reported higher percentage of normal for current symptoms (some participants did not answer this question), difference in percentage ratings ranged from 2% to 75% (M=16.09, SD =13.52).
Side effects of DDS
There are four common side effects of DDS, which need to be monitored to minimize reactions and “do no H.A.R.M.” (ie, Herxheimer reactions, Anemia, Rashes, Methemoglobinemia). Herxheimer reactions represent inflammatory cytokine release (ie, tumor necrosis factor-alpha, interleukin-6 [IL-6], and IL-8) associated with bacterial killing.
Anemia is secondary to the drugs’ effect on folic acid metabolism, but could potentially be due to hemolytic anemia if there was glucose-6-phosphate dehydrogenase19 deficiency (which was ruled out in our patients).
Rashes may be due to sulfa sensitivity (although many patients allergic to sulfamethoxazole/trimethoprim tolerate DDS), and methemoglobinemia is due to increased oxidative stress affecting the ability of hemoglobin to efficiently carry oxygen. Elevated methemoglobin levels can result in increased fatigue, headaches, blue hands, and lips as well as shortness of breath.
About 66.70% of participants experienced Herxheimer reactions,
48.30% anemia,
7% rashes (which were mild),
and 18.4% elevated methemoglobin levels with 3.5% experiencing blue hands, 3% blue lips, and 21% shortness of breath. Shortness of breath may have also been due to active and inadequately treated babesiosis, which can cause cough/and shortness of breath with respiratory distress.
Side effects resolved quickly once stopping the drug and using higher doses of folic acid to reverse anemia, and glutathione with N-acetyl-cysteine to lower elevated methemoglobin levels, based on the published scientific literature and the first author’s clinical experience. Methylene blue can also lower methemoglobin levels. Minor side effects of DDS included temporary elevations in bilirubin, especially in those with Gilbert’s syndrome.
No patients suffered any long-term effects or developed Clostridium difficile during the months of DDS CT. All patients were instructed to take a minimum of three different probiotics with a total of over 100 billion live organisms/day, which contained mixtures of prebiotics (lecithin and oleic acid), lactobacilli (L. rhamnosis, L. acidophilus, L. paracasei), bifidobacterium (B. lactis, strains BL-04 and Bi-07), and Saccharomyces boulardii. It has been published in the scientific literature that these strains significantly decrease the incidence of antibiotic-associated diarrhea and support a healthy intestinal environment and immune health, although only S. boulardii has been shown to be effective for the prevention of C. difficile diarrhea.
Lyme disease testing
Our study showed that the most common IgM and IgG Borrelia-specific bands were 23, 31, 34, 39, 83/93 kDa for patients during their treatment in our medical facility, which occasionally spanned years (Figures 1 and 2). A chart review revealed that these bands changed and/or expanded over time. Indeterminate WB bands (weak positives) were not included in our study to eliminate false positives and increase sensitivity. Most patients studied did however have new indeterminate Borrelia-specific WB bands (23, 31, 34, 39, 83/93 kDa) appear and change over time during their illness. Figure 3 compares the number of individuals with EM rashes, positive CDC criteria WBs (IgM and IgG), and positive Lyme testing by IFA, ELISA, C6 ELISA, and ELISpot (LTT). Only a small number of patients were tested using LTT, which were done by other medical providers prior to enrolling in the study. Positive CDC WBs were defined as at least 2/3 reactive IgM WB bands (23, 39, 41 kDa) and a positive CDC IgG WB was defined as having at least 5/10 IgG WB bands (18, 23 [OspC], 28, 30, 39 [BmpA], 41 [Fla], 45, 58, 66, and 83/93 kDa).
Repeat WB testing during treatment showed that the 31 kDa band was positive on the IgM WB 46.2% of the time, and positive on the IgG WB 28.4% of the time. For the IgM WB, the 34 kDa band appeared 21.5% of the time and was positive on the IgG WB 11.7% of the time. Table 2 shows the frequencies of negative ELISA and C6 ELISA with the presence of bands 31 and 34 kDa and negative/positive CDC IgG and IgM WBs.
Co-infections
Many Lyme patients in our study struggled with other tick-borne illnesses. For the current work, we included information on the following tick transmissible infections as well as other infectious agents that participants may have been exposed to during their lifetime (unrelated to tick transmission). These were collected directly from the patient charts using indirect testing, that is, antibody titers (which indicate prior exposure, but not necessarily active infection) and direct testing, that is, PCR, fluorescent in situ hybridization (FISH) (which are indicative of active infection):
Anaplasma, (N=27, 13.5%),
Babesia (Babesia microti and Babesia duncani [N=104, 52%]),
Bartonella (B. henselae and B. quintana [N=93, positive by titer, PCR, FISH, and/or VEGF, 46.5%]),
Brucella (N=20, 10%),
Chlamydia pneumoniae (N=102, 51%),
cytomegalovirus (N=74, 37%),
Coxsackie, (N=15, 7.5%)
Epstein–Barr virus (EBV) (N=160, 80%),
Ehrlichia (N=29, 14.5%),
Helicobacter pylori (N=15, 7.5%),
Herpes simplex virus (HSV1) (N=46, 23%),
HSV2 (N=23, 11.5%),
human herpes virus 6 (HHV6) (N=162, 81%),
Mycoplasma (M. pneumonia, M. fermentans, and M. penetrans [N=164, 82%]),
Parvovirus (N=23, 11.5%),
Q-Fever (Coxiella burnetti [N=17, 8.5%]),
RMSF (Rickettsia [N=20, 10%]),
Toxoplasmosis (N=23, 11.5%),
tularemia (N=33, 16.5%),
typhus (N=10,5%),
and West Nile Virus (N=13, 6.5%).
Participants tested positive for exposure to between 0 and 16 infections (M=5.87, SD=2.29).
In addition to their Lyme disease, of 200 participants:
0.5% had no evidence of other infections/coinfections,
26% had evidence of prior exposure to 2–4 infections/coinfections,
64% had evidence of prior exposure to 5–8 infections/coinfections, 8% had evidence of prior exposure to 9–12 infections/coinfections,
and 1.5% had evidence of exposure to >12 infections/co-infections.
Figure 4 illustrates the high frequency of tick transmissible infections and other infectious agents in our 200 patients, most notably for Babesia, Bartonella, C. pneumoniae, EBV, HHV6, and mycoplasma.
New findings: co-infections are the rule and several tick species have spread
New findings include evidence of more than one co-infection in the majority of the 200 patients (Figure 4) and serological evidence of not only B. microti (N=51, 25.5%) but also B. duncani (N=56, 28%). Some patients had evidence of antibody titers for both the species (N=20, 10%; Figure 5). Out of 32 patients who were seronegative for B. microti and/or B. duncani, 37.5% were positive by direct testing (PCR, FISH). One was PCR positive (3%) and 11 were FISH positive (34.5%), illustrating the need for a broad screening approach to detect babesiosis.
B. duncani babesiosis has been reported to exist primarily in the Western United States, although the spread of WA-1 babesiosis has occasionally been found in diverse geographic areas of the United States.30 Based on positive antibody titers for B. duncani from patients living in the Northeast, Upper Midwest, and Southwestern United States (Table 3; Figure 6), which were reported from several national and specialty laboratories (Quest Diagnostics, LabCorp, BioReference Laboratory, Medical Diagnostics Laboratory, and IgeneX), this finding implies that there has been a spread of B. duncani across the United States, and especially in the Northeastern United States. Figure 6 illustrates antibody-positive B. duncani cases by home state in 200 patients.
(Trav here again - now skipping to:)
Conclusion
Many of our patients infected with Lyme disease and associated coinfections had severe symptoms, often relapsed with commonly used therapies, and did not present with an EM rash nor meet the CDC two-tiered surveillance criteria. Almost two-thirds of patients had been exposed to between five and eight infections/coinfections and 14.5% of patients were PCR positive for B. burgdorferi despite seemingly “adequate” antibiotic therapy for months or years prior to DDS therapy (N=29, 14.5%).
Evidence of persistent infection with HHV6, Bartonella, and/or Mycoplasma was also confirmed by PCR in several patients, although many in our study had evidence of other medical problems accounting for ongoing symptoms. These included associated immune dysfunction/immune deficiency, inflammation, environmental toxins with detoxification problems, GI problems, allergies, nutritional deficiencies, hormone, and autonomic nervous system dysregulation as well as sleep and psychiatric disorders in those suffering with post treatment Lyme symptoms. None of these factors had been addressed in the three prior NIH randomized controlled Lyme trials, nor the European PLEASE trial and could explain in part why patients remained ill. Many patients with late Lyme disease in those trials failed conventional beta lactam, tetracycline, macrolide, or other antibiotic therapies even if given for 4–6 weeks. These included those patients with evidence of carditis, arthritis, and neuroborreliosis, including but not limited to symptoms of diplopia (3rd and 4th cranial nerves [CN]), Bell’s palsy (7th CN), deafness (8th CN), disequilibrium with ataxia (8th CN), tongue palsy (12th CN), dropped shoulder (11th CN), and foot drop or leg paralysis (spinal cord involvement). Part II of this retrospective chart review will therefore address in detail the abnormalities found on the MSIDS map in those suffering with chronic Lyme disease/PTLDS, which could account for resistant, chronic symptomatology. MSIDS is a precision medical model that considers genetic, environmental, and lifestyle factors155 as well as individual differences in infectious burden, customizing and selecting appropriate and optimal therapies, tailoring and targeting treatments for individual differences. The goal of precision medicine is to address the individual needs of patients, improve clinical outcomes, and minimize side effects.
The rising numbers of individuals suffering with Lyme and other long-term disabling illnesses alert us to a necessary shift in the paradigm for the diagnosis and treatment of chronic disease and consideration of this precision medical approach. The MSIDS model and the use of persister drugs like DDS and pyrazinamide traditionally used for slow growing mycobacterial infections represent new effective therapeutic options in tick-borne disorders. Multi-drug therapies for extended duration have been used for successful eradication of Q-fever, mycobacterial diseases (ie, DDS with antituberculous drugs have been used effectively in leprosy regimens for half a century), as well as in other illnesses involving intracellular microorganisms like Brucella. DDS CT along with several agents that disrupt biofilms decreased the severity of eight major Lyme symptoms in our study in those with PTLDS/chronic Lyme disease, along with diagnosing and adequately treating multiple species of intracellular bacteria. Bartonella, Mycoplasma, rickettsia, tularemia, and Brucella along with parasitic infections like Babesia and viral infections including HHV-6 were all likely sources contributing to the burden of illness. In summary, DDS CT, along with identifying and treating tick-borne co-infections, and abnormalities on the MSIDS map all affected chronic symptomatology and provides an expanded medical resource for those failing traditional therapy.
With that said, I do want to post about a new protocol that does seem to be having some success in an area that has begged for any help for a long time now - chronic Lyme disease. (Yep, I rebel against PTLD because it's NOT POST infection, it's CONTINUING infection processes that are keeping us sick - just like with ANY OTHER DISEASE).
If you are someone considering using this treatment, please do go to the link and read the FULL article.
Precision medicine: retrospective chart review and data analysis of 200 patients on dapsone combination therapy for chronic Lyme disease/post-treatment Lyme disease syndrome: part 1
Authors Horowitz RI, Freeman PR
Received 6 November 2018
Accepted for publication 17 January 2019
Published 18 February 2019 Volume 2019:12 Pages 101—119
Purpose:
We collected data from an online survey of 200 of our patients, which evaluated the efficacy of dapsone (diaminodiphenyl sulfone, ie, DDS) combined with other antibiotics and agents that disrupt biofilms for the treatment of chronic Lyme disease/post-treatment Lyme disease syndrome (PTLDS). We also collected aggregate data from direct retrospective chart review, including laboratory testing for Lyme, other infections, and associated tick-borne coinfections. This helped us to determine the frequency of exposure to other infections/coinfections among a cohort of chronically ill Lyme patients, evaluate the efficacy of newer “persister” drug regimens like DDS, and determine how other infections and tick-borne coinfections may be contributing to the burden of chronic illness leading to resistant symptomatology.
Patients and methods:
A total of 200 adult patients recruited from a specialized Lyme disease medical practice had been ill for at least 1 year. We regularly monitored laboratory values and participants’ symptom severity, and the patients completed the online symptom questionnaire both before beginning treatment and after 6 months on DDS combination therapy (DDS CT). Paired-samples t-tests and Wilcoxon signed-rank nonparametric test were performed on each of eight major Lyme symptoms, both before DDS CT and after 6 months of therapy.
Results:
DDS CT statistically improved the eight major Lyme symptoms. We found multiple species of intracellular bacteria including rickettsia, Bartonella, Mycoplasma, Chlamydia, Tularemia, and Brucella contributing to the burden of illness and a high prevalence of Babesia complicating management with probable geographic spread of Babesia WA1/duncani to the Northeast. Borrelia, Bartonella, and Mycoplasma species, as well as Babesia microti had variable manifestations and diverse seroreactivity, with evidence of persistence despite commonly prescribed courses of anti-infective therapies. Occasional reactivation of viral infections including human herpes virus 6 was also seen in immunocompromised individuals.
Conclusion: DDS CT decreased eight major Lyme symptoms severity and improved treatment outcomes among patients with chronic Lyme disease/PTLDS and associated coinfections.
(Trav here - skipping to the section called:)
Results
DDS status consisted of 53.70% currently taking DDS for at least 6 months, and 46.30% no longer taking DDS. Dosages included 25 mg (12%), 50 mg (23.5%), 75 mg (12%), and 100 mg (51.5%). DDS treatment is occasionally pulsed – instead of taking the medication daily, it can be taken 3 days a week, or every other day, and so on, depending on the severity of Herxheimer reactions with regular use. About 20.5% of participants indicated that their DDS treatment was pulsed. Reasons for stopping DDS treatment were “My symptoms improved” (N=22), “I had an adverse reaction” (N=46), and “I switched to a different protocol” (N=22).
The percent severity rating for each symptom in pre-dapsone (pre-DDS) and DDS-treated patients are available in Table 1. Thirty-five cases were missing both pre-DDS and DDS severity data or either one. These cases were removed from this table and from t-test analyses leaving symptom severity data for 165 patients.
In order to analyze this, paired-samples t-tests were performed on each symptom with pre-DDS and DDS conditions of: fatigue and/or tiredness: t(164)=10.69, P<0.001, muscle and/or joint pain: t(164)=8.13, P<0.001, headache: t(164)=5.35, P<0.001, tingling and/or numbness and/or burning of extremities: t(164)=6.71, P<0.001, sleep problems: t(164)=6.17, P<0.001, forgetfulness and/or brain fog: t(164)=9.84, P<0.001, difficulty with speech and/or writing: t(164)=8.70, P<0.001, and day sweats and/or night sweats and/or flushing: t(164)=8.36, P<0.001.
A Wilcoxon signed-rank nonparametric test (which was run due to the small range of severity ratings) showed a statistically significant change in severity ratings of the same eight symptoms for pre-DDS and DDS conditions. Results indicated that for fatigue and/or tiredness: Z=−8.624, P<0.001, muscle and/or joint pain: Z=−7.295, P<0.001, headache: Z=−5.587, P<0.001, tingling and/or numbness and/or burning of extremities: Z=–7.302, P<0.001, sleep problems: Z=−6.363, P<0.001, forgetfulness and/or brain fog: Z=–8.169, P<0.001, difficulty with speech and/or writing: Z=−7.873, P<0.001, day sweats and/or night sweats and/or flushing: Z=–8.081, P<0.001.
These results further confirm that patients had a significant change in all eight chronic Lyme symptoms (Table 1).
We used two antibiotic combinations (these were the only combinations with similar group sizes, an assumption which must be met to do statistical analyses) to evaluate which combinations were the most effective:
DDS and a tetracycline with rifampin
DDS and a tetracycline with rifampin and a cephalosporin or a macrolide
(Most people were on rifampin, having one group with rifampin and another without would have given us grossly disproportionate group sizes).
There was no significant difference between the two groups, and both groups were effective in decreasing symptomatology. Further detailed data analysis will be necessary to determine if the addition of a cephalosporin and/or a macrolide temporarily improved symptoms (we often rotate antibiotics during the clinical course based on a patient’s response).
Unpublished scientific research done by Dr Eva Sapi’s team at the University of New Haven evaluated DDS CTs in culture, and their effect on lowering Borrelia biofilm mass. These results were presented as a poster presentation at the ILADS 16th International Lyme Conference in 2016 in Boston16 and showed that DDS combined with doxycycline, rifampin and stevia was the most effective three drug/herbal biofilm combination therapy, confirmed in our clinical study. Further translational clinical research, moving from the laboratory to the bedside will be necessary however to evaluate the efficacy of one regimen over another, especially in patients with associated coinfections. We were also not able to differentiate changes in symptom outcome based on different DDS doses, due to inadequate numbers of individuals in each dosage group.
Before rating the severity of their symptoms via questionnaire, patients were asked for a pre-DDS and DDS “Percent Normal” (on a 100-point scale) apart from evaluating their eight hallmark symptoms of Lyme disease. These data come from symptom ratings collected via an online Surveymonkey.com questionnaire. Success in the DDS trial was operationally defined as improvement in percent of normal after 6 months on DDS. Failure was operationally defined as remaining the same or worsening of percentage of normal after at least 6 months of DDS CT.
A paired-samples t-test demonstrates a significant difference from pre-DDS to DDS conditions: t(180)=12.83, P<0.001 (pre-M=51.34%, DDS M=65.85%). Of 181 participants who gave both pre-DDS and DDS percentage scores, 14 participants reported feeling worse currently than they did before the DDS, 22 participants reported no difference, while all other participants (145) currently reported a higher percentage of normal. Of the 145 participants who reported higher percentage of normal for current symptoms (some participants did not answer this question), difference in percentage ratings ranged from 2% to 75% (M=16.09, SD =13.52).
Side effects of DDS
There are four common side effects of DDS, which need to be monitored to minimize reactions and “do no H.A.R.M.” (ie, Herxheimer reactions, Anemia, Rashes, Methemoglobinemia). Herxheimer reactions represent inflammatory cytokine release (ie, tumor necrosis factor-alpha, interleukin-6 [IL-6], and IL-8) associated with bacterial killing.
Anemia is secondary to the drugs’ effect on folic acid metabolism, but could potentially be due to hemolytic anemia if there was glucose-6-phosphate dehydrogenase19 deficiency (which was ruled out in our patients).
Rashes may be due to sulfa sensitivity (although many patients allergic to sulfamethoxazole/trimethoprim tolerate DDS), and methemoglobinemia is due to increased oxidative stress affecting the ability of hemoglobin to efficiently carry oxygen. Elevated methemoglobin levels can result in increased fatigue, headaches, blue hands, and lips as well as shortness of breath.
About 66.70% of participants experienced Herxheimer reactions,
48.30% anemia,
7% rashes (which were mild),
and 18.4% elevated methemoglobin levels with 3.5% experiencing blue hands, 3% blue lips, and 21% shortness of breath. Shortness of breath may have also been due to active and inadequately treated babesiosis, which can cause cough/and shortness of breath with respiratory distress.
Side effects resolved quickly once stopping the drug and using higher doses of folic acid to reverse anemia, and glutathione with N-acetyl-cysteine to lower elevated methemoglobin levels, based on the published scientific literature and the first author’s clinical experience. Methylene blue can also lower methemoglobin levels. Minor side effects of DDS included temporary elevations in bilirubin, especially in those with Gilbert’s syndrome.
No patients suffered any long-term effects or developed Clostridium difficile during the months of DDS CT. All patients were instructed to take a minimum of three different probiotics with a total of over 100 billion live organisms/day, which contained mixtures of prebiotics (lecithin and oleic acid), lactobacilli (L. rhamnosis, L. acidophilus, L. paracasei), bifidobacterium (B. lactis, strains BL-04 and Bi-07), and Saccharomyces boulardii. It has been published in the scientific literature that these strains significantly decrease the incidence of antibiotic-associated diarrhea and support a healthy intestinal environment and immune health, although only S. boulardii has been shown to be effective for the prevention of C. difficile diarrhea.
Lyme disease testing
Our study showed that the most common IgM and IgG Borrelia-specific bands were 23, 31, 34, 39, 83/93 kDa for patients during their treatment in our medical facility, which occasionally spanned years (Figures 1 and 2). A chart review revealed that these bands changed and/or expanded over time. Indeterminate WB bands (weak positives) were not included in our study to eliminate false positives and increase sensitivity. Most patients studied did however have new indeterminate Borrelia-specific WB bands (23, 31, 34, 39, 83/93 kDa) appear and change over time during their illness. Figure 3 compares the number of individuals with EM rashes, positive CDC criteria WBs (IgM and IgG), and positive Lyme testing by IFA, ELISA, C6 ELISA, and ELISpot (LTT). Only a small number of patients were tested using LTT, which were done by other medical providers prior to enrolling in the study. Positive CDC WBs were defined as at least 2/3 reactive IgM WB bands (23, 39, 41 kDa) and a positive CDC IgG WB was defined as having at least 5/10 IgG WB bands (18, 23 [OspC], 28, 30, 39 [BmpA], 41 [Fla], 45, 58, 66, and 83/93 kDa).
Repeat WB testing during treatment showed that the 31 kDa band was positive on the IgM WB 46.2% of the time, and positive on the IgG WB 28.4% of the time. For the IgM WB, the 34 kDa band appeared 21.5% of the time and was positive on the IgG WB 11.7% of the time. Table 2 shows the frequencies of negative ELISA and C6 ELISA with the presence of bands 31 and 34 kDa and negative/positive CDC IgG and IgM WBs.
Co-infections
Many Lyme patients in our study struggled with other tick-borne illnesses. For the current work, we included information on the following tick transmissible infections as well as other infectious agents that participants may have been exposed to during their lifetime (unrelated to tick transmission). These were collected directly from the patient charts using indirect testing, that is, antibody titers (which indicate prior exposure, but not necessarily active infection) and direct testing, that is, PCR, fluorescent in situ hybridization (FISH) (which are indicative of active infection):
Anaplasma, (N=27, 13.5%),
Babesia (Babesia microti and Babesia duncani [N=104, 52%]),
Bartonella (B. henselae and B. quintana [N=93, positive by titer, PCR, FISH, and/or VEGF, 46.5%]),
Brucella (N=20, 10%),
Chlamydia pneumoniae (N=102, 51%),
cytomegalovirus (N=74, 37%),
Coxsackie, (N=15, 7.5%)
Epstein–Barr virus (EBV) (N=160, 80%),
Ehrlichia (N=29, 14.5%),
Helicobacter pylori (N=15, 7.5%),
Herpes simplex virus (HSV1) (N=46, 23%),
HSV2 (N=23, 11.5%),
human herpes virus 6 (HHV6) (N=162, 81%),
Mycoplasma (M. pneumonia, M. fermentans, and M. penetrans [N=164, 82%]),
Parvovirus (N=23, 11.5%),
Q-Fever (Coxiella burnetti [N=17, 8.5%]),
RMSF (Rickettsia [N=20, 10%]),
Toxoplasmosis (N=23, 11.5%),
tularemia (N=33, 16.5%),
typhus (N=10,5%),
and West Nile Virus (N=13, 6.5%).
Participants tested positive for exposure to between 0 and 16 infections (M=5.87, SD=2.29).
In addition to their Lyme disease, of 200 participants:
0.5% had no evidence of other infections/coinfections,
26% had evidence of prior exposure to 2–4 infections/coinfections,
64% had evidence of prior exposure to 5–8 infections/coinfections, 8% had evidence of prior exposure to 9–12 infections/coinfections,
and 1.5% had evidence of exposure to >12 infections/co-infections.
Figure 4 illustrates the high frequency of tick transmissible infections and other infectious agents in our 200 patients, most notably for Babesia, Bartonella, C. pneumoniae, EBV, HHV6, and mycoplasma.
New findings: co-infections are the rule and several tick species have spread
New findings include evidence of more than one co-infection in the majority of the 200 patients (Figure 4) and serological evidence of not only B. microti (N=51, 25.5%) but also B. duncani (N=56, 28%). Some patients had evidence of antibody titers for both the species (N=20, 10%; Figure 5). Out of 32 patients who were seronegative for B. microti and/or B. duncani, 37.5% were positive by direct testing (PCR, FISH). One was PCR positive (3%) and 11 were FISH positive (34.5%), illustrating the need for a broad screening approach to detect babesiosis.
B. duncani babesiosis has been reported to exist primarily in the Western United States, although the spread of WA-1 babesiosis has occasionally been found in diverse geographic areas of the United States.30 Based on positive antibody titers for B. duncani from patients living in the Northeast, Upper Midwest, and Southwestern United States (Table 3; Figure 6), which were reported from several national and specialty laboratories (Quest Diagnostics, LabCorp, BioReference Laboratory, Medical Diagnostics Laboratory, and IgeneX), this finding implies that there has been a spread of B. duncani across the United States, and especially in the Northeastern United States. Figure 6 illustrates antibody-positive B. duncani cases by home state in 200 patients.
(Trav here again - now skipping to:)
Conclusion
Many of our patients infected with Lyme disease and associated coinfections had severe symptoms, often relapsed with commonly used therapies, and did not present with an EM rash nor meet the CDC two-tiered surveillance criteria. Almost two-thirds of patients had been exposed to between five and eight infections/coinfections and 14.5% of patients were PCR positive for B. burgdorferi despite seemingly “adequate” antibiotic therapy for months or years prior to DDS therapy (N=29, 14.5%).
Evidence of persistent infection with HHV6, Bartonella, and/or Mycoplasma was also confirmed by PCR in several patients, although many in our study had evidence of other medical problems accounting for ongoing symptoms. These included associated immune dysfunction/immune deficiency, inflammation, environmental toxins with detoxification problems, GI problems, allergies, nutritional deficiencies, hormone, and autonomic nervous system dysregulation as well as sleep and psychiatric disorders in those suffering with post treatment Lyme symptoms. None of these factors had been addressed in the three prior NIH randomized controlled Lyme trials, nor the European PLEASE trial and could explain in part why patients remained ill. Many patients with late Lyme disease in those trials failed conventional beta lactam, tetracycline, macrolide, or other antibiotic therapies even if given for 4–6 weeks. These included those patients with evidence of carditis, arthritis, and neuroborreliosis, including but not limited to symptoms of diplopia (3rd and 4th cranial nerves [CN]), Bell’s palsy (7th CN), deafness (8th CN), disequilibrium with ataxia (8th CN), tongue palsy (12th CN), dropped shoulder (11th CN), and foot drop or leg paralysis (spinal cord involvement). Part II of this retrospective chart review will therefore address in detail the abnormalities found on the MSIDS map in those suffering with chronic Lyme disease/PTLDS, which could account for resistant, chronic symptomatology. MSIDS is a precision medical model that considers genetic, environmental, and lifestyle factors155 as well as individual differences in infectious burden, customizing and selecting appropriate and optimal therapies, tailoring and targeting treatments for individual differences. The goal of precision medicine is to address the individual needs of patients, improve clinical outcomes, and minimize side effects.
The rising numbers of individuals suffering with Lyme and other long-term disabling illnesses alert us to a necessary shift in the paradigm for the diagnosis and treatment of chronic disease and consideration of this precision medical approach. The MSIDS model and the use of persister drugs like DDS and pyrazinamide traditionally used for slow growing mycobacterial infections represent new effective therapeutic options in tick-borne disorders. Multi-drug therapies for extended duration have been used for successful eradication of Q-fever, mycobacterial diseases (ie, DDS with antituberculous drugs have been used effectively in leprosy regimens for half a century), as well as in other illnesses involving intracellular microorganisms like Brucella. DDS CT along with several agents that disrupt biofilms decreased the severity of eight major Lyme symptoms in our study in those with PTLDS/chronic Lyme disease, along with diagnosing and adequately treating multiple species of intracellular bacteria. Bartonella, Mycoplasma, rickettsia, tularemia, and Brucella along with parasitic infections like Babesia and viral infections including HHV-6 were all likely sources contributing to the burden of illness. In summary, DDS CT, along with identifying and treating tick-borne co-infections, and abnormalities on the MSIDS map all affected chronic symptomatology and provides an expanded medical resource for those failing traditional therapy.