Post by Admin/ Traveler on Oct 31, 2018 16:32:26 GMT
Trav here. I added spacing, removed reference numbers and underlined some things to highlight them for those that can't/don't wish to read the whole thing.
Evaluating polymicrobial immune responses in patients sufering from tick-borne diseases
"Abstract
There is insufficient evidence to support screening of various tick-borne diseases (TBD) related microbes alongside Borrelia in patients suffering from TBD. To evaluate the involvement of multiple microbial immune responses in patients experiencing TBD we utilized enzyme-linked immunosorbent assay. Four hundred and thirty-two human serum samples organized into seven categories followed Centers for Disease Control and Prevention two-tier Lyme disease (LD) diagnosis guidelines and Infectious Disease Society of America guidelines for post-treatment Lyme disease syndrome.
All patient categories were tested for their immunoglobulin M (IgM) and G (IgG) responses against 20 microbes associated with TBD. Our findings recognize that microbial infections in patients suffering from TBDs do not follow the one microbe, one disease Germ Theory as 65% of the TBD patients produce immune responses to various microbes.
We have established a causal association between TBD patients and TBD associated co-infections and essential opportunistic microbes following Bradford Hill’s criteria. This study indicated an 85% probability that a randomly selected TBD patient will respond to Borrelia and other related TBD microbes rather than to Borrelia alone. A paradigm shift is required in current healthcare policies to diagnose TBD so that patients can get tested and treated even for opportunistic infections."
"Discussions
To evaluate the involvement of polymicrobial infections in TBD, 432 patients diagnosed at different TBD stages were tested for their IgM and IgG immune responses to 20 microbes associated with TBDs. The study outcome indicated that polymicrobial infections existed at all stages of TBD with IgM and IgG responses to several microbes. Additionally, IgM and IgG responses to multiple TBD associated co-infections and opportunistic infections were large in patients that reacted to Borrelia compared to patients with no reaction to Borrelia.
However, on average 20% patients responded (IgM and IgG) to only TBD associated co-infections and opportunistic infections that demonstrates the importance of other TBD microbes in addition to Borrelia. Results presented in this study propose that infections in patients suffering from TBDs do not obey the one microbe one disease Germ Theory. Based on these results and substantial literature on polymicrobial infections in TBD patients, we examined the probability of a causal relationship between TBD patients and polymicrobial infections following Hill’s nine criteria.
An average effect size of d = 1.5 for IgM and IgG responses is considered very large. According to common language effect size statistics, d = 1.5 indicates 85% probability that a randomly selected patient will respond to Borrelia and other TBD microbes rather than to only Borrelia. Reports from countries such as Australia, Germany, Netherlands, Sweden, the United Kingdom, the USA, and others indicate that 4% to 60% of patients suffer from LD and other microbes such as Babesia microti and human granulocytic anaplasmosis (HGA).
However, previous findings are limited to co-infections (i.e., Babesia, Bartonella, Ehrlichia, or Rickettsia species) in patients experiencing a particular stage of LD (such as Erythema migrans). In contrast, a broader spectrum of persistent, co-infections, and opportunistic infections associated with diverse stages of TBD patients have been demonstrated in this study. From a clinical standpoint, the likelihood for IgM and IgG immune responses by TBD patients to the Borrelia spirochetes versus the Borrelia persistent forms, and responses to just Borrelia versus Borrelia with many other TBD microbes has been quantified for the first time.
Borrelia pathogenesis could predispose individuals to polymicrobial infections because it can suppress, subvert, or modulate the host’s immune system to create a niche for colonization by other microbes. Evidence in animals and humans frequently indicate co-existence of Borrelia with other TBD associated infections. Interestingly, IgM and IgG immune levels by patients to multiple forms of Borrelia resulted in immune responses to 14 other TBD microbes. In contrast, patient responses to either form of Borrelia (spirochetes or persistent forms) resulted in reactions to an average of 8 other TBD microbes. Reaction to two forms of Borrelia reflected an increase in disease severity indicating biological gradient for causation as required by Hill’s criteria.
Multiple microbial infections in TBD patients seem plausible because ticks can carry more than eight different microbes depending on tick species and geography. Moreover, Qiu and colleagues reported the presence of at least 18 bacterial genera shared among three different tick species and up to 127 bacterial genera in Ixodes persulcatus. Interestingly, research indicates Chlamydia-like organism in Ixodes ricinus ticks and human skin that may explain immune responses to Chlamydia spp., seen in this study. Additionally, prevalence of TBD associated co-infections such as B. abortus, E. chaffeensis, and opportunistic microbes such as C. pneumoniae, C. trachomatis, Cytomegalovirus, Epstein-Barr virus, and M. pneumoniae have been recorded in the general population of Europe and the USA.
However, true incidence of these microbes is likely to be higher considering underreporting due to asymptomatic infections and differences in diagnostic practices and surveillance systems across Europe and in the USA. More importantly, clinical evidence for multiple microbes has been reported in humans and livestock to mention the least. Our findings regarding the presence of polymicrobial infections at all stages of TBD further supports the causal relationship between TBD patients and polymicrobial infections. Various microbial infections in TBD patients have been linked to the reduced health-related quality of life (HRQoL) and increased disease severity.
An association between multiple infections and TBD patients relates well to other diseases such as periodontal, and respiratory tract diseases. Oral cavities may contain viruses and 500 different bacterial species. Our findings demonstrate that TBD patients may suffer from multiple bacterial and viral infections. In respiratory tract diseases, influenza virus can stimulate immunosuppression and predispose patients to bacterial infections causing an increase in disease severity. Likewise, Borrelia can induce immunosuppression that may predispose patients to other microbial infections causing an increase in disease severity.
Traditionally, positive IgM immune reaction implies an acute infection, and IgG response portrays a dissemination, persistent or memory immunity due to past infections. Depending on when TBD patients seek medical advice, the level of anti-Borrelia antibodies can greatly vary as an Erythema migrans (EM) develops and may present with IgM, IgG, collective IgM/IgG, or IgA62. This study recommends both IgM and IgG in diagnosing TBD as unconventional antibody profiles have been portrayed in TBD patients. Presence of long-term IgM and IgG antibodies have been reported in LD patients that were tested by the CDC two-tier system. In 2001, Kalish and colleagues reported anti-Borrelia IgM or IgG persistence in patients that suffered from LD 10–20 years ago. Similarly, Hilton and co-workers recorded persistent anti-Borrelia IgM response in 97% of late LD patients that were considered cured following an antibiotic treatment.
Similar events of persistent IgM and IgG antibody reactions were demonstrated in patients treated for Borrelia arthritis and acrodermatitis chronica atrophicans, chronic cutaneous borreliosis, and Lyme neuroborreliosis. A clear phenomenon of immune dysfunction is occurring, which might account for the disparities in LD patient’s antibody profiles and persistence. Borrelia suppresses the immune system by inhibition of antigen-induced lymphocyte proliferation, reducing Langerhans cells by downregulation of major histocompatibility complex class II molecules on these cells, stimulating the production of interleukin-10 and anti-inflammatory immunosuppressive cytokine, and causing disparity in regulation and secretion of cytokines. Other studies have demonstrated low production or subversion of specific anti-Borrelia antibodies in patients with immune deficiency status.
Following Hill’s nine criteria a causal association between TBD patients and polymicrobial infections can be established because the likelihood of TBD patients responding to Borrelia and various other TBD microbes is substantial (strength of association). Evidence concerning immune responses to multiple forms of Borrelia and 14 other TBD microbes versus responses to either type of Borrelia and 8 other TBD microbes explains Hill’s biological gradient criteria. Also, immune responses to several microbes at all stages of TBD and the large difference in immune responses by individuals to only Borrelia (10%) and Borrelia with many other TBD microbes (60%) realize Hill’s specificity and experimental evidence standards. Former studies that reveal tick microbiome can contain various microbes, co-infections in LD patients from multiple countries, and the ability of Borrelia to manipulate its host’s immune system to promote colonization by other microbes meet Hill’s plausibility, consistency, temporality, and coherence of association conditions. Finally, the role of polymicrobial infections in periodontal60, respiratory tract61, and other diseases fulfil Hill’s analogy criteria.
Our study has several limitations. First, commercial laboratories that contributed samples to our study had strict policies for patient de-identification and data protection. Thus, the demographic information such as age, sex, region and ethnicity relating to many patients included in this study are missing. Second, all Cohen’s d effect size analyses included in this study were substantively significant (Cohen’s d) but not statistically noteworthy (t statistic). However, the statistically non-significant effect size is not futile because unlike the t statistic, Cohen’s d is independent of sample variability and size.
In the USA alone, the economic healthcare burden for patients suffering from LD and ongoing symptoms is estimated to be $1.3 billion per year. Additionally, 83% of all TBD diagnostic tests performed by the commercial laboratories in the USA accounted for only LD70. Globally, the commercial laboratories’ ability to diagnose LD has increased by merely 4% (weighted mean for ELISA sensitivity 62.3%) in the last 20 years. This study provides evidence regarding polymicrobial infections in patients suffering from different stages of TBDs. Literature analyses and results from this study followed Hill’s criteria indicating a causal association between TBD patients and polymicrobial infections. Also, the study outcomes indicate that patients may not adhere to traditional IgM and IgG responses."
Evaluating polymicrobial immune responses in patients sufering from tick-borne diseases
"Abstract
There is insufficient evidence to support screening of various tick-borne diseases (TBD) related microbes alongside Borrelia in patients suffering from TBD. To evaluate the involvement of multiple microbial immune responses in patients experiencing TBD we utilized enzyme-linked immunosorbent assay. Four hundred and thirty-two human serum samples organized into seven categories followed Centers for Disease Control and Prevention two-tier Lyme disease (LD) diagnosis guidelines and Infectious Disease Society of America guidelines for post-treatment Lyme disease syndrome.
All patient categories were tested for their immunoglobulin M (IgM) and G (IgG) responses against 20 microbes associated with TBD. Our findings recognize that microbial infections in patients suffering from TBDs do not follow the one microbe, one disease Germ Theory as 65% of the TBD patients produce immune responses to various microbes.
We have established a causal association between TBD patients and TBD associated co-infections and essential opportunistic microbes following Bradford Hill’s criteria. This study indicated an 85% probability that a randomly selected TBD patient will respond to Borrelia and other related TBD microbes rather than to Borrelia alone. A paradigm shift is required in current healthcare policies to diagnose TBD so that patients can get tested and treated even for opportunistic infections."
"Discussions
To evaluate the involvement of polymicrobial infections in TBD, 432 patients diagnosed at different TBD stages were tested for their IgM and IgG immune responses to 20 microbes associated with TBDs. The study outcome indicated that polymicrobial infections existed at all stages of TBD with IgM and IgG responses to several microbes. Additionally, IgM and IgG responses to multiple TBD associated co-infections and opportunistic infections were large in patients that reacted to Borrelia compared to patients with no reaction to Borrelia.
However, on average 20% patients responded (IgM and IgG) to only TBD associated co-infections and opportunistic infections that demonstrates the importance of other TBD microbes in addition to Borrelia. Results presented in this study propose that infections in patients suffering from TBDs do not obey the one microbe one disease Germ Theory. Based on these results and substantial literature on polymicrobial infections in TBD patients, we examined the probability of a causal relationship between TBD patients and polymicrobial infections following Hill’s nine criteria.
An average effect size of d = 1.5 for IgM and IgG responses is considered very large. According to common language effect size statistics, d = 1.5 indicates 85% probability that a randomly selected patient will respond to Borrelia and other TBD microbes rather than to only Borrelia. Reports from countries such as Australia, Germany, Netherlands, Sweden, the United Kingdom, the USA, and others indicate that 4% to 60% of patients suffer from LD and other microbes such as Babesia microti and human granulocytic anaplasmosis (HGA).
However, previous findings are limited to co-infections (i.e., Babesia, Bartonella, Ehrlichia, or Rickettsia species) in patients experiencing a particular stage of LD (such as Erythema migrans). In contrast, a broader spectrum of persistent, co-infections, and opportunistic infections associated with diverse stages of TBD patients have been demonstrated in this study. From a clinical standpoint, the likelihood for IgM and IgG immune responses by TBD patients to the Borrelia spirochetes versus the Borrelia persistent forms, and responses to just Borrelia versus Borrelia with many other TBD microbes has been quantified for the first time.
Borrelia pathogenesis could predispose individuals to polymicrobial infections because it can suppress, subvert, or modulate the host’s immune system to create a niche for colonization by other microbes. Evidence in animals and humans frequently indicate co-existence of Borrelia with other TBD associated infections. Interestingly, IgM and IgG immune levels by patients to multiple forms of Borrelia resulted in immune responses to 14 other TBD microbes. In contrast, patient responses to either form of Borrelia (spirochetes or persistent forms) resulted in reactions to an average of 8 other TBD microbes. Reaction to two forms of Borrelia reflected an increase in disease severity indicating biological gradient for causation as required by Hill’s criteria.
Multiple microbial infections in TBD patients seem plausible because ticks can carry more than eight different microbes depending on tick species and geography. Moreover, Qiu and colleagues reported the presence of at least 18 bacterial genera shared among three different tick species and up to 127 bacterial genera in Ixodes persulcatus. Interestingly, research indicates Chlamydia-like organism in Ixodes ricinus ticks and human skin that may explain immune responses to Chlamydia spp., seen in this study. Additionally, prevalence of TBD associated co-infections such as B. abortus, E. chaffeensis, and opportunistic microbes such as C. pneumoniae, C. trachomatis, Cytomegalovirus, Epstein-Barr virus, and M. pneumoniae have been recorded in the general population of Europe and the USA.
However, true incidence of these microbes is likely to be higher considering underreporting due to asymptomatic infections and differences in diagnostic practices and surveillance systems across Europe and in the USA. More importantly, clinical evidence for multiple microbes has been reported in humans and livestock to mention the least. Our findings regarding the presence of polymicrobial infections at all stages of TBD further supports the causal relationship between TBD patients and polymicrobial infections. Various microbial infections in TBD patients have been linked to the reduced health-related quality of life (HRQoL) and increased disease severity.
An association between multiple infections and TBD patients relates well to other diseases such as periodontal, and respiratory tract diseases. Oral cavities may contain viruses and 500 different bacterial species. Our findings demonstrate that TBD patients may suffer from multiple bacterial and viral infections. In respiratory tract diseases, influenza virus can stimulate immunosuppression and predispose patients to bacterial infections causing an increase in disease severity. Likewise, Borrelia can induce immunosuppression that may predispose patients to other microbial infections causing an increase in disease severity.
Traditionally, positive IgM immune reaction implies an acute infection, and IgG response portrays a dissemination, persistent or memory immunity due to past infections. Depending on when TBD patients seek medical advice, the level of anti-Borrelia antibodies can greatly vary as an Erythema migrans (EM) develops and may present with IgM, IgG, collective IgM/IgG, or IgA62. This study recommends both IgM and IgG in diagnosing TBD as unconventional antibody profiles have been portrayed in TBD patients. Presence of long-term IgM and IgG antibodies have been reported in LD patients that were tested by the CDC two-tier system. In 2001, Kalish and colleagues reported anti-Borrelia IgM or IgG persistence in patients that suffered from LD 10–20 years ago. Similarly, Hilton and co-workers recorded persistent anti-Borrelia IgM response in 97% of late LD patients that were considered cured following an antibiotic treatment.
Similar events of persistent IgM and IgG antibody reactions were demonstrated in patients treated for Borrelia arthritis and acrodermatitis chronica atrophicans, chronic cutaneous borreliosis, and Lyme neuroborreliosis. A clear phenomenon of immune dysfunction is occurring, which might account for the disparities in LD patient’s antibody profiles and persistence. Borrelia suppresses the immune system by inhibition of antigen-induced lymphocyte proliferation, reducing Langerhans cells by downregulation of major histocompatibility complex class II molecules on these cells, stimulating the production of interleukin-10 and anti-inflammatory immunosuppressive cytokine, and causing disparity in regulation and secretion of cytokines. Other studies have demonstrated low production or subversion of specific anti-Borrelia antibodies in patients with immune deficiency status.
Following Hill’s nine criteria a causal association between TBD patients and polymicrobial infections can be established because the likelihood of TBD patients responding to Borrelia and various other TBD microbes is substantial (strength of association). Evidence concerning immune responses to multiple forms of Borrelia and 14 other TBD microbes versus responses to either type of Borrelia and 8 other TBD microbes explains Hill’s biological gradient criteria. Also, immune responses to several microbes at all stages of TBD and the large difference in immune responses by individuals to only Borrelia (10%) and Borrelia with many other TBD microbes (60%) realize Hill’s specificity and experimental evidence standards. Former studies that reveal tick microbiome can contain various microbes, co-infections in LD patients from multiple countries, and the ability of Borrelia to manipulate its host’s immune system to promote colonization by other microbes meet Hill’s plausibility, consistency, temporality, and coherence of association conditions. Finally, the role of polymicrobial infections in periodontal60, respiratory tract61, and other diseases fulfil Hill’s analogy criteria.
Our study has several limitations. First, commercial laboratories that contributed samples to our study had strict policies for patient de-identification and data protection. Thus, the demographic information such as age, sex, region and ethnicity relating to many patients included in this study are missing. Second, all Cohen’s d effect size analyses included in this study were substantively significant (Cohen’s d) but not statistically noteworthy (t statistic). However, the statistically non-significant effect size is not futile because unlike the t statistic, Cohen’s d is independent of sample variability and size.
In the USA alone, the economic healthcare burden for patients suffering from LD and ongoing symptoms is estimated to be $1.3 billion per year. Additionally, 83% of all TBD diagnostic tests performed by the commercial laboratories in the USA accounted for only LD70. Globally, the commercial laboratories’ ability to diagnose LD has increased by merely 4% (weighted mean for ELISA sensitivity 62.3%) in the last 20 years. This study provides evidence regarding polymicrobial infections in patients suffering from different stages of TBDs. Literature analyses and results from this study followed Hill’s criteria indicating a causal association between TBD patients and polymicrobial infections. Also, the study outcomes indicate that patients may not adhere to traditional IgM and IgG responses."