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Successful diagnosis and treatment of Borrelia miyamotoi in a patient with joint and muscle pains, ME/CFS and cognitive dysfunction following tick bites: a case report

Published online by Cambridge University Press:  25 September 2024

A response to the following question: What is the current and expected evolution of prevalence, geographical spread and impact of ticks and tick-borne diseases, and what strategies are needed to improve management, testing, diagnosis and treatment of these diseases amongst patients and animal populations?

Louis Teulières ,
Ying Jia ,
Martha Clokie  and
Jinyu Shan Open the ORCID record for Jinyu Shan [Opens in a new window]
Louis Teulières
Affiliation:
PhelixRD Charity, St Honoré, Paris, France
Ying Jia
Affiliation:
Leicester Centre for Phage Research, Department of Genetics, Genomics, and Cancer Sciences, University of Leicester, Leicester, UK
Martha Clokie
Affiliation:
Leicester Centre for Phage Research, Department of Genetics, Genomics, and Cancer Sciences, University of Leicester, Leicester, UK
Jinyu Shan*
Affiliation:
Leicester Centre for Phage Research, Department of Genetics, Genomics, and Cancer Sciences, University of Leicester, Leicester, UK
*
Corresponding author: Jinyu Shan; Email: js401@le.ac.uk
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Abstract

Introduction

Diagnosing Borrelia miyamotoi disease (BMD) presents challenges due to its overlap with Lyme disease (LD) symptoms and the lack of reliable laboratory diagnostics. This case study demonstrates the successful use of phage-based PCR (phb-PCR) in identifying B. miyamotoi in a patient with multiple tick bites. A 46-year-old female presented with joint and muscle pain, chronic fatigue, and cognitive impairment after being bitten by ticks in Europe. Standard diagnostic tests, including Enzyme-linked immunosorbent assay (ELISA), immunoblot for LD, and antibody tests for Bartonella, Anaplasma, and autoimmune conditions, all returned negative results. However, phb-PCR identified the presence of B. miyamotoi. The patient was treated with intravenous ceftriaxone, oral azithromycin, and intravenous vitamin and mineral therapy, resulting in significant improvement in symptoms, including reduced pain, improved cognitive function, and decreased fatigue. This case emphasises the importance of direct diagnostic methods like phb-PCR for accurately identifying BMD, especially when conventional serological tests fail. Clinicians should consider testing for B. miyamotoi in cases of complex tick-borne diseases for timely and effective management.

Keywords

Borrelia miyamotoitick-borne diseases (TBDs)phage-based PpCR (phb-PpCR)myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)cognitive dysfunctioncase report

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Type
Results
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Research Directions: One Health , Volume 2 , 2024 , e12
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Copyright
© The Author(s), 2024. Published by Cambridge University Press

Introduction

Diagnosing tick-borne diseases (TBDs) like Lyme disease (LD) and tick-borne relapsing fever (TBRF) is challenging because they share overlapping symptoms, such as fever, chills, headaches, muscle and joint pain, fatigue, arthritis and neurological manifestations (Guérin et al., Reference Guérin, Shawky, Zedan, Octave Séphane, Avalle Bérangère, Maffucci and Padiolleau-Lefèvre2023). Although both LD and TBRF diagnoses are difficult, the presence of the erythema migrans (EM) rash in approximately 60%–80% of LD patients provides a slight advantage in identifying LD (Steere et al., Reference Steere, Strle, Wormser, Hu, Branda, Hovius and Mead2016; Grąźlewska and Holec-Gąsior, Reference Grąźlewska and Holec-Gąsior2023). In contrast, the absence of this characteristic rash in TBRF complicates its diagnosis (Jakab et al., Reference Jakab, Kahlig, Kuenzli and Neumayr2022).

The geographic distribution of LD-causing Borrelia species varies greatly. For instance, Borrelia burgdorferi sensu stricto (s.s.) is the most common LD-causing species in the United States, whereas B. garinii and B. afzelii are predominant in Europe and Asia. Additionally, other Borrelia species such as B. mayonii, B. spielmanii, B. bissettii and B. valaisiana are also linked to LD, although they are encountered less frequently (Marques et al., Reference Marques, Strle and Wormser2021). This geographic specificity begs the question of the need for regionally tailored diagnostic and treatment strategies.

The increasing complexity of relapsing fever (RF)-causing Borrelia species has significantly complicated their diagnosis and management. Borrelia species commonly causing TBRF include B. coriaceae, B. lonestari, B. duttonii, B. crocidurae, B. hispanica, B. parkeri, B. turicatae and B. hermsii, all of which are transmitted by soft-bodied ticks (Ras et al., Reference Ras1996). In contrast, B. recurrentis, which also causes RF, is transmitted by the human body louse (Cutler et al., Reference Cutler, Moss, Fukunaga, Wright, Fekade and Warrell1997). Additionally, B. miyamotoi, discovered in Japan in 1995, is an exception among TBRF Borrelia species because it is transmitted by hard-bodied ticks, the same vectors responsible for LD (Fukunaga et al., Reference Fukunaga1995). Consequently, a single bite from a hard-bodied tick could potentially transmit both LD and TBRF. This co-transmission of LD and TBRF has overwhelmed diagnostic resources, highlighting the need for improved detection methods and more adaptable testing protocols that are practical for clinical use.

Diagnosing B. miyamotoi disease (BMD), a type of TBRF, is challenging because it shares symptoms with LD but lacks the characteristic EM rash (Platonov et al., Reference Platonov, Karan, Kolyasnikova, Makhneva, Toporkova, Maleev, Fish and Krause2011; Krause and Barbour, Reference Krause and Barbour2015). Due to these diagnostic challenges, laboratory detection of B. miyamotoi is crucial. However, current serological detection methods are unsuitable due to cross-reactivity (Koetsveld et al., Reference Koetsveld, Platonov, Kuleshov, Wagemakers, Hoornstra, Ang, Szekeres, van Duijvendijk, Fikrig, Embers, Sprong and Hovius2020; Grąźlewska and Holec-Gąsior, Reference Grąźlewska and Holec-Gąsior2023). The CDC (Centers for Disease Control and Prevention) recommends PCR testing to detect B. miyamotoi, but bacteria-based PCR methods often have low sensitivity (Karan et al., Reference Karan, Makenov, Kolyasnikova, Stukolova, Toporkova and Olenkova2018; Boyer et al., Reference Boyer, Koetsveld, Zilliox, Sprong, Talagrand-Reboul, Hansmann, de Martino, Boulanger, Hovius and Jaulhac2020).

To enhance PCR sensitivity, phage-based PCR (phb-PCR) has emerged as a promising solution for the sensitive detection of bacterial species. Unlike traditional PCR, which targets bacterial DNA directly, phb-PCR detects multiple-copy phage sequences associated with the bacteria, providing higher sensitivity (Luo et al., Reference Luo, Scahill and Banaei2010; Shan et al., Reference Shan, Jia, Teulières, Patel and Clokie2021). This approach leverages the intrinsic specificity of phages for their bacterial hosts, ensuring that phage detection strongly indicates the presence of the target bacteria (Mandilara et al., Reference Mandilara, Smeti, Mavridou, Lambiri, Vatopoulos and Rigas2006; Shivaram et al., Reference Shivaram, Bhatt, Verma, Clase and Simsek2023). Researchers have successfully used phb-PCR to detect tuberculosis, Borrelia burgdorferi s.l. and Borrelia miyamotoi (Swift et al., Reference Swift, Meade, Barron, Bennett, Perehenic, Hughes, Stevenson and Rees2020; Shan et al., Reference Shan, Jia, Teulières, Patel and Clokie2021; Shan et al., Reference Shan, Jia, Hickenbotham, Teulières and Clokie2023).

In this case report, we showcased the positive impact of phb-PCR in diagnosing BMD and developing an effective treatment plan. After encountering multiple negative serological tests and struggling to identify the causative agent, we turned to phb-PCR. Recognising the increasing cases of B. miyamotoi, we specifically tested for this pathogen (Wormser et al., Reference Wormser, Shapiro and Fish2019; Xu et al., Reference Xu, Luo, Ribbe, Pearson, Ledizet and Rich2021; Cleveland et al., Reference Cleveland, Anderson and Brissette2023). Our approach exemplifies the potential of phb-PCR in identifying B. miyamotoi infections and guiding appropriate treatment strategies. Testing for B. miyamotoi when serological tests yield negative results in complicated tick-borne diseases could be a wise decision when coupled with clinical judgement. Clinicians, scientists and patient charity workers should collaborate to raise awareness of tick-borne diseases and BMD, ensuring patients receive timely and accurate diagnostics and treatment.

Methods

We explored the complex medical history of a 46-year-old female patient who experienced three distinct tick exposures. The first exposure occurred in July 2006, the second in April 2016, and the third in June 2016. Following these exposures, the patient presented with symptoms including joint and muscle pains, fever, chill, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and cognitive dysfunction (‘brain fog’), but did not exhibit the hallmark EM rash of LD.

The various diagnostic tests conducted for the patient are summarised in Table 1. The patient underwent diagnostic evaluation at the National Reference Centre for Lyme Diseases in Strasbourg, France. Initial screening used Enzygnost® Borrelia Lyme IgM and Enzygnost® Borrelia Lyme link VlsE/IgG Enzyme-linked immunosorbent assay (ELISA) by Siemens to detect the patient’s immune response to B. burgdorferi s.l. species (Hjetland et al., Reference Hjetland, Nilsen, Grude and Ulvestad2014). Immunoblot testing employed the Borrelia Europe plus TpN17 LINE immunoblot by Sekisui Virotech to analyse the detailed immune response to specific Borrelia antigens (De Bont et al., Reference De Bont, Lagrou and Depypere2022).

Table 1.

Summary of diagnostic test results for the patient

Subsequent diagnostic efforts included multiple tests to identify the causative agent. Vircell’s Bartonella indirect immunofluorescence assay (IFA) kits were used to screen for IgG antibodies against B. henselae and B. quintana (Aydin et al., Reference Aydin, Bülbül, Telli and Gültekin2014), while Focus Diagnostics IFA kits were employed to detect IgG and IgM antibodies against Anaplasma phagocytophilum (Chochlakis et al., Reference Chochlakis, Psaroulaki, Kokkini, Kostanatis, Arkalati, Karagrannaki, Tsiatis, Tselentis and Gikas2009).

To explore potential autoimmune disorders, an antinuclear antibodies (ANA) test was conducted using the indirect immunofluorescence technique on HEp-2 cells (Sack et al., Reference Sack, Conrad, Csernok, Frank, Hiepe, Krieger, Kromminga, Von Landenberg, Messer, Witte and Mierau2009). Additionally, specific antibodies against extractable nuclear antigens (ENAs) and other nuclear and cytoplasmic components were tested using ELISA for specific autoantibodies included anti-Ro/SS-A, anti-La/SS-B, anti-Sm, anti-RNP, anti-Scl-70 and anti-dsDNA antibodies. Finally, anti-double stranded DNA (anti-dsDNA) were assessed using ELISA for IgG and IgM (Subasic et al., Reference Subasic, Karamehic, Gavrankapetanovic, Hodzic, Kasumovic, Delic-Sarac and Prljaca-Zecevic2009).

A proprietary phb-PCR test designed to detect B. miyamotoi was employed (Shan et al., Reference Shan, Clokie and Teulières2018). This test, offered by RED Laboratories, was performed in compliance with Good Laboratory Practice and conducted according to the MIQE guidelines (Bustin et al., Reference Bustin, Benes, Garson, Hellemans, Huggett, Kubista, Mueller, Nolan, Pfaffl, Shipley, Vandesompele and Wittwer2009). The phb-PCR test has been evaluated using analytical, clinical and tick samples and its accuracy and reliability have been validated and peer-reviewed, with results published in scientific literature (Shan et al., Reference Jakab, Kahlig, Kuenzli and Neumayr2021, Reference Kubiak, Szczotko and Dmitryjuk2023). The PCR product was sequenced using the Sanger method.

To evaluate the patient’s progress post-treatment, a series of detailed follow-up assessments were conducted:

  1. 1. Quality of life measurements: Quality of life was assessed using the Short Form Health Survey (SF-36) (Ware et al., Reference Ware and Sherbourne1992). The SF-36 evaluates multiple dimensions of health, including physical functioning, bodily pain, general health perceptions, vitality, social functioning, emotional role functioning and mental health.

  2. 2. Symptom severity tracking: Symptom severity was tracked using the Fatigue Severity Scale (Shahid et al., Reference Shahid and Shahid2012) and the Visual Analogue Scale (Hawker et al., Reference Hawker, Mian, Kendzerska and French2011) for pain assessment. These scales provide objective data on symptom progression and treatment response, which is essential for effectively managing and adjusting therapeutic strategies.

  3. 3. Cognitive function assessment: Cognitive function in patients was evaluated using the Montreal Cognitive Assessment (Nasreddine et al., Reference Nasreddine, Phillips, Bédirian, Charbonneau, Whitehead, Collin, Cummings and Chertkow2005). This assessment is crucial for detecting cognitive impairments commonly seen in LD and TBDs and tracking improvements with treatment.

  4. 4. Laboratory testing: We conducted phb-PCR on the patient’s sample after completing the treatment to confirm the absence of B. miyamotoi.

Results

1. Diagnostic results

For clarity and ease of access, detailed diagnostic results and interpretations are summarised in Table 1. Each individual test and its results are explained in the text below.

The patient’s diagnostic evaluation for LD yielded negative results. The IgG and IgM ELISA showed IgG levels below the diagnostic threshold (<4 U/mL) and a negative IgM result. Additionally, the immunoblot detected no reactive bands. These findings collectively suggest that the patient has not been exposed to B. burgdorferi sensu lato and does not have an active or previous infection.

Subsequent diagnostic efforts using IFA tests revealed no evidence of exposure to B. henselae or B. quintana, as indicated by negative IgG results (<1:64) for both pathogens. For A. phagocytophilum, the IFA tests showed an inconclusive IgM result at 1:20 and a negative IgG result (<1:64). These findings jointly suggest that there is no detectable immune response indicative of infection by B. henselae, B. quintana or A. phagocytophilum in the patient.

The ANA test for autoimmune markers showed a positive result at a dilution of 1:320 with a homogeneous irregular/speckled pattern. This positive ANA suggests a possible autoimmune aetiology. However, specific autoantibodies, including anti-Ro/SS-A, anti-La/SS-B, anti-Sm, anti-RNP and anti-Scl-70 (detailed in Table 2), were all negative, indicating no evidence of specific autoimmune diseases commonly associated with these antibodies. Additionally, anti-dsDNA antibodies tested negative, with levels measured at <30 U/mL, which is below the reference value of <50 U/mL.

Table 2.

Autoantibodies, their target antigens, associated diseases in autoimmune conditions

In summary, while the positive ANA result suggests a potential autoimmune condition, the absence of specific autoantibodies does not support the initial ANA finding, thereby excluding certain autoimmune diseases.

Given the negative results from the serological tests, we decided to switch from antibody-based methods to a direct test for detecting B. miyamotoi. The phb-PCR assay detected B. miyamotoi, and sequencing of the PCR product confirmed its identity. All controls (positive, negative, internal and extraction) in the PCR functioned correctly.

2. Therapeutic interventions

Following the detection of B. miyamotoi from the patient’s blood, a targeted treatment regimen was established, focusing on antibiotic therapy against B. miyamotoi, complemented by comprehensive nutritional support (Eikeland et al., Reference Eikeland, Henningsson, Lebech, Kerlefsen, Mavin, Vrijlandt, Hovius, Lernout, Lim, Dobler, Fingerle, Gynthersen, Lindgren and Reiso2024). The treatment regimen involved:

Antibiotic therapy

  • Intravenous Ceftriaxone: Administered in 12-day cycles.

  • Oral Azithromycin: Administered concurrently with the intravenous ceftriaxone cycles.

  • Rest Periods: Each antibiotic cycle was followed by a three-week rest period.

Nutritional support

During the antibiotic treatment phase, the patient received intravenous nutrient infusions for 18 days. This nutritional support was critical in maintaining the patient’s overall health and aiding recovery (Yadav et al., Reference Yadav, Shah, George, Baral, Miraj, Bagchi, Das and Downs2023). The infusions included:

  • Vitamin C

  • B complex vitamins

  • Essential minerals

  • Calcium gluconate

  • Neurobion (Vitamin B1)

  • Spasmag (Magnesium Sulphate)

  • Cyanocobalamin

Symptom improvement

Table 3 illustrates the significant clinical improvements observed with the treatment regimen. The SF-36 scores showed an overall enhancement in quality of life. The patient experienced a marked reduction in fatigue and pain severity scores, along with improved cognitive function and enhanced general well-being. Fatigue and pain scores dropped from high and sever to low and moderate, while cognitive function improved from low to acceptable, indicating substantial recovery. Additionally, the negative phb-PCR result post-treatment confirms the clearance of B. miyamotoi infection. This result provides strong microbiological evidence of the treatment’s effectiveness.

Table 3.

Improvement in symptoms before and after treatment

Following the completion of the treatment regimen, the patient underwent regular follow-up assessments to monitor for potential recurrence of the infection and to evaluate overall health and symptomatology. The therapeutic effects have been sustained for eight months, during which the patient has not experienced any relapse of symptoms. After this period, the patient experienced some flare-ups, which were successfully managed with non-antibiotic therapies, including non-corticosteroid anti-inflammatory medications and painkillers.

Discussion

Given the complexities and challenges associated with diagnosing TBDs, and in light of the guidance provided by the CDC, IDSA (Infectious Diseases Society of America) and ECDC (European Centre for Disease Prevention and Control), our decision to use phb-PCR for diagnosing B. miyamotoi was justified by several factors. Initially, the patient underwent standard serological testing for LD and other common co-infections such as Bartonella and A. phagocytophilum, which all returned negative results. These tests are typically prioritised due to the higher prevalence of LD and its co-infections, as well as the more established diagnostic protocols available for these diseases. Additionally, comprehensive autoimmune screenings were conducted to rule out conditions that could mimic TBD symptoms.

Despite these negative serological results, the clinical presentation of the patient continued to suggest a tick-borne aetiology, warranting further investigation. The CDC and IDSA both acknowledge that B. miyamotoi is an emerging pathogen and recommend considering it in differential diagnoses, particularly when standard tests do not yield conclusive results, but clinical suspicion remains high (Lantos et al., Reference Lantos, Rumbaugh, Bockenstedt, Falck-Ytter, Aguero-Rosenfeld, Auwaerter, Baldwin, Bannuru, Belani, Bowie, Branda, Clifford, DiMario, Halperin, Krause, Lavergne, Liang, Meissner, Nigrovic, Nocton, Osani, Pruitt, Rips, Rosenfeld, Savoy, Sood, Steere, Strle, Sundel, Tsao, Vaysbrot, Wormser and Zemel2020; Kubiak et al., Reference Kubiak, Szczotko and Dmitryjuk2021; Burde et al., Reference Burde, Bloch, Kelly and Krause2023; Coder et al., Reference Coder, Price, Tewari, Witmier, Chapman, Chroscinski, Long, Livengood and Boyer2024). Phb-PCR offers enhanced sensitivity and specificity by targeting the phage genes associated with B. miyamotoi, which are part of the pathogen’s epigenetic makeup and present in multiple copies within the bacterial cells.

Therefore, the use of phb-PCR was a logical next step to accurately identify B. miyamotoi, allowing for the timely initiation of an effective treatment regimen. This approach underscores the importance of utilising advanced diagnostic techniques when standard methods fail to provide definitive answers, ultimately enhancing patient care and outcomes.

After detecting B. miyamotoi, we initiated a treatment regimen involving intravenous ceftriaxone and oral azithromycin, supplemented with nutrient infusions. This approach leverages the distinct mechanisms of action of two antibiotics, thereby reducing the risk of antibiotic resistance development. The inclusion of nutritional supplementation was not merely an adjunct but a pivotal component that mitigates the side effects commonly associated with prolonged antibiotic use, such as gastrointestinal disturbances and nutrient depletion. This strategy supports the body’s natural defences and facilitates a more effective recovery.

We recognise the complexities in TBDs. This case report advocates for clinicians to recognise the rising incidence of B. miyamotoi in ticks and patients when making differential diagnoses of TBDs. Utilising sensitive direct diagnostic tests, such as phage-based PCR, enhances diagnostic accuracy. This prevents delayed diagnoses and misdiagnoses, reduces patient suffering and addresses antibiotic resistance issues. This case exemplifies the synergy between laboratory diagnostics and clinical judgment, ultimately improving patient care. By integrating advanced diagnostics with clinical expertise, we can refine the diagnostic algorithm for TBRF and significantly enhance patient outcomes.

Conclusions

This case report highlights the critical importance of direct diagnostic methods for accurately identifying BMD. Diagnosing BMD is challenging due to its symptom overlap with LD and unreliable serological tests. In this case, multiple negative serological tests prompted the use of phb-PCR, which successfully detected B. miyamotoi in the patient’s blood. This detection facilitated a tailored treatment plan that included intravenous ceftriaxone, oral azithromycin and nutritional support, resulting in significant symptom improvement.

The success of phb-PCR in diagnosing BMD underscores its value in managing complex TBDs. Clinicians should consider B. miyamotoi testing when serological tests for LD and other common TBDs yield negative results, yet the clinical presentation suggests a tick-borne aetiology. Incorporating BMD testing into diagnostic protocols will ensure timely and accurate treatment.

Data availability statement

The findings of this case report are detailed within the article. Due to privacy and ethical considerations, individual patient data is not publicly accessible. For inquiries about the study’s methodologies and anonymized data, please contact the corresponding author, Jinyu Shan, at the provided email address. Data requests will be considered in line with ethical standards and patient confidentiality.

Acknowledgements

We express our sincere gratitude towards Mr. François-Xavier Louvet for his invaluable contribution to our research. His boundless enthusiasm and unwavering support have significantly enriched our work. We are profoundly thankful for his inspiration throughout this research endeavour.

Author contributions

Louis Teulières and Jinyu Shan co-conceived the idea for this paper. Louis Teulières handled the clinical aspects of the work and provided the outline for the diagnostic and treatment approaches. Jinyu Shan, with the assistance of Ying Jia, was responsible for the meticulous drafting and critical writing of the manuscript with constant conversation with Louis Teulières. Martha Clokie proofread the manuscript.

Financial support

We gratefully acknowledge the main funding received for the study from Phelix Research and Development (Phelix R&D, 37 Langton Street, SW10 0JL London, UK, Charity Number 1,156,666).

Competing interests

The authors declare no conflict of interest.

Ethics statement

The research conducted and presented in this paper was carried out with strict adherence to ethical principles, respecting the dignity, privacy and rights of the patient involved. Prior to conducting this study, informed consent was obtained from the patient, ensuring she was fully aware of the research’s nature, objectives, potential benefits and risks. The study was designed and executed with a commitment to maintaining confidentiality and safeguarding the patient’s personal and medical information, in accordance with the Declaration of Helsinki and relevant local regulations.

The authors have taken meticulous care to ensure that the research methodologies employed were ethically sound, scientifically justified and conducted under the appropriate oversight.

Furthermore, this paper does not contain any data that could lead to the identification of the patient, and all personal information has been anonymised to protect her privacy. The collaboration between the authors from PhelixRD Charity and the University of Leicester was founded on mutual respect, integrity and a shared goal of advancing medical knowledge for the benefit of patients suffering from tick-borne diseases.

References

Connections references

Lawrence, N and Brailey, A (2023). What is the current and expected evolution of prevalence, geographical spread and impact of ticks and tick-borne diseases, and what strategies are needed to improve management, testing, diagnosis and treatment of these diseases amongst patients and animal populations? Research Directions: One Health, 1-4. https://doi.org/10.1017/one.2023.11 CrossRefGoogle Scholar

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Figure 0

Table 1. Summary of diagnostic test results for the patient

Figure 1

Table 2. Autoantibodies, their target antigens, associated diseases in autoimmune conditions

Figure 2

Table 3. Improvement in symptoms before and after treatment

Author comment: Phage-Based PCR Revolution: Decoding and Defeating Borrelia miyamotoi in a Complex Tick-Borne Disease Case — R0/PR1

Published online by Cambridge University Press:  25 September 2024
DOI: https://doi.org/10.1017/one.2024.7.pr1 [Opens in a new window]
Jinyu Shan [Opens in a new window] Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom of Great Britain and Northern Ireland
Revision round: 0
Role: author

Comments

No accompanying comment.

Review: Phage-Based PCR Revolution: Decoding and Defeating Borrelia miyamotoi in a Complex Tick-Borne Disease Case — R0/PR2

Published online by Cambridge University Press:  25 September 2024
DOI: https://doi.org/10.1017/one.2024.7.pr2 [Opens in a new window]
Date of review:  20 February 2024
Revision round: 0
Role: reviewer
Recommendation/decision: minor-revision

Comments

This is a really important paper. Patients with chronic lyme disease currently have limited access to treatments. If the test presented could be validated in a large cohort with the response to treatment fully assessed with subsequent follow up this would pave the way for placebo controlled trials of antibiotic/other treatments. Although this is acase report there are few points the authors should try to address

1) Improvements were noted post treatment. There is no attempt to quantify the level of improvement. How did the improvements impact on the patients quality of life? Some of measures of this would be useful.

2) How long did the effects last? How is the patient today? This doesn't need a lot of detail but would be useful information to know.

3) Importantly if the phage test is going to be used as a marker of live infection. Did a negative test link to improvements? If the patient is still well post treatment it is important that a phage test is carried out. If the test is negative this supports the idea of a live Borellia infection that has been treated by antibiotics/other agents. If positive it suggests either i) the antibiotics/other agents have not cleared the infection ii) there is not a live infection and the phage DNA is remnant of a previous infection or ii) the impact of the antibiotics on improving the health of the patient are due to unknown off target effects.

A follow up on the patients health post treatment is really important and could perhaps be ethically included in the paper.

Presentation

Overall score 3 out of 5
Is the article written in clear and proper English? (30%)
4 out of 5
Is the data presented in the most useful manner? (40%)
2 out of 5
Does the paper cite relevant and related articles appropriately? (30%)
4 out of 5

Context

Overall score 4 out of 5
Does the title suitably represent the article? (25%)
4 out of 5
Does the abstract correctly embody the content of the article? (25%)
4 out of 5
Does the introduction give appropriate context and indicate the relevance of the results to the question or hypothesis under consideration? (25%)
4 out of 5
Is the objective of the experiment clearly defined? (25%)
4 out of 5

Results

Overall score 3 out of 5
Is sufficient detail provided to allow replication of the study? (50%)
3 out of 5
Are the limitations of the experiment as well as the contributions of the results clearly outlined? (50%)
5 out of 5

Review: Phage-Based PCR Revolution: Decoding and Defeating Borrelia miyamotoi in a Complex Tick-Borne Disease Case — R0/PR3

Published online by Cambridge University Press:  25 September 2024
DOI: https://doi.org/10.1017/one.2024.7.pr3 [Opens in a new window]
Leona Gilbert [Opens in a new window] Te?ted, Jyväskylä, 40100 , Finland
Date of review:  21 February 2024
Revision round: 0
Role: reviewer
Recommendation/decision: major-revision

Comments

Authors from the manuscript titled “Phage-Based PCR Revolution: Decoding and Defeating Borrelia miyamotoi in a Complex Tick-Borne Disease Case” have the goal of presenting a case report of a 46 year with various symptoms and the utility of phage-based PCR assay for the diagnosis of Borrelia miyamotoi. The case report is interesting and would add to the field, but there are major issues with the narrative and evidence that must be addressed below.

Abstract

*”two-tiered serology approach”. Why are the authors mentioning this here this implies that you are going to test for Borrelia burgdorferi sl group and not relapsing fever such as Borrelia miyamotoi. So this statement of "failed to ascertain the presence of an infectious" is misleading as it makes sense that the two-tiered approach did not find Borrelia miyamotoi. Authors must reword this statement as the CDC recommended laboratory diagnosis is PCR or serological assays and not the two-tier approach.

*In the following sentence, “However, the application of a phage-based PCR assay by R.E.D Laboratories proved pivotal, leading to the successful identification of Borrelia miyamotoi as the causative pathogen.” What is meant by as the causative pathogen to what? All the patient’s symptoms or? Consider removing R.E.D Laboratories from the abstract as this should be in the methods section.

*What is meant by “precise diagnosis?” The authors don’t explicitly demonstrate in the abstract the use of precision as a parameter of the phage-based PCR assay.

*Similar advice is to reword the use of “conclusive findings from the phage-based PCR assay” if the authors demonstrate this in the abstract. It is suggested that results are provided to demonstrate precision and conclusive findings from this PCR technique.

*Authors must reword the last sentence as Borrelia miyamotoi diagnostic criteria does not follow the two-tier system as it

*Similarly, why are the authors using the words “complex tick-borne diseases” as this patient was only diagnosed with serology for Relapsing fever and not other tick-borne diseases.

Introduction:

*Awkward sentence. Please reword. “In contrast, Borrelia miyamotoi was first identified in Japanese ticks in 1995 and increasingly acknowledged globally [8].”

*Spacing issues: chronic health complications [14] .

*Misleading sentence as B miyamotoi does not following standard detection methods.

“It often escapes detection with standard methods because of its link to relapsing fever and nonspecific symptoms [10, 12].”

*The third paragraph of the Introduction is convoluted as it starts with the diagnosis of tick-borne diseases, then talks about antibiotic treatment, then talks about B miyamotoi and escapes detections. What is not disclosed is the unique diagnostic challenges with B miyamotoi. Authors are advised to present these as the two-tier method (standard method) is not the diagnostic route for diagnosing B miyamotoi infection.

*It would be good to correlate B miyamotoi infection symptoms from in the abstract to intro to results to discussion, as this is not done.

*Authors must provide citations to support their statement of “sensitive detection” in the following statement “In this challenging diagnostic landscape, phage-based PCR assays represent a promising solution for the sensitive detection of Borrelia species.”

*It is also advised to have only citations that actually demonstrate “intrinsic specificities “in the following statement “intrinsic specificity that phages have for their bacterial hosts [15-17].” Similarly, in the following statement about “correlation”, “This specificity is underpinned by a 100% correlation between phages and their respective bacterial hosts, ensuring that the presence of a phage is indicative of the presence of the target bacteria [15-18].” It is a must to have only those citations that actually demonstrate intrinsic specificity and 100% correlation as results-

*The following needs a citation “Therefore, targeting phages in PCR assays offers a method with potentially higher sensitivity compared to traditional PCR methods that target bacterial DNA directly.”

*A citation for the following is needed: This increased sensitivity is due to the combination of phages' high specificity for their hosts and the amplification effect provided by the presence of multiple copies of phages in bacterial populations.

*The following is misleading as this patient is about Relapsing fever and not lyme disease. Authors must reword. “Consequently, phage-based PCR assays could lead to more accurate and earlier detection of Borrelia species, improving diagnostic capabilities and potentially allowing for more timely and effective treatment of Lyme disease.”

*Again, the choice of citations for the following needs to be scrutinized to really support the authors’ statement in the following sentence: “This approach underscores the importance of integrating the biology of phages into diagnostic tools, leveraging their natural relationship with bacteria to enhance the detection and management of bacterial infections”. It is really advised also to cite others’ work here to support this statement and not rely on author’s own work only.

*Also, the generalization of Borrelia in the last paragraph of the introduction needs to be more accurate as it groups all the borrelia into one, but the author should not, as relapsing fever is its own clad. “This report explores the effectiveness of phage-based PCR in diagnosing a Borrelia-related tick-borne disease case. It underscores the vital role of phage-based diagnostic methods in accurately identifying Borrelia infections, guiding effective treatment strategies, and enhancing patient outcomes, especially where conventional methods fall short”. To bring it more accurate, authors should say B miyamotoi disease and infection and remove the word where conventional methods fall short.

Methods

In general more explicit details are needed with supplier names on the tests, phage-based PCR protocol, and exact protocols for treatment regimen (antibiotic therapy ad nutritional support), post-treatment assessment and how improvements were assessed.

*Figure 1. Please be more explicit in the details in the figure. For example, what Initial Enzyme Immunoassay (EIA) and Immunoblot were used, and for what pathogens? The same thing for IFAs and pathogens. What is meant by specific autoantibodies, and which tests were used? Then, it is misleading to say that there was breakthrough in diagnosis if B miyamotoi was not investigated in the earlier steps as by convention, PCR should have been used to diagnose B miyamotoi, not this diagnostic algorithm. In fact, Figure 1 demonstrates that if you don’t look for B miyamotoi by PCR you will not find it. Also it is hard to ascertain from the figure if serological tests for B miyamotoi were used. The figure image itself is pixelated. And what is meant by each entry in the image should be described shortly in the image and then fully in the text. For example, what is meant by post-treatment assessment? Etc.

*When were the “several tick exposures”? What year and time of year?

*The evaluation for Lyme disease needs more information. For example, what exact test was used for the EIA and Immunoblot? What species of Lyme Borrelia were they testing for?

*Same question for the IFA. What exactly were the tick-borne pathogens that were tested for? Or antibodies for? And why are the authors only focusing of disclosing Bartonella and Anaplasma bacteria when they said “other tick-borne pathogens”?

*What is the exact test was used for the ANA? And the other tests for auto-antibody tests?

*Where is the phage-based PCR protocol described in the methods? It must be described.

*Lines 132 to 134 are results and not methods

Results

The results need to accurately demonstrate the findings of this research. A summative table of all the test results should be provided, etc.

*Right now the results does not do this as it has methods in it. It is advised that these parts be moved to the methods section and authors truly write a results section again. It is also strongly encouraged that the authors be very explicit describing in treatment therapy and post-treatment assessment. For example, how were the symptoms assessed exactly (method’s section)? Authors could provide a figure displaying the improved symptoms, for example, of an item in the results section.

Discussion

*Again authors are cautioned in using misleading statements like “Traditional diagnostic methods had fallen short, unable to identify the underlying cause of the patient's symptoms, which led to significant uncertainties in determining the appropriate treatment pathway.” as the authors did not used traditional relapsing fever diagnostics in their algorithm displayed in figure 1.

Also this statement “This technology's ability to detect elusive pathogens like B. miyamotoi, which are often not identified by standard testing methods, is crucial in shaping effective and targeted treatment plans”

Also this statement “In particular, this case report accentuates the critical function of phage-based PCR in diagnosing tick-borne diseases, especially when conventional antibody-based tests return inconclusive or negative results.”

Also this statement “The assay's heightened sensitivity and specificity for detecting B. miyamotoi, which frequently elude standard testing protocols, was instrumental in guiding the therapeutic approach.”

Also, this statement, as not a comprehensive treatment protocol, is provided by the authors: “This comprehensive treatment strategy not only focuses on eradicating the B. miyamotoi infection but also on supporting the patient’s overall health, leading to substantial symptom improvement and contributing to a more effective and complete recovery.”

Also, this statement, “In this clinical case, the phage-based PCR assay emerges as a key diagnostic tool for accurately detecting Borrelia species, including B. miyamotoi, which are often missed by traditional methods.”

*Because there are no exact results in this case report, authors cannot state the following: “conclusively identifying B. miyamotoi as the aetiological agent”. Where is the evidence for this? Please provide it in a figure or supplementary table.

*Similarly, there are many statements in the discussion that have no evidence to add credibility to them, as there are no results to substantiate many of the statements the authors are making. For example and not all-inclusive: The successful treatment, evidenced by the patient's substantial recovery, underscores the indispensable role of advanced diagnostic tools like phage-based PCR in clinical settings.

How do authors demonstrate successful treatment, and what is meant by “substantial recovery”? Frankly where is the evidence.

*There are various areas in the discussion the authors are repeating themselves and also in the conclusion.

Other Items

Do Phelix Research and Development have ties to RedLabs? If so then this needs to be disclosed.

It is strongly recommended that authors structure and explicitly write this case reports according to the CARE guidelines so that the true, full impact of this case report is valued.

Riley DS, Barber MS, Kienle GS, Aronson JK, von Schoen-Angerer T, Tugwell P, Kiene H, Helfand M, Altman DG, Sox H, Werthmann PG, Moher D, Rison RA, Shamseer L, Koch CA, Sun GH, Hanaway P, Sudak NL, Kaszkin-Bettag M, Carpenter JE, Gagnier JJ. CARE guidelines for case reports: explanation and elaboration document. J Clin Epidemiol. 2017 May 18. pii: S0895-4356(17)30037-9. doi: 10.1016/j.jclinepi.2017.04.026.

Presentation

Overall score 3 out of 5
Is the article written in clear and proper English? (30%)
4 out of 5
Is the data presented in the most useful manner? (40%)
2 out of 5
Does the paper cite relevant and related articles appropriately? (30%)
4 out of 5

Context

Overall score 4 out of 5
Does the title suitably represent the article? (25%)
4 out of 5
Does the abstract correctly embody the content of the article? (25%)
4 out of 5
Does the introduction give appropriate context and indicate the relevance of the results to the question or hypothesis under consideration? (25%)
4 out of 5
Is the objective of the experiment clearly defined? (25%)
4 out of 5

Results

Overall score 3 out of 5
Is sufficient detail provided to allow replication of the study? (50%)
3 out of 5
Are the limitations of the experiment as well as the contributions of the results clearly outlined? (50%)
5 out of 5

Decision: Phage-Based PCR Revolution: Decoding and Defeating Borrelia miyamotoi in a Complex Tick-Borne Disease Case — R0/PR4

Published online by Cambridge University Press:  25 September 2024
DOI: https://doi.org/10.1017/one.2024.7.pr4 [Opens in a new window]
Jolyon Medlock [Opens in a new window] UK Health Security Agency, London, SW1P 3JR, United Kingdom of Great Britain and Northern Ireland
Date of review:  12 March 2024
Revision round: 0
Role: Editor in Chief
Recommendation/decision: major-revision

Comments

No accompanying comment.

Author comment: Successful diagnosis and treatment of Borrelia miyamotoi in a patient with joint and muscle pains, ME/CFS, and cognitive dysfunction following tick bites: a case report — R1/PR5

Published online by Cambridge University Press:  25 September 2024
DOI: https://doi.org/10.1017/one.2024.7.pr5 [Opens in a new window]
Jinyu Shan [Opens in a new window] Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom of Great Britain and Northern Ireland
Revision round: 1
Role: author

Comments

No accompanying comment.

Decision: Successful diagnosis and treatment of Borrelia miyamotoi in a patient with joint and muscle pains, ME/CFS, and cognitive dysfunction following tick bites: a case report — R1/PR6

Published online by Cambridge University Press:  25 September 2024
DOI: https://doi.org/10.1017/one.2024.7.pr6 [Opens in a new window]
Richard Kock [Opens in a new window] Independent Scholar, Kent, United Kingdom of Great Britain and Northern Ireland
Revision round: 1
Role: Editor in Chief
Recommendation/decision: accept

Comments

I have cross checked reviewer comments to author response and in text and it looks as if all matters are dealt with satisfactorily.

It contributes to the question in part and for a specific disease rarely diagnosed. It is contemporary and significant even as a single case report: What is the current and expected evolution of prevalence, geographical spread and impact of ticks and tick-borne diseases, and what strategies are needed to improve management, testing, diagnosis and treatment of these diseases amongst patients and animal populations?