Systematic Reviews and Meta-Analyses

1 Breitschwerdt et al. 2025 β€” Babesia and Bartonella DNA in Chronic Fatigue

(Breitschwerdt et al. 2025)

Full Citation:: Breitschwerdt EB, Maggi RG, Bush JC, Kingston E. Babesia and Bartonella Species DNA in Blood and Enrichment Blood Cultures from People with Chronic Fatigue and Concurrent Neurological Symptoms. Pathogens. 2025;15(1):2. DOI:: 10.3390/pathogens15010002 PMID:: 41598986 Study Design:: Cross-sectional; PCR + enrichment blood culture (BAPGM) Sample Size:: n=50 self-selected (fatigue β‰₯6mo + β‰₯1 neurological symptom); no healthy controls Key Findings::

  • Babesia DNA detected in 24% (12/50, 95% CI 12–36%)

  • Bartonella DNA detected in 26% (13/50, 95% CI 13.8–38.2%)

  • Combined Babesia/Bartonella infection: 46% (23/50); 2/50 co-infected with both

  • Blood enrichment culture increased detection yield vs direct PCR

  • Fatigue duration ranged from 6 months to 19 years Conclusion:: Provides PCR-based evidence of Babesia and Bartonella infection in chronic fatigue patients with neurological symptoms. Combined 46% infection rate is the basis for the β€œ~50%” claim circulating in patient communities, though Babesia alone is 24%. Limitations:: No healthy control group (cannot determine if rate exceeds background seroprevalence); small n; enrichment culture specificity debated; authors are Galaxy Diagnostics co-founders (COI); no species identification for most Babesia detections; self-selected sample. Certainty Assessment::

  • Quality: Low (Pathogens; pilot; no controls; significant COI)

  • Sample: Small (n=50, no control group)

  • Replication: None (single group at NC State)

  • Score: 0.45

2 Maggi et al. 2024 β€” Babesia odocoilei and Bartonella Co-Infections

(Maggi et al. 2024)

Full Citation:: Maggi RG, Calchi AC, Moore CO, Kingston E, Breitschwerdt EB. Human Babesia odocoilei and Bartonella spp. co-infections in the Americas. Parasites & Vectors. 2024;17:302. DOI:: 10.1186/s13071-024-06385-4 PMID:: 38992682 Study Design:: Case series; molecular diagnostics (PCR, DNA sequencing) Sample Size:: n=7 with chronic non-specific symptoms Key Findings::

  • 7/7 confirmed Babesia odocoilei infection; 6/7 co-infected with Bartonella spp.

  • Documents B. odocoilei as emerging human pathogen in the Americas

  • All patients had chronic non-specific symptoms overlapping with ME/CFS Conclusion:: Babesia odocoilei infection occurs more frequently than previously recognized and frequently presents with Bartonella co-infection. Limitations:: Very small case series; no controls; same research group as Breitschwerdt2025BabesiaCFS; no ME/CFS diagnostic criteria used. Certainty Assessment::

  • Score: 0.30

3 Scott et al. 2021 β€” Babesia odocoilei in Symptomatic Humans

(Scott et al. 2021)

Full Citation:: Scott JD, Sajid MS, Pascoe EL, Foley JE. Detection of Babesia odocoilei in Humans with Babesiosis Symptoms. Diagnostics. 2021;11(6):947. DOI:: 10.3390/diagnostics11060947 PMID:: 34070625 Study Design:: Case series Sample Size:: n=5 with babesiosis symptoms Key Findings::

  • Babesia odocoilei DNA detected in all 5 symptomatic individuals

  • Fatigue reported as a presenting symptom of babesiosis Conclusion:: Provides evidence that Babesia odocoilei is a human pathogen producing fatigue as a core symptom. Limitations:: Small case series; no controls; no ME/CFS diagnosis. Certainty Assessment::

  • Score: 0.35

4 Locke et al. 2023 β€” Neurologic Complications of Babesiosis

(Locke et al. 2023)

Full Citation:: Locke S, O’Bryan J, Zubair AS, Rethana M, Moffarah AS, Krause PJ, Farhadian SF. Neurologic Complications of Babesiosis, United States, 2011–2021. Emerging Infectious Diseases. 2023;29(6):1127–1135. DOI:: 10.3201/eid2906.221890 PMID:: 37209667 Study Design:: Retrospective surveillance analysis (CDC data) Sample Size:: US population-level data 2011–2021 Key Findings::

  • Neurologic complications documented in babesiosis patients

  • Fatigue, headache, and cognitive symptoms reported as persistent sequelae Conclusion:: Babesia infection can produce chronic neurologic symptoms including fatigue, establishing it as a potential trigger for post-infectious fatigue syndromes. Limitations:: Retrospective; relies on ICD coding; population-level, not ME/CFS-specific. Certainty Assessment::

  • Score: 0.65

5 MacDonald et al. 1996 β€” CFS Case-Control: Null Babesia Result

(MacDonald et al. 1996)

Full Citation:: MacDonald KL, Osterholm MT, LeDell KH, White KE, Schenck CH, Chao CC, Persing DH, Johnson RC, Peterson PK. A case-control study to assess possible triggers and cofactors in chronic fatigue syndrome. American Journal of Medicine. 1996;101(1):103–110. DOI:: 10.1016/S0002-9343(96)00245-6 PMID:: 8644768 Study Design:: Matched case-control Sample Size:: n=47 CFS, n=47 matched community controls Key Findings::

  • Babesia microti antibodies: 0/47 CFS cases positive

  • 2/47 controls positive (babesiosis not associated with CFS)

  • No serological evidence of past Babesia exposure in CFS Conclusion:: This study found no association between Babesia infection and CFS, using serological methods available in 1996. Important null result that contrasts with the Breitschwerdt 2025 PCR findings. Limitations:: 1996-era serology (may lack sensitivity vs modern PCR); small n for seroprevalence assessment. Certainty Assessment::

  • Score: 0.50

6 Moezzi et al. 2025 β€” Haptoglobin and Post-Exertional Malaise

(Moezzi et al. 2025)

Full Citation:: Moezzi A, Ushenkina A, Widgren A, Bergquist J, Li P, Xiao W, Rostami-Afshari B, Leveau C, Elremaly W, Caraus I, Franco A, Godbout C, Nepotchatykh O, Moreau A. Haptoglobin phenotypes and structural variants associate with post-exertional malaise and cognitive dysfunction in myalgic encephalomyelitis. Journal of Translational Medicine. 2025;23. DOI:: 10.1186/s12967-025-07006-z PMID:: 40877900 Study Design:: Longitudinal case-control; discovery (n=61 ME, n=20 controls) + validation (n=89 ME, n=24 controls) Sample Size:: n=140 ME, n=44 controls (total 184) Key Findings::

  • ME patients show significant reduction in haptoglobin (Hp) levels after post-exertional stress

  • Lower baseline Hp associated with impaired cognitive performance

  • Hp phenotypes differ in their association with PEM severity

  • Hp structural proteoforms identified by HPLC analysis Conclusion:: Haptoglobin is a biomarker of PEM and cognitive dysfunction in ME. Directly relevant to Babesia β†’ hemolysis β†’ haptoglobin depletion β†’ oxidative stress pathway. Limitations:: No direct Babesia testing in these patients; haptoglobin depletion may arise from multiple causes beyond hemolysis. Certainty Assessment::

  • Score: 0.65

7 Prevalence and Epidemiology

Full Citation:: Lim E-J, Ahn Y-C, Jang E-S, Lee S-W, Lee S-H, Son C-G. Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Journal of Translational Medicine. 2020;18(1):100. DOI:: 10.1186/s12967-020-02269-0 PMID:: 32093722 PMCID:: PMC7038594 Key Findings:: Pooled prevalence 0.89% (95% CI: 0.60–1.33%); women 1.36% vs men 0.86%; children/adolescents 0.55%.

Full Citation:: Centers for Disease Control and Prevention. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults: United States, 2021–2022. NCHS Data Brief No. 488. Hyattsville, MD: National Center for Health Statistics; 2023. URL:: https://www.cdc.gov/nchs/products/databriefs/db488.htm Key Findings:: 1.3% of US adults have ME/CFS; prevalence increases with age through 60–69 years; 84–91% remain undiagnosed.

8 Cognitive Impairment

Full Citation:: Sebaiti MA, Hainselin M, Gounden Y, et al. Systematic review and meta-analysis of cognitive impairment in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Scientific Reports. 2022;12(1):2157. DOI:: 10.1038/s41598-021-04764-w PMID:: 35145174 Key Findings:: Large effect size for verbal working memory deficits; no significant difference in visual working memory.

9 Long COVID and ME/CFS Overlap

Full Citation:: Wong TL, Weitzer DJ. Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)β€”A Systematic Review and Comparison of Clinical Presentation and Symptomatology. Medicina. 2021;57(5):418. DOI:: 10.3390/medicina57050418 PMCID:: PMC8145228

Full Citation:: The persistence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) after SARS-CoV-2 infection: A systematic review and meta-analysis. Journal of Infection. 2024;89(4):101231. DOI:: 10.1016/j.jinf.2024.106231 PMID:: 39353473 Key Findings:: Approximately half of Long COVID patients fulfill ME/CFS diagnostic criteria.

10 Sleep Abnormalities

Full Citation:: Baig S, Engelbrecht K, Engelbrecht F, et al. Objective sleep measures in chronic fatigue syndrome patients: A systematic review and meta-analysis. Sleep Medicine Reviews. 2023;69:101775. DOI:: 10.1016/j.smrv.2023.101775 PMID:: 37116254 PMCID:: PMC10281648 Sample:: 24 studies; 801 adults (426 ME/CFS, 375 controls); 477 adolescents Key Findings:: Longer sleep latency, reduced sleep efficiency, longer REM latency, altered sleep microstructure.

Full Citation:: Maksoud R, du Preez S, Eaton-Fitch N, et al. Systematic Review of Sleep Characteristics in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Healthcare. 2021;9(5):568. DOI:: 10.3390/healthcare9050568 PMCID:: PMC8150292

11 Evidence Mapping

Full Citation:: Toogood PL, Clauw DJ, Engel CC, et al. Recent research in myalgic encephalomyelitis/chronic fatigue syndrome: an evidence map. BMC Medicine. 2025;23(1):134. PMCID:: PMC11973615 Scope:: Mapping ME/CFS evidence from 2018–2023.

References

Breitschwerdt, Edward B, Ricardo G Maggi, Janice C Bush, and Emily Kingston. 2025. β€œBabesia and Bartonella Species DNA in Blood and Enrichment Blood Cultures from People with Chronic Fatigue and Concurrent Neurological Symptoms.” Pathogens 15 (1): 2. https://doi.org/10.3390/pathogens15010002.
Locke, Steven, Jane O’Brien, Adeel S Zubair, Mayanka Rethana, Ali S Moffarah, Peter J Krause, and Shelli F Farhadian. 2023. β€œNeurologic Complications of Babesiosis, United States, 2011–2021.” Emerging Infectious Diseases 29 (6): 1127–35. https://doi.org/10.3201/eid2906.221890.
MacDonald, Kristine L, Michael T Osterholm, Kathleen H LeDell, Karen E White, Charlotte H Schenck, Chun C Chao, David H Persing, James L Hadler, Homayoon Farzadegan, and Lyle R Petersen. 1996. β€œA Case-Control Study to Assess Possible Triggers and Cofactors in Chronic Fatigue Syndrome.” American Journal of Medicine 101 (6): 103–10. https://doi.org/10.1016/S0002-9343(96)00245-6.
Maggi, Ricardo G, Ana Claudia Calchi, Charlotte O Moore, Emily Kingston, and Edward B Breitschwerdt. 2024. β€œHuman Babesia Odocoilei and Bartonella Spp. Co-Infections in the Americas.” Parasites & Vectors 17: 302. https://doi.org/10.1186/s13071-024-06385-4.
Moezzi, Adam, Anna Ushenkina, Anders Widgren, Jonas Bergquist, et al. 2025. β€œHaptoglobin Phenotypes and Structural Variants Associate with Post-Exertional Malaise and Cognitive Dysfunction in Myalgic Encephalomyelitis.” Journal of Translational Medicine 23 (1). https://doi.org/10.1186/s12967-025-07006-z.
Scott, John D, Muhammad S Sajid, Emily L Pascoe, and Janet E Foley. 2021. β€œDetection of Babesia Odocoilei in Humans with Babesiosis Symptoms.” Diagnostics 11 (6): 947. https://doi.org/10.3390/diagnostics11060947.