Severe ME/CFS: Assessment Methodology

1 Fricke et al. 2026 β€” ACHTSAM Study Protocol

Full Citation:: Fricke C, Deibert P, Maier P, Kern W, Krumnau O, Barsch F. ACHTSAM study protocol: outreach diagnostics and assessment of tolerability in severe ME/CFSβ€”a pilot study. BMJ Open. 2026;16(3):e113095. (Fricke et al. 2026) DOI:: 10.1136/bmjopen-2025-113095 Trial Registration:: DRKS00035231; FRKS005506 Study Design:: Prospective, non-interventional observational pilot study with home-based outreach assessments. Population:: \(n\)=25 patients with severe to very severe ME/CFS (Bell score \(\leq\) 30), University Medical Centre Freiburg, Germany. Key Innovation:: First systematic investigation of which diagnostic procedures can be safely and tolerably administered to severe and very severe ME/CFS patients in their home environment. Addresses the critical gap that \(>\) 60% of severe ME/CFS patients cannot complete standard inpatient diagnostic protocols. Assessment Battery::

- *Phase 1*: Validated remote questionnaires (Composite Autonomic Score-31, Short Form 12, DePaul Symptom Questionnaire–PEM, Munich Berlin Symptom Questionnaire, Fatigue Life Experience Inventory)
- *Phase 2a*: Home visits for resting ECG, HRV with paced breathing, pupillography, cognitive assessments (MoCA, TMT-B, SDMT), osteosonography, body composition, blood sampling, salivary cortisol
- *Phase 2b*: Near-infrared spectroscopy (NIRS) for muscle oxygenation, neurocognitive/psychological assessment, handgrip dynamometry, Schellong test, EndoPAT endothelial function, salivary cortisol

Primary Hypotheses::

- H1: $<$ 50% of standard clinical assessments will be fully completable due to PEM or exhaustion
- H2: Non-invasive supine-position assessments will have β‰₯80% completion; high-burden tests $<$ 30%
- H3: Very severe patients (Bell $\leq$ 20) will tolerate β‰₯20% fewer assessments than severe (Bell 21–30)
- H4: Autonomic, endothelial, and pupillary parameters will show deviations in a substantial proportion

Significance:: Establishes methodological framework for inclusive severe ME/CFS research; home-based approach reduces clinic-induced stress and PEM risk; includes pilot biobank component for future biomarker investigations (viral reactivation, autoantibodies). Limitations:: Study protocol only (results pending April 2026); small sample (\(n\)=25); no control group; geographically restricted to 50km radius of Freiburg; sequential assessment design precludes attribution of PEM to individual procedures. Certainty:: N/A (protocol paper; certainty will depend on results). Relevance:: Directly addresses systematic exclusion of severe patients from ME/CFS research (Sections Mortality Figures: Memorial Record Selection Bias and The Devastating Reality of Severe ME/CFS); informs future trial design for this underserved population.

2 Zuberbier et al. 2022 β€” EAACI/GA^2LEN Urticaria Guideline (Fourfold Up-Dosing)^

Full Citation:: Zuberbier T, Abdul Latiff AH, Abuzakouk M, et al. The international EAACI/GA2LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy. 2022;77(3):734–766. DOI:: 10.1111/all.15090 PMID:: 34536239 Published:: March 2022 Study Type:: International evidence-based clinical guideline Key Recommendations::

- Step 1: Standard-dose second-generation H1 antihistamine
- Step 2: Up to *fourfold dose* of the same second-generation H1 antihistamine (if inadequate after 2–4 weeks)
- Step 3: Add-on therapy (omalizumab, cyclosporine, or other agents)
- Recommendation applies class-wide to all second-generation H1 antihistamines

Certainty:: High (multi-society guideline with formal evidence grading) Clinical Relevance:: Provides the formal basis for higher-than-standard antihistamine dosing adopted by MCAS specialists. Developed for chronic spontaneous urticaria (CSU), but extrapolated to MCAS based on shared histamine-mediated pathophysiology. See Section Antihistamine Up-Dosing in MCAS.

3 van den Elzen et al. 2017 β€” Antihistamine Up-Dosing Safety

Full Citation:: van den Elzen MT, van Os-Medendorp H, van den Brink I, et al. Effectiveness and safety of antihistamines up to fourfold or higher in treatment of chronic spontaneous urticaria. Clinical and Translational Allergy. 2017;7:4. DOI:: 10.1186/s13601-017-0141-3 PMID:: 28228950 PMCID:: PMC5309999 Published:: February 2017 Study Design:: Retrospective cohort study Sample Size:: 171 patients; 59 received above-fourfold doses (median 8\(\\times\), range 5–12\(\\times\) standard) Key Findings::

- Only 10% of patients at above-fourfold doses reported side effects (predominantly somnolence)
- *No serious adverse events* at any dose level
- 62% of patients at standard dose were uncontrolled; 45% responded to dose increase

Certainty:: Medium (retrospective, single-center, but largest dataset on high-dose safety) Clinical Relevance:: Provides reassurance for dose escalation beyond standard in MCAS patients. Key safety data supporting Section Antihistamine Up-Dosing in MCAS.

4 Podder et al. 2023 β€” Up-Dosing Efficacy Review

Full Citation:: Podder I, Dhabal A, Chakraborty SS. Efficacy and Safety of Up-dosed Second-generation Antihistamines in Uncontrolled Chronic Spontaneous Urticaria: A Review. Journal of Clinical and Aesthetic Dermatology. 2023;16(3):44–50. PMCID:: PMC10027330 Published:: March 2023 Study Type:: Systematic review of up-dosing trials Key Findings::

- Fexofenadine: 83% responder rate at up-dosing (highest among all antihistamines studied) β€” Grade A recommendation
- Cetirizine/levocetirizine: 54% responder rate β€” Grade A recommendation
- Desloratadine: 30% responder rate at 4$\\times$ β€” Grade B recommendation
- Drowsiness increases (9.5–59%) but no dose-dependent systemic complications

Certainty:: High (systematic review with evidence grading) Clinical Relevance:: Provides drug-specific efficacy data for choosing which H1 antihistamine to up-dose. Fexofenadine emerges as the most effective candidate for escalation.

5 Salvucci et al. 2023 β€” Antihistamines in Long COVID

Full Citation:: Salvucci F, Codella R, Coppola A, et al. Antihistamines improve cardiovascular manifestations and other symptoms of long-COVID attributed to mast cell activation. Frontiers in Cardiovascular Medicine. 2023;10:1202696. DOI:: 10.3389/fcvm.2023.1202696 PMCID:: PMC10388239 Published:: July 2023 Study Design:: Prospective observational study Sample Size:: 14 long-COVID patients with MCAS features Intervention:: Fexofenadine 180 mg + famotidine 40 mg daily for 20 days Key Findings::

- 29% complete symptom disappearance
- Fatigue resolved in 43%
- Brain fog resolved in 43%
- Tachycardia resolved in 57%

Certainty:: Low-Medium (small sample, no control group, short treatment duration) Clinical Relevance:: Provides preliminary evidence for H1+H2 combination in post-viral fatigue with MCAS features. Supports antihistamine trial in ME/CFS patients with mast cell activation phenotype.

6 Molderings et al. 2016 β€” MCAS Pharmacological Treatment Options

Full Citation:: Molderings GJ, Haenisch B, Bogdanow M, Fimmers R, N{"o}then MM. Pharmacological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Archives of Pharmacology. 2016;389(7):671–694. DOI:: 10.1007/s00210-016-1247-1 PMID:: 27132234 PMCID:: PMC4903110 Published:: July 2016 Study Type:: Comprehensive pharmacological review Key Content::

- Systematic review of all pharmacological interventions for MCAS
- H1 and H2 antihistamine dose escalation strategies
- Mast cell stabilizers, leukotriene inhibitors, and biologics
- Treatment algorithm based on clinical response

Certainty:: Medium (expert review; limited by sparse RCT evidence for MCAS) Clinical Relevance:: Primary reference for MCAS pharmacotherapy. Supports stepwise antihistamine escalation approach used in Section No Formal H2 Up-Dosing Guideline.

7 Nurmatov et al. 2015 β€” H1 Antihistamines in Mast Cell Activation (Systematic Review)

Full Citation:: Nurmatov UB, Rhatigan E, Simons FER, Sheikh A. H1-antihistamines for primary mast cell activation syndromes: a systematic review. Allergy. 2015;70(9):1052–1061. DOI:: 10.1111/all.12672 PMID:: 26095756 Published:: September 2015 Study Design:: Systematic review Key Findings::

- Only 5 small, mostly historical trials identified for H1 antihistamines in primary mast cell activation syndromes
- Evidence base is extremely limited
- Highlights major gap between widespread clinical use and formal trial evidence

Certainty:: High (rigorous systematic review methodology) Clinical Relevance:: Documents the evidence gap underlying MCAS antihistamine dosing. Fourfold up-dosing recommendation is extrapolated from CSU guidelines, not supported by MCAS-specific trials.

References

Fricke, Carmen, Peter Deibert, Philipp Maier, Winfried Kern, Oliver Krumnau, and Friedrich Barsch. 2026. β€œACHTSAM Study Protocol: Outreach Diagnostics and Assessment of Tolerability in Severe ME/CFSβ€”a Pilot Study.” BMJ Open 16 (3): e113095. https://doi.org/10.1136/bmjopen-2025-113095.