ER/UC-PEM Index™ Innovative PEM Detection for Faster ME/CFS Diagnosis

Introduction

Myalgic encephalomyelitis/chronic fatigue syndrome is common, costly, and routinely missed until someone reads the chart as a timeline. Patients describe a delayed crash after effort that lasts days to weeks. CDC and NICE name this pattern post-exertional malaise and make it central to diagnosis (CDC, 2024; NICE NG206, 2021). Yet most people with ME/CFS still do not have a diagnosis, and many wait years for recognition, with the National Academies reporting both large underdiagnosis and long diagnostic lag that harms care and employment (Institute of Medicine, 2015; Bernhoff et al., 2022; Solve M.E., 2023).

The prevailing approach asks patients to perform new exertion to “prove” PEM or to return for repeat testing that rarely changes care. That creates risk, especially for those with orthostatic intolerance, sensory hypersensitivity, or limited cardiopulmonary reserve. It also bakes in inaccuracy. Pulse oximeters can overestimate oxygenation in people with darker skin, which widens the gap between numbers and symptoms during crashes unless clinicians document the limitation up front (Sjoding et al., 2020; Fawzy et al., 2022; FDA draft communications, 2024–2025).

The CYNAERA ER/UC-PEM Index solves the recognition problem without provoking symptoms. It treats routine emergency, urgent-care, and primary-care records as a natural experiment. If encounter timing clusters within 72 hours and the history fits CDC and NICE PEM language, the chart already contains what is needed to diagnose. Orthostatic features can be inferred from triage, supine, post-ambulation, and discharge vitals that are commonly recorded. Bedside logic aligns with the Heart Rhythm Society and practical NASA Lean guidance used by frontline clinics (Sheldon et al., 2015; Raj, 2022; Bateman Horne Center, 2025).

Early recognition matters economically and clinically. The longer a patient remains unstabilized, the more cycles of PEM entrench disability, slow recovery, and raise per-patient costs. Energy-envelope studies and cohort analyses point in the same direction. Stabilize earlier. Crash less. Protect function (Jason et al., 2009; O’Connor et al., 2017; Ghali et al., 2022). On the system side, a records-first diagnosis pathway lowers payer spend from duplicate testing and avoidable revisits, and it makes trial recruitment cheaper by expanding a computable pool of confirmed patients for EHR-enabled screening (Getz, Tufts CSDD; O’Brien et al., 2021; Kalankesh et al., 2024).

This paper turns that philosophy into an operating manual. It defines the ER/UC-PEM Index. It specifies exactly what to extract from the chart, what to write so it counts, and when to stop repeating tests. It restores the population view using the US-CUCC™ prevalence model that combines pre-pandemic ME/CFS with the Long COVID pipeline. It quantifies labor-market losses and shows how payers can structure incentives for fast, safe recognition. It also provides a telehealth training plan that any clinic can scale in an hour, plus automation modules that generate ready-to-sign notes for clinicians and one-page packets for patients.

Safety first. Science forward. Prove PEM from records, not exertion.

What PEM is

Post-exertional malaise is the delayed, disproportionate crash that follows physical, cognitive, orthostatic, or emotional effort. Onset is typically 12–48 hours and can extend to 72 hours or longer, followed by days to weeks of relapse. Both CDC and NICE describe this timing and pattern and make PEM central to clinical recognition of ME/CFS (CDC clinical materials; NICE NG206).

The 2015 National Academies report elevated PEM to a core diagnostic feature and emphasized cognitive impairment as a key domain for documentation (Institute of Medicine, 2015).

Why this matters now

Underdiagnosis is the norm. The National Academies estimated 836,000 to 2.5 million Americans with ME/CFS and concluded that 84–91 percent were undiagnosed (National Academies, 2015).

Diagnostic delays are long. A Swedish cohort paper reported a 3.6-year mean delay from onset to diagnosis (Bernhoff et al., 2022). Solve M.E.’s US cohort analysis found an average of 16.2 years in 2020 respondents, highlighting a worsening trend (Solve M.E., 2023).

Current diagnosed prevalence is already large. CDC’s NCHS Data Brief 488 found that 1.3 percent of US adults had ME/CFS in 2021–2022 based on being told by a clinician and still having the condition, about 3.3 million adults, while noting this excludes undiagnosed people (Vahratian, Lin, Bertolli, Unger, 2023).

US-CUCC™ Prevalence Model

Logic: Correct historical undercount, then add the Long COVID pipeline using a fixed conversion rate so only the LC input varies.

Formula: Revised ME/CFS Prevalence = Pre-pandemic diagnosed + (LC × 0.40 × 0.40) + (LC × 0.40 × 0.60) (CYNAERA Institute, 2025).

• Conservative scenario using a CDC LC base of ~20M:1.5M + (20M × 0.16) + (20M × 0.24) ≈ ~9.5M total.

• Research-range scenario using ~50M LC:1.5M + 8M + 12M ≈ ~21.5M total.

• Consensus bridge. Midpoint ≈ ~18.5M, aligning with patient-led estimates and RECOVER signals (Davis et al., 2023; NIH RECOVER, 2023; Yong et al., 2022).

The CYNAERA ER/UC-PEM Index™

A safer, auditable way to diagnose PEM from records without provocation testing. It leverages routine data captured in emergency and urgent-care settings.

Step 1. Timing rule

Treat clustered encounters within a 72-hour window as PEM-positive if any of the following occur: ER + urgent care, two urgent-care visits, or urgent care + primary care. This aligns with the delayed PEM trajectory described by CDC and NICE. Document the index exertion if known, but do not require replication.

Step 2. Patient story paired to chartable signals

Record patient language and map it to clinical correlates.

• “This is not normal tired. I feel flu-ish or poisoned.” → Post-exertional symptom exacerbation per CDC and NICE.

  
  

• “My brain shut down, words are hard.” → Cognitive slowing or executive dysfunction, emphasized by the National Academies.

  
  

• “Everything hurts more.” → Pain flare consistent with guideline descriptions of PEM (NICE; CDC).

  
  

• “I feel dizzy, like I might faint.” → Orthostatic features. Check for HR rise ≥30 bpm in adults or ≥40 bpm in adolescents within 10 minutes upright, and assess BP changes per POTS/OI consensus (Sheldon et al., HRS 2015; Raj, 2022).

  
  

• “I cannot breathe right but my lungs seem clear.” → Possible air hunger. Note that pulse-ox can overestimate oxygenation in darker skin, creating symptom–SpO₂ mismatch (Sjoding et al., NEJM 2020; Fawzy et al., JAMA IM 2022; FDA 2025 draft guidance).

  
  

• “Light and sound are unbearable.” → Sensory hypersensitivity described in NICE and CDC materials.

  
  

• “My shoulders feel heavy and my walking gets stiff for a bit.” → Transient motor slowing during the flare. Record as functional change supporting the PEM context.

  
  

• “My face feels hot or heat behind my ears.” → Autonomic dysregulation; flushing may not be visible on darker skin. Rely on patient report and palpation, not color alone. See skin-of-color guidance and nursing assessments on detecting erythema and flushing in darker skin tones (dermatology and nursing literature summaries; FDA pulse-ox draft).

Step 3. Vitals to capture or extract from the chart

• Heart rate: Resting tachycardia above baseline or orthostatic increase ≥30 bpm in adults or ≥40 bpm in adolescents within 10 minutes upright (HRS consensus; Raj, 2022).

• Blood pressure: Drop ≥20 systolic or ≥10 diastolic when upright, or narrow pulse pressure of about one quarter of systolic. Bedside orthostatic guidance appears in Bateman Horne materials and the NASA Lean instructions.

• SpO₂ caveat: Record pre- and post-a short walk such as to the bathroom. If symptoms suggest dyspnea and SpO₂ reads “normal,” document potential skin-tone reading bias with citations to NEJM, JAMA IM, and FDA draft guidance.

• Temperature: Low-grade fever or chills with negative infection workup can fit PEM timing per guideline context (NICE; CDC).

Patient prompt that helps: “Please check HR and oxygen before and after I walk to the bathroom, and note what I feel at each point.” This is standard nursing practice and shows up in flowsheets and triage data elements used in ED severity tools (AHRQ ESI handbook).

Step 4. Labs and workup signals if already ordered

• Inflammatory drift: CRP or ESR bump within the crash window is supportive when infection workup is negative. Treat as context, not a requirement (NICE cautions on over-testing and misattribution).

• Electrolytes: Mild hyponatremia, hypokalemia, or low CO₂ can appear during severe PEM in some patients. Interpret in context and avoid provoking exertion for repeat labs without benefit.

• Negative studies: Negative imaging and cultures during severe presentation support PEM rather than an acute infection when timing fits (NICE; CDC).

Step 5. Documentation language that counts

• “Symptoms began [X] hours after exertion, consistent with the delayed PEM trajectory described by CDC and NICE.”

• “PEM observed via opportunistic encounter pattern within 72 hours. Further provocation testing is not indicated.”

• “Possible pulse-ox overestimation relative to symptoms in a patient with darker skin per Sjoding 2020 and Fawzy 2022; FDA draft guidance addresses skin-tone performance.”

Step 6. Actionable implications

• No repeats. A single documented PEM-positive cluster is enough for diagnosis and care planning. NICE discourages interventions that provoke symptom exacerbation and CDC prioritizes preventing worsening of symptoms.

• Chartable and codable. Use this documentation when coding for ME/CFS or Long COVID and when supporting accommodations or disability. CDC materials center PEM as a functional driver.

• Safer than provocation. Two-day CPET can objectify PEM but carries risk and access barriers; reserve for narrow cases when benefits clearly exceed risks (clinical reviews and patient-safety framing).

How to audit past visits and labs for PEM

Clinician workflow inside the EHR

1. Pull a 90-day encounter timeline. Scan for encounter pairs that fall within 72 hours of each other. Focus on ER, urgent care, and primary care.

2. Open each encounter and review:• Triage and nursing flowsheets for vitals after standing or waiting. ESI materials emphasize vital signs as core inputs to acuity and are routinely recorded (AHRQ ESI).• Bed-assignment vitals for supine readings.• Any post-ambulation vitals, for example after bathroom trips.• Discharge vitals for recovery pattern.

3. Check labs and imaging. Note negative infectious workups that coincide with crash timing.

4. If orthostatic concerns co-occur, apply POTS thresholds (Sheldon et al., HRS 2015; Raj, 2022).

5. For patients with darker skin, interpret SpO₂ with caution and document bias risk using NEJM and JAMA IM studies and FDA draft guidance. Avoid chasing repeats if the clinical picture is clear.

6. Write one integrated note that links timing, story, vitals, labs, and negatives. Do not order duplicative tests once PEM is established.

Patient workflow using the portal

• Download after-visit summaries for ER, urgent care, and primary care. Mark dates that fall within 72 hours of each other.

• In each summary, highlight triage vitals, bed vitals, walking or bathroom vitals, and discharge vitals.

• Note what you felt at each timepoint, including dizziness, ear or facial heat, shoulder heaviness, stiff walking that comes and goes, and frontal “tickle.” Guidance on skin of color reminds clinicians that erythema and flushing are harder to see in darker skin, so your report matters. Pair this with pulse-ox bias citations so the chart captures the full picture (Sjoding 2020; Fawzy 2022; FDA draft guidance).

• Bring a one-page summary to your next visit and ask the clinician to label this as PEM using CDC and NICE timing language.

Stabilize early or the burden compounds

Longer time to diagnosis is associated with worse outcomes and a more persistent disease course in cohort work, which implies higher per-patient economic burden over time (Ghali et al., 2022). Energy-envelope studies show that staying within energy limits improves function and reduces relapses, strengthening the case for early stabilization to prevent repeated PEM cycles (Jason et al., 2009; O’Connor et al., 2017; CDC prevention guidance).

Economic impact in the United States

Per-patient annual direct and indirect costs have been estimated in the $22,000–$29,000 range in pre-pandemic analyses, with national burden estimates in the tens of billions even before Long COVID (Jason & Mirin, 2021). Costs rise with severity, lost productivity, and caregiver time, and extend across health systems and households (Jason et al., 2008; Cullinan et al., 2020; National Academies, 2015).

Clinical-trial acceleration effect: recruitment is the most failure-prone and expensive operational step. Tufts CSDD and partners have shown that about 11 percent of sites enroll zero patients and roughly 37 percent under-enroll, driving delays and costs. EHR phenotyping and computable criteria reduce screening burden, time, and spend by pre-identifying eligible cohorts (Getz, Tufts CSDD; O’Brien et al., 2021; Beskow et al., 2020; systematic reviews through 2024). A faster diagnosis pipeline for ME/CFS means cheaper, larger, and more diverse trial pools.

Payer partnership and incentive design

Faster recognition of PEM from records cuts avoidable spend in three places:

1. duplicate testing triggered by diagnostic uncertainty,

2. ED and urgent-care revisits during undiagnosed crashes,

3. prolonged work disability and caregiver time that spill into medical and pharmacy utilization. This aligns with CDC and NICE guidance to avoid worsening symptoms and to document PEM from history and routine observations, which naturally reduces provocation-driven visits (CDC; NICE).

Pilot mechanics

• Population. Members with repeated ER or urgent-care use, post-viral syndromes, or Long COVID flags.

• Intervention. CYNAERA auto-scan packet plus one 20–30 minute tele evaluation using the ER/UC-PEM Index.

• Outcomes in 90–180 days. Time to diagnosis, duplicate test rate, ED or urgent-care revisit rate, days to work accommodation, and member-reported function.

• Accuracy guardrail. Pulse-ox skin color flaw note and documentation prompts for skin of color.

Contract options

• Shared-savings pilot. Plan pays a per-case ops fee; any measured reduction in all-cause ED revisits and duplicative testing against a pre-period baseline yields shared savings.

• Fixed-fee + KPI bonus. Flat payment per completed audit plus bonuses for hitting documentation quality gates and follow-up adherence.

• Copay support. Plan waives or reduces copays for the audit visit to front-load stabilization. This is inexpensive compared to a single ED visit and increases uptake.

• Data exchange. Plan provides de-identified claims bundles to pre-rank members for outreach; CYNAERA returns audit packets and diagnosis confirmation for care-management routing.

What payers will ask for. Precise inclusion rules, ICD pathways for coding, a safety statement about avoiding exertional provocation, and a de-duplication method so repeat audits are not billed unless clinically indicated.

Scale-up through short remote training

A one-hour remote training that teaches the ER/UC-PEM Index workflow, orthostatic capture, and safe documentation can be delivered to as many clinicians per site as desired. This aligns with the broader clinical move to remote consulting in systems like the NHS and the widespread use of patient-held devices for vitals (NHS England remote consulting guidance; UK implementation research).

Capacity math: If 1,000 US clinicians each confirmed just 5 PEM-positive cases per week via chart audit and short follow-ups, that is ~260,000 diagnoses per year. At 5,000 clinicians, it is 1.3 million per year. This is conservative relative to the 3.3 million already diagnosed adults, and it ignores audits that also surface orthostatic intolerance and POTS (NCHS 488; HRS POTS criteria).

CYNAERA automation modules that make this instant

CYNAERA offers a bundled, license-ready stack that automates PEM flagging inside EHR workflows so clinicians and patients can surface the right dates and vitals in minutes. Core timeline and clustering come from SymCas and SymCas-Timeline, with CrashSync aligning labs to crash windows. Diagnostic Clustering Suppression Flag and Late-Day Flare Pattern Flag correct common EHR grouping misses. Cognitive and sensory correlates are captured via MindMirror, Cognitive Fluctuation Index, and SENSORY-SIGNALS-Mod. Output to the chart is handled through Pre-Triage and ICDx-USA for note generation and coding.

For fast prep and equity-aware care, the bundle can include Electrolyte Stability Index and VitalGuard for context signals, plus pediatric support through SymCas-Youth and POTS_MCAS_Pediatric_Referral. Programs can track outcomes with EDRS to show reduced rehospitalization while ICDx-USA anchors consistent coding. This configuration keeps pre-visit review and tele-visit time inside standard appointment blocks while making PEM documentation auditable from routine records.

Strategic clinic partnerships without fundraising

Clinics trying to increase daily throughput can add an ME/CFS diagnosis track that is safety-first, documentation-rich, and fast to teach. The track uses the ER/UC-PEM Index and optional opportunistic orthostatic review. Because it relies on records, telehealth, and existing vitals, it scales without on-site tilt tables. This is consistent with mainstream remote-care guidance and device-data use caveats (NHS England; BHC resources).

Clinical-trial acceleration effect

Higher diagnosis rates make recruitment faster and cheaper. Trials often fail on recruitment; industry analyses show ~11 percent of sites enroll zero and ~37 percent under-enroll (Getz, Tufts CSDD). EHR phenotyping and computable criteria shrink screening time and cost (O’Brien et al., 2021; Kalankesh et al., 2024). A records-first diagnosis pipeline grows eligible cohorts and lowers cost per randomized participant.

Global expansion: UK, South Korea, Brazil

Why these three. Each market combines a large reachable population online, clear telehealth lanes, and clinical guidance compatible with a “records, not exertion” PEM approach.

South Korea

Telehealth runway. The government announced nationwide allowance of telemedicine across hospitals and clinics in 2024, with formal codification advancing in 2025 via bills before the National Assembly. Connectivity. Internet use is essentially universal (≈98 percent of the population in 2023), enabling digital outreach and portal-based record pulls at scale. Operating clarity. Legal commentary and 2025 practice guides describe the transition from pilot restrictions toward a stable regulatory footing for digital health.

Brazil

Telehealth law. Law 14.510/2022 permanently authorizes telehealth nationwide across public and private systems and regulated health professions. Connectivity. Household internet access reached about 84 percent in 2023–2024, providing a very large funnel for scheduling and follow-up without in-person provocation.

United Kingdom

Clinical anchor. NICE NG206 centers PEM for diagnosis and is explicitly compatible with remote assessment based on history and routine observations. Telehealth culture. National guidance for remote consultations is maintained by NHS England and professional bodies, which normalizes tele pathways in everyday practice. Connectivity. Internet penetration is in the high-90s (≈98 percent at the start of 2023).

With the one-hour training and PEM auto-scan packet, a tele clinician completes 10–12 targeted evaluations/day with about 70 percent confirmation, which is ~1,610–1,932 confirmed diagnoses per clinician-year on a 230-day schedule. If each country onboards 100 clinicians, two-year output is roughly ~322,000–386,000 confirmed diagnoses per country on standard scheduling, without exertional testing. (Operational assumption from CYNAERA training and workflow; tele-suitability in each market supported by sources above.)

Optional add-on: orthostatic testing

When the chart contains triage and supine vitals plus a bathroom walk, clinicians can approximate a NASA Lean sequence and apply POTS thresholds without provoking new exertion. The Bateman Horne Center provides clinician instructions and the HRS consensus details diagnostic cut-offs (BHC NASA Lean; Sheldon et al., HRS 2015).

Conclusion

The CYNAERA ER/UC-PEM Index turns routine records into a safe diagnostic engine. Clinicians can document PEM from encounter timing, patient presentations, vitals already in the chart, and negative workups. That prevents provocation, shortens time to stabilization, and reduces repeat crashes that entrench disability and raise per-patient costs.

At scale, the throughput is decisive. With one hour of remote training and unlimited seats per site, 5,000 clinicians can document about 8 to 9.7 million cases in a single year and about 16 to 19 million in two years. Against the US-CUCC™ midpoint, that is enough to address most of the undiagnosed population in 24 months. Even under higher prevalence scenarios, a two-year run can reach roughly three-quarters to more than 90% of those still undiagnosed. That is millions of Americans moved from uncertainty to care.

The economic stakes are large. ME/CFS drives tens of billions in annual costs in the United States, mostly productivity losses. Globally, the job market absorbs tens of millions of FTEs in lost work each year. Faster, records-first diagnosis lowers payer spend on duplicates and avoidable revisits, preserves work capacity for a meaningful share of patients, and makes clinical trial recruitment faster and cheaper by expanding the confirmed pool with computable, EHR-ready criteria.

CYNAERA’s approach is safety first and science forward. One PEM-positive cluster documented from the record is enough to act. No repeats. No exertional provocation. High trust and high throughput that patients, clinicians, payers, and trial sponsors can all get behind.

References

• Bateman Horne Center (BHC). Clinical Care Guide, First Edition 2025; NASA 10-Minute Lean Test instructions; ME/CFS education and guidebook pages. 2022–2025.

• Beskow LM et al. “EHR phenotyping for research recruitment.” 2020.

• Bernhoff G et al. “A comparison of health-related factors between patients diagnosed with ME/CFS and patients with related symptom picture but no diagnosis.” 2022.

• CDC. ME/CFS clinical care materials including PEM timing and symptom-worsening prevention; Managing PEM toolkit. 2019–2025.

• CTTI / Getz K., Tufts CSDD. “The Cost of Clinical Trial Delays” and related Impact Reports. 2015–2022.

• Cullinan J et al. “Understanding the economic impact of ME/CFS.” HRB Open Research. 2020.

• FDA. Draft guidance and press materials on pulse oximeter performance across skin tones. 2025.

• Ghali A et al. “Factors influencing the prognosis of patients with ME/CFS.” 2022.

• Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. 2015.

• IBGE. Internet access in Brazilian households, 2023–2024. 2024–2025.

• ITU. Internet use facts and figures; Korea 97.9 percent individuals online (2023).

• Jason LA et al. “The economic impact of ME/CFS” 2008; “Energy envelope” trials 2009; updates with Mirin 2021.

• NICE. NG206: Myalgic encephalomyelitis/chronic fatigue syndrome: diagnosis and management. 2021.

• NHS England. Remote consulting guidance. 2020–2024; primary care implementation research.

• NCHS, CDC. Data Brief 488: ME/CFS in Adults, United States 2021–2022. Vahratian, Lin, Bertolli, Unger. 2023.

• Open Medicine Foundation (OMF). Clinical Care Guide for ME/CFS, Long COVID & IACCs; resource center. 2025.

• Raj SR. “Diagnosis and management of POTS.” CMAJ. 2022.

• Sheldon RS et al. Heart Rhythm Society Expert Consensus Statement on POTS. 2015.

• Sjoding MW et al. “Racial bias in pulse oximetry measurement.” NEJM. 2020. Fawzy A et al. JAMA Internal Medicine. 2022.

• Solve M.E. Time to ME/CFS diagnosis report. 2023.

• South Korea Health Ministry via Reuters. Nationwide telemedicine allowance. 2024.

• Brazil Law 14.510/2022. National Telehealth Act summaries. 2023–2025.

• Trials recruitment and EHR integration. O’Brien EC et al., 2021; Kalankesh LR et al., 2024.

Author’s Note:

All insights, frameworks, and recommendations in this white paper reflect the author's independent analysis and synthesis. References to researchers, clinicians, and advocacy organizations acknowledge their contributions to the field but do not imply endorsement of the specific frameworks, conclusions, or policy models proposed herein. This information is not medical guidance.

Applied Infrastructure Models Supporting This Analysis

Several standardized diagnostic and forecasting models developed through CYNAERA were utilized or referenced in the construction of this white paper. These tools support real-time surveillance, economic forecasting, and symptom stabilization planning for infection-associated chronic conditions (IACCs).

Note: These models were developed to bridge critical infrastructure gaps in early diagnosis, stabilization tracking, and economic impact modeling. Select academic and public health partnerships may access these modules under non-commercial terms to accelerate independent research and system modernization efforts.

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Learn More: https://www.cynaera.com/systems

About the Author 

Cynthia Adinig is an internationally recognized systems strategist, health policy advisor, and the founder of CYNAERA, an AI-powered intelligence platform advancing diagnostic reform, clinical trial simulation, and real-world modeling for infection-associated chronic conditions (IACCs). She has developed 400+ Core AI Frameworks, 1 Billion + Dynamic AI Modules. including the IACC Progression Continuum™, US-CCUC™, and RAEMI™, which reveal hidden prevalence, map disease pathways, and close gaps in access to early diagnosis and treatment.

Her clinical trial simulator, powered by over 675 million synthesized individual profiles, offers unmatched modeling of intervention outcomes for researchers and clinicians.

Cynthia has served as a trusted advisor to the U.S. Department of Health and Human Services, collaborated with experts at Yale and Mount Sinai, and influenced multiple pieces of federal legislation related to Long COVID and chronic illness. 

She has been featured in TIME, Bloomberg, USA Today, and other leading publications. Through CYNAERA, she develops modular AI platforms that operate across 32+ sectors and 180+ countries, with a local commitment to resilience in the Northern Virginia and Washington, D.C. region.