Long COVID in 2025 reviews pathophysiology clinical management and the pharmacist role

Five years after the acute waves of COVID-19, Long COVID has settled into public health planning as a common post-infectious condition with sustained clinical, economic and social effects. The term describes persistent or fluctuating symptoms that follow SARS-CoV-2 infection and cannot be explained by an alternative diagnosis. Debate over wording has narrowed, yet definitions still shape who is counted, who is treated, and how research is funded. This review synthesises current definitions, burden, risk architecture, mechanisms under study, clinical phenotypes, and the practical UK pathway from assessment to management. It also sets out the expanding contribution of the pharmacist, tracks the research and policy arc from 2023 to 2025, and closes with priorities for action. The aim is clear utility for researchers and professionals who need precise framing, defensible claims and pragmatic guidance.

Definitions across leading health bodies influence care and research

Global authorities converge on a pragmatic core. The World Health Organisation uses the term post-COVID-19 condition and centres onset within 3 months of infection with symptoms lasting at least 2 months that are not better explained by another diagnosis. The UK’s NICE guideline NG188 operationalises Long COVID as an umbrella with 2 timed categories that start at 4 weeks and extend beyond 12 weeks to guide NHS pathways and referral points. In the United States, the Centres for Disease Control and Prevention and the National Academies classify Long COVID as an infection-associated chronic condition. That framing matters because it unlocks recognition, disability routes, long-term funding arguments and normalises chronic care models even when routine biomarkers are normal. Divergent definitions therefore change case ascertainment, service access and trial eligibility, which sustains variation in prevalence estimates and complicates international comparisons.

Real fact: The term long COVID emerged from patient communities on social media in 2020 and was later adopted by health agencies.

Prevalence in 2025 shows a substantial global and UK burden

Synthesis from 2023 to 2025 points to a high burden with heterogeneity by method and population. A large 2025 meta analysis pooling 429 studies reported an estimated global prevalence of 36% among people with confirmed COVID-19, with higher pooled estimates in Europe than in North America. Population-based figures produce lower proportions but still show scale, with several analyses suggesting 6% to 7% of adults affected worldwide. In the UK, the Office for National Statistics, reporting up to 7 March 2024, estimated 3.3% of people in England and Scotland with self-reported Long COVID, nearly 2 million individuals. Of those reporting Long COVID, 75% reported some impairment of daily activities, and 19% described severe limitation of daily life. These proportions align with persistent workforce absence and pressure on long term condition services.

Diagnostic practice separates long covid from acute illness and overlapping syndromes

Diagnosis is clinical and rests on a detailed history, targeted examination and exclusion of alternative explanations. A confirmed positive test is not required, which reflects limited early testing and imperfect sensitivity. Overlap with other post-infectious and chronic syndromes is common. Many patients fulfil criteria for myalgic encephalomyelitis or chronic fatigue syndrome, with shared features that include debilitating fatigue, cognitive dysfunction often called brain fog, unrefreshing sleep and post exertional malaise. Post-exertional symptom exacerbation after minor mental or physical effort is strongly predictive of this phenotype. Some features such as persistent loss of smell or taste are more specific to Long COVID. Long COVID should also be distinguished from post-intensive care syndrome, which follows critical illness of any cause and carries its own patterns of weakness, cognitive change and psychological distress.

Risk factors in 2025 clarify who is most vulnerable

Risk concentrates in identifiable groups. UK surveillance shows higher prevalence in people aged 45 to 64 years. Female sex remains a consistent risk factor. A 2025 meta-analysis reported an odds ratio of 1.55 with a 95% confidence interval of 1.25 to 1.92 for females compared with males. Socioeconomic gradients are evident, with higher odds in more deprived communities. These patterns indicate a syndemic profile in which exposure risk, capacity to rest and recover, and access to timely care interact with biology.

Clinical risk factors are now well described. Greater severity of the acute illness, including hospital or ICU admission, increases risk. Comorbidities add risk in aggregate, with an estimated pooled odds ratio of 1.59 and notable signals for asthma at 41% increased odds and chronic obstructive pulmonary disease at 32% increased odds, alongside hypertension and cardiovascular disease. Vaccination reduces risk principally by lowering severe acute disease and also through other proposed mechanisms. Being unvaccinated is associated with higher odds of Long COVID, with pooled estimates near 2.34 compared with vaccinated individuals. Variant context matters. UK data suggest about 50% lower odds of Long COVID after an Omicron BA.1 compatible infection than after Delta in double vaccinated adults. Reinfection carries new risk each time. About 2.4% of adults who did not report Long COVID after a first infection did so after a second, and emerging analyses link 3 or more infections with much higher prevalence than a single infection.

Mechanisms under study outline a working model of disease

Mechanistic work from 2023 to 2025 supports a network model rather than a single cause. Four processes recur across studies and likely interact.

Immune dysregulation persists months after infection with evidence of altered T cell phenotypes including exhausted cytotoxic subsets, sustained monocyte activation and raised inflammatory mediators such as interleukin-6 and C-reactive protein. Patterns overlap with other post infectious states and may help explain symptom persistence without overt organ injury on routine tests.

Viral persistence is supported by detection of viral RNA and proteins in tissues such as gut, lymph nodes and nervous tissue well beyond the acute phase. Persistent antigen could maintain immune activation and skew responses, consistent with longitudinal findings of activated virus specific T cell pools more than 2 years after infection.

Endothelial injury with microclots is repeatedly described. Inflammatory endothelialitis and a prothrombotic milieu appear to favour amyloid like fibrin structures that resist fibrinolysis. These structures can lodge within microvasculature and impair oxygen delivery, providing a plausible link to exertional intolerance, pain, dysautonomia and cognitive symptoms through diffuse tissue hypoxia.

Autonomic dysfunction is common, with frequent orthostatic intolerance and postural orthostatic tachycardia syndrome presentations. Proposed drivers include direct viral effects on autonomic fibres, autoantibodies and secondary injury from chronic inflammation and hypoxia. Standard autonomic tests can be normal despite disabling symptoms, which underscores the need for careful clinical correlation.

An integrated model that combines viral persistence, immune dysregulation, endothelial injury, and microclots can account for multi-system variation. The dominant process likely differs between patients, which supports future stratification in trials and clinical services.

Clinical phenotypes explain the multi system presentation

More than 200 symptoms have been catalogued across organ systems and often fluctuate in relapsing remitting patterns. A fatigue and post exertional malaise phenotype captures patients with marked energy limits and crashes after modest effort. A neurocognitive phenotype features attention, processing speed and memory deficits with headaches and sleep disturbance. A cardiopulmonary phenotype includes breathlessness, chest pain, palpitations and tachycardia. Musculoskeletal pain is frequent, as are gastrointestinal symptoms including nausea, abdominal pain, diarrhoea or constipation. Dermatological changes and hair shedding are reported. Menstrual variability is noted, with symptom intensification around menses in some patients. Phenotype recognition supports targeted investigation and avoids one size fits all plans that risk harm.

Paediatric presentations differ from adult patterns and require age specific assessment

Children and young people develop Long COVID but with age dependent profiles. Infants and toddlers most often present with sleep disturbance, irritability, poor appetite and cough. Preschool children show daytime tiredness and low energy. School age children frequently report headache, concentration or memory problems, sleep issues and abdominal pain. Adolescents report tiredness, diffuse pain and cognitive difficulties that begin to mirror adult patterns. Assessment should use age-appropriate tools and caregiver reports where relevant, while avoiding adult-centric assumptions that miss paediatric signs.

UK diagnostic pathways align with NICE NG188 for safe exclusion and timely referral

In UK practice, NICE guideline NG188 structures assessment and referral. The pathway starts at 4 weeks after suspected or confirmed infection when new or ongoing symptoms persist. Primary care leads with a person centred assessment that captures physical, cognitive, psychological and functional impact. Shared decision making governs remote or in person review. Validated tools such as the COVID-19 Yorkshire Rehabilitation Scale are widely used to record symptoms and track change.

Timed case definitions guide thresholds. Ongoing symptomatic COVID-19 spans 4 to 12 weeks. Post COVID-19 syndrome extends beyond 12 weeks when no alternative diagnosis explains symptoms. Safety sits first. Clinicians order targeted investigations to exclude acute or dangerous conditions and to consider common differentials such as anaemia, new cardiac or lung disease, diabetes and thyroid dysfunction. Typical first line tests include full blood count, kidney and liver function, inflammatory markers, ferritin, natriuretic peptide, HbA1c and thyroid function. Respiratory symptoms prompt chest X-ray. Cardiac symptoms prompt ECG. The frequent finding of normal tests must not invalidate the clinical picture. Microvascular disease and dysautonomia often evade routine testing, and expected results can coexist with significant disability. Referral to a multidisciplinary Long COVID service is advised when symptoms persist beyond 12 weeks with functional impairment after initial exclusion work is complete or sooner if red flags emerge.

Management focuses on rehabilitation symptom control and harm avoidance

There are no disease modifying medicines with proven benefit as of 2025. Care therefore emphasises rehabilitation, targeted symptomatic treatment and harm avoidance delivered by a multidisciplinary team.

Multidisciplinary rehabilitation brings together physiotherapy for breathlessness and graded functional retraining where appropriate, occupational therapy for cognitive strategies and activity planning, psychological support for anxiety and mood, and dietetic input where nutrition or appetite is affected. For patients with post exertional symptom exacerbation, pacing is central. Pacing balances physical, cognitive and emotional loads to keep activity within a safe envelope and prevent crashes. This approach is distinct from programmes that prescribe fixed incremental increases in activity. For patients with post exertional symptom exacerbation, fixed increments can trigger harm through repeated exacerbations and should be avoided. Clear documentation of the patient’s energy limits and agreed symptom thresholds supports safe progression.

Symptomatic pharmacology has a place. Low dose beta blockers can reduce tachycardia in confirmed orthostatic intolerance. Analgesics, sleep agents and antidepressants are used as per standard indications. The research pipeline remains active across antivirals, immunomodulators and anti-thrombotic strategies, with mixed early signals and a need for larger trials. Metformin is under study for prevention. Until robust results arrive, prescribing should remain conservative and tethered to established indications and careful monitoring.

The specialist clinic model faces uneven commissioning and access

NHS England funded more than 100 specialist services to provide assessment and multidisciplinary care. The model tiers support individuals through online resources and self-management, with community services and specialist teams available for those with complex needs. Since 2024, commissioning has shifted to Integrated Care Boards with reduced ringfencing. Several services have scaled back or closed, with fewer than half confirmed open by March 2025 in one sector report. The result is postcode variation, risks to the specialist workforce and longer waits. Data collection specific to post-COVID assessment has also decreased since 2023, which limits planning and evaluation. Service leaders face the challenge of sustaining expertise while embedding Long COVID within broader long term condition pathways.

Pharmacists expand their role in long covid care across settings

The pharmacist is often the most accessible clinician for people living with Long COVID, and the role has widened across general practice, community and hospital teams.

Structured medication reviews reduce polypharmacy and rationalise treatment. Pharmacists reconcile medicines across multiple prescribers, identify interactions including those linked to off label treatments and supplements, and align regimens with patient priorities. A detailed medication history can signal phenotype and guide adjustments that improve tolerability and adherence.

Patient education and counselling add practical value. Pharmacists explain safe use of over-the-counter products for pain, fever and sleep problems, set expectations about fluctuating recovery, and signpost to trustworthy resources such as the NHS education platform and local support groups. Validation of the patient experience is clinically relevant because it reduces friction in care and supports adherence to agreed plans.

Ongoing monitoring is a natural extension. Pharmacists track adverse effects, reinforce key rehabilitation messages such as pacing and breathing techniques during routine encounters, and act as a consistent touchpoint when specialist access is limited. To reach full potential, this role needs formal commissioning, defined training and read-write access to shared records that allow safe, proactive interventions.

Research and policy from 2023 to 2025 reshape definitions and priorities

The research arc has delivered both mechanistic insight and service facing evidence. A genome wide association study in 2025 identified a variant near FOXP4 associated with about 60% higher risk, linking susceptibility to lung biology. Immune profiling studies have yielded panels of soluble markers associated with clinical manifestations that could seed diagnostics and stratification. UK work has demonstrated the therapeutic value of collaborative, patient co designed self management programmes that emphasise validation and personalised pacing.

Policy has been more volatile. UK research investment exceeded £50 million early in the programme, and service investment reached hundreds of millions by early 2024. Since then, national ringfencing has eased and commissioning has localised. Advocacy groups report fewer dedicated funding calls and warn of service retrenchment. In contrast, classification by US bodies as an infection associated chronic condition has accelerated alignment with chronic disease models. The risk is a widening gap between emerging biological clarity and practical service delivery unless funding and commissioning keep pace.

Patient experience and public health impacts require sustained action

Qualitative studies track significant life change. Many patients report persistent symptoms, mental health strain and financial stress more than a year after infection. Feeling dismissed compounds distress and delays care. Surveys record exhaustive experimentation with unproven treatments when access is limited. The economic footprint is material. Analyses attribute a share of rising economic inactivity to Long COVID, estimate six figure reductions in employment and significant GDP drag. Costs to the NHS rise through repeat admissions and higher primary care use for a subset of patients even as emergency visits fall overall. A shadow cost sits with informal caregivers, often women, who reduce hours or leave work to support relatives. Estimates in the billions underline the need to count caregiving in economic models and to design policies that mitigate gendered impacts.

Conclusion sets out prognosis next steps and priorities for 2025 and beyond

Outcomes vary. Many improve over time, with typical recovery within 4 to 9 months, yet a significant minority remain symptomatic for years. UK survey data suggest more than one third of people with self-reported Long COVID have lived with symptoms for longer than 2 years, while meta-analytic work finds 20% with at least one symptom at 3 years. Children recover more often, yet substantial proportions remain unwell at 2 years, with female sex and deprivation linked to slower recovery.

Priorities are clear. Trials must shift scale and precision, targeting viral persistence, immune dysregulation, endothelial injury and microclots with stratified entry criteria and validated outcome measures. Diagnostic development should progress from panels toward clinically usable biomarkers that support case definition and trial enrolment. Paediatric research needs depth across development, education and family impact. Rehabilitation research should define safe protocols for those with post exertional symptom exacerbation and specify effective mixes of physiotherapy, occupational therapy and psychological care. Policy should stabilise specialist services, embed expertise into long term condition pathways and equip pharmacists with commissioning, training and records access that match their frontline role. Translating evidence into durable services is now the decisive task.