The cost of primary care consultations associated with long COVID in non-hospitalised patients: a retrospective cohort study using UK primary care data (preprint)

Background: Over 2 million people in the UK self-reported long COVID (symptoms continuing >12 weeks after the first COVID-19 infection) as of December 2022. Long COVID can lead to significant patient burden; however, the economic impact of managing long COVID in primary care is unknown. Objectives: To assess incremental costs of primary care consultations associated with post-Covid-19 condition or long COVID, to estimate associated national costs for the United Kingdom population, and to assess risk factors associated with increased costs. Design: A retrospective cohort study using a propensity score matching approach with an incremental cost method to estimate primary care consultation costs associated with long COVID. Setting: UK-based primary care general practitioner (GP), nurse and physiotherapist consultation data from the Clinical Practice Research Datalink Aurum primary care database from 31st January 2020 to 15th April 2021. Participants: 472,173 non-hospitalised adults with confirmed SARS-CoV-2 infection were 1:1 propensity score matched to a pool of eligible patients with the same index date, the same number of prior consultations, and similar background characteristics, but without a record of COVID-19. Patients diagnosed with Long COVID (3,871) and those with World Health Organisation (WHO) defined symptoms of long COVID (30,174) formed two subgroups within the cohort with confirmed SARS-CoV-2 infection. Methods: Costs were calculated using a bottom-up costing approach with consultation cost per working hour in the British pound sterling (GBP) obtained from the Personal Social Services Research Unit, Unit Costs of Health and Social Care 2021. The average incremental cost in comparison to patients with no record of COVID-19 was produced for each patient group, considering only consultation costs at least 12 weeks from the SARS-CoV-2 infection date or matched date for the comparator group (from 15th April 2020 to 15th April 2021). A sensitivity analysis was undertaken which restricted the study population to only those who had at least 24 weeks of follow-up. National costs were estimated by extrapolating incremental costs to the cumulative incidence of COVID-19 in the UK Office for National Statistics COVID-19 Infection Survey. The impacts of risk factors on the cost of consultations beyond 12 weeks from SARS-CoV-2 infection were assessed using an econometric ordinary least squares (OLS) regression model, where coefficients were interpreted as the percentage change in cost due to a unit increase in the specific factor. Results The incremental cost of primary care consultations potentially associated with long COVID was 2.44 GBP per patient with COVID-19 per year. This increased to 5.72 GBP in the sensitivity analysis. Extrapolating this to the UK population produced a cost estimate of 23,382,452 GBP (90% credible interval: 21,378,567 GBP to 25,526,052 GBP) or 54,814,601 GBP (90% credible interval: 50,116,967 GBP to 59,839,762 GBP) in the sensitivity analysis. Among patients with COVID-19 infection, a long COVID diagnosis and longer-term reporting of symptoms were associated with a 43% and 44% increase in primary care consultation costs respectively, compared to patients without long COVID symptoms. Older age (49% relative increase in costs in those aged 80 years or older compared to those aged 18 to 29 years), female sex (4% relative increase in costs compared to males), obesity (4% relative increase in costs compared to those of normal weight), comorbidities and the number of prior consultations were all associated with an increase in the cost of primary care consultations. By contrast, those from black ethnic groups had a 6% reduced relative cost compared to those from white ethnic groups. Conclusions: The costs of primary care consultations associated with long COVID in non-hospitalised adults are substantial. Costs are significantly higher among those diagnosed with long COVID, those with long COVID symptoms, older adults, females, and those with obesity and comorbidities.

Long Covid symptoms and diagnosis in primary care: a cohort study using structured and unstructured data in The Health Improvement Network primary care database (preprint)

BACKGROUND: Long Covid is a widely recognised consequence of COVID-19 infection, but little is known about the burden of symptoms that patients present with in primary care, as these are typically recorded only in free text clinical notes. Our objectives were to compare symptoms in patients with and without a history of COVID-19, and investigate symptoms associated with a Long Covid diagnosis. METHODS: We used primary care electronic health record data from The Health Improvement Network (THIN), a Cegedim database. We included adults registered with participating practices in England, Scotland or Wales. We extracted information about 89 symptoms and 'Long Covid' diagnoses from free text using natural language processing. We calculated hazard ratios (adjusted for age, sex, baseline medical conditions and prior symptoms) for each symptom from 12 weeks after the COVID-19 diagnosis. FINDINGS: We compared 11,015 patients with confirmed COVID-19 and 18,098 unexposed controls. Only 20% of symptom records were coded, with 80% in free text. A wide range of symptoms were associated with COVID-19 at least 12 weeks post-infection, with strongest associations for fatigue (adjusted hazard ratio (aHR) 3.99, 95% confidence interval (CI) 3.59, 4.44), shortness of breath (aHR 3.14, 95% CI 2.88, 3.42), palpitations (aHR 2.75, 95% CI 2.28, 3.32), and phlegm (aHR 2.88, 95% CI 2.30, 3.61). However, a limited subset of symptoms were recorded within 7 days prior to a Long Covid diagnosis in more than 20% of cases: shortness of breath, chest pain, pain, fatigue, cough, and anxiety / depression. INTERPRETATION: Numerous symptoms are reported to primary care at least 12 weeks after COVID-19 infection, but only a subset are commonly associated with a GP diagnosis of Long Covid.

The Incidence of Immune Mediated Inflammatory Diseases Following COVID-19: a Matched Cohort Study in UK Primary Care (preprint)

Abstract Objective To assess whether there is an association between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2) infection and the incidence of immune mediated inflammatory diseases (IMIDs). Design Matched cohort study. Setting Primary care electronic health record data from the Clinical Practice Research Datalink Aurum database. Participants The exposed cohort included 458,147 adults aged 18 years and older with a confirmed SARS CoV-2 infection by reverse transcriptase polymerase chain reaction (RT-PCR) or lateral flow antigen test, and no prior diagnosis of IMIDs. They were matched on age, sex, and general practice to 1,818,929 adults in the unexposed cohort with no diagnosis of confirmed or suspected SARS CoV-2 infection and no prior diagnosis of IMIDs. Main Outcome Measures The primary outcome measure was a composite of the incidence of any of the following IMIDs: 1. autoimmune thyroiditis, 2. coeliac disease, 3. inflammatory bowel disease (IBD), 4. myasthenia gravis, 5. pernicious anaemia, 6. psoriasis, 7. rheumatoid arthritis (RA), 8. Sjogrens syndrome, 9. systemic lupus erythematosus (SLE), 10. type 1 diabetes mellitus (T1DM), and 11. vitiligo. The secondary outcomes were the incidence of each of these conditions separately. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for the primary and secondary outcomes comparing the exposed to the unexposed cohorts, and adjusting for age, sex, ethnic group, smoking status, body mass index, relevant infections, and medications. Results 537 patients (0.11%) in the exposed cohort developed an IMID during the follow-up period over 0.29 person years, giving a crude incidence rate of 3.54 per 1000 person years. This was compared 1723 patients (0.09%) over 0.29 person years in the unexposed cohort, with an incidence rate of 2.82 per 1000 person years. Patients in the exposed cohort had a 22% relative increased risk of developing an IMID, compared to the unexposed cohort (aHR 1.22, 95% CI 1.10 to 1.34). The incidence of three IMIDs were statistically significantly associated with SARS CoV-2 infection. These were T1DM (aHR 1.56, 95% CI 1.09 to 2.23), IBD (1.52, 1.23 to 1.88), and psoriasis (1.23, 1.05 to 1.42). Conclusions SARS CoV-2 was associated with an increased incidence of IMIDs including T1DM, IBD and psoriasis. Further research is needed to replicate these findings in other populations and to measure autoantibody profiles in cohorts of individuals with COVID-19, including Long COVID and matched controls.

Non-pharmacological therapies for post-viral syndromes, including Long COVID: A systematic review (preprint)

Background: Post-viral syndromes (PVS), including Long COVID, are symptoms sustained from weeks to years following an acute viral infection. Non-pharmacological treatments for these symptoms are poorly understood. This review summarises evidence for the effectiveness of non-pharmacological treatments for symptoms of PVS. It also summarises the symptoms and health impacts of PVS in individuals recruited to studies evaluating treatments. Methods and findings: We conducted a systematic review to evaluate the effectiveness of non-pharmacological interventions for PVS, as compared to either standard care, alternative non-pharmacological therapy, or placebo. The outcomes of interest were changes in symptoms, exercise capacity, quality of life (including mental health and wellbeing), and work capability. We searched five databases (Embase, MEDLINE, PsycINFO, CINAHL, MedRxiv) for randomised controlled trials (RCTs) published between 1st January 2001 to 29th October 2021. We anticipated that there would be few RCTs specifically pertaining to Long COVID, so we also included observational studies only if they assessed interventions in individuals where the viral pathogen was SARS-COV-2. Relevant outcome data were extracted, study quality appraised using the Cochrane Risk of Bias tool, and the findings were synthesised narratively. Quantitative synthesis was not planned due to substantial heterogeneity between the studies. Overall, five studies of five different interventions (Pilates, music therapy, telerehabilitation, resistance exercise, neuromodulation) met the inclusion criteria. Aside from music-based intervention, all other selected interventions demonstrated some support in the management of PVS in some patients. Conclusions: In this study, we observed a lack of robust evidence evaluating non-pharmacological treatments for PVS, including Long COVID. Considering the prevalence of prolonged symptoms following acute viral infections, there is an urgent need for clinical trials evaluating the effectiveness and cost-effectiveness of non-pharmacological treatments for patients with PVS as well as what may work for certain sub-groups of patients with differential symptom presentation. Registration: The study protocol was registered with PROSPERO [CRD42021282074] in October 2021 and published in BMJ Open in 2022. Keywords: Post-viral syndromes, PVS, COVID-19, Long COVID, post-COVID-19 condition, post-acute sequelae of SARS-CoV-2 infection (PASC), rehabilitation, systematic review, non-pharmacological intervention

Assessment of 115 symptoms for Long COVID (post-COVID-19 condition) and their risk factors in non-hospitalised individuals: a retrospective matched cohort study in UK primary care (preprint)

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) infection is frequently associated with a wide range of persistent symptoms, now referred to as post-COVID-19 condition, or Long COVID. The objectives of this study were to assess which symptoms are associated with confirmed SARS CoV-2 beyond 12 weeks post-infection in non-hospitalised individuals, and the risk factors associated with developing persistent symptoms. We undertook a retrospective matched cohort study between 31st January 2020 and 15th April 2021 using data from a large database of UK-based primary care electronic health records, Clinical Practice Research Datalink (CPRD) Aurum. We selected 486,149 adult patients with a confirmed diagnosis of SARS CoV-2 infection that had not been hospitalised within 28 days of the diagnosis (infected cohort). We propensity score matched them to 1,944,580 patients without a coded record of either confirmed or suspected COVID-19 (uninfected cohort). Outcomes were the presence of 115 separate symptoms at ≥12 weeks post-infection, and Long COVID, defined as having at least one of the symptoms included in the World Health Organisation case definition. Separate Cox proportional hazards models were used to estimate adjusted hazard ratios (aHR) for individual symptoms and Long Covid. 62 symptoms were significantly associated with prior exposure to SARS CoV-2 after 12 weeks. The largest adjusted hazard ratios (aHR) were for anosmia (aHR 6.49, 95% CI 5.02 to 8.39), hair loss (3.99, 3.63 to 4.39), sneezing (2.77, 1.40 to 5.50), difficulties with ejaculation (2.63, 1.61 to 4.28), reduced libido (2.36, 1.61 to 3.47), shortness of breath at rest (2.20, 1.57 to 3.08), fatigue (1.92, 1.81 to 2.03), pleuritic chest pain (1.86, 1.41 to 2.46), hoarse voice (1.78, 1.44 to 2.20), and fever (1.75, 1.54 to 1.98). Among the infected cohort, risk factors for Long COVID included younger age (aHR 0.75, 95% CI 0.70 to 0.81, for those aged ≥70 years compared to those aged 18 to 30 years), female sex (1.52, 1.48 to 1.56), belonging to an ethnic minority group (1.14 [1.07 to 1.22] for mixed race, 1.21 [1.10 to 1.34] for black ethnic groups, and 1.06 [1.03 to 1.10] for other ethnic minority groups, compared to white ethnic groups), socioeconomic deprivation (1.11 [1.07 to 1.16] for the most compared to the least socioeconomically deprived quintile), smoking (1.12, 1.08 to 1.15), obesity (1.10, 1.07 to 1.14), and a wide range of comorbidities such as COPD. SARS CoV-2 in non-hospitalised individuals is associated with a plethora of symptoms being reported at ≥12 weeks post-infection, with a higher risk associated with younger age, female sex, ethnic minority groups, socioeconomic deprivation, smoking, obesity, and several comorbidities.

Development and validation of the Symptom Burden Questionnaire™ for Long COVID: a Rasch analysis (preprint)

ObjectiveTo describe the development and initial validation of a novel patient-reported outcome measure of Long COVID symptom burden, the Symptom-Burden Questionnaire for Long COVID (SBQ-LC). Method and FindingsThis multi-phase, prospective mixed-methods study took place between April and August 2021 in the United Kingdom (UK). A conceptual framework and initial item pool were developed from published systematic reviews. Further concept elicitation and content validation was undertaken with adults with lived experience (n = 13) and clinicians (n = 10), and face validity was confirmed by the Therapies for Long COVID Study Patient and Public Involvement group (n = 25). The draft SBQ-LC was field tested by adults with self-reported Long COVID recruited via social media and international Long COVID support groups (n = 274). Thematic analysis of interview and survey transcripts established content validity and informed construction of the draft questionnaire. Rasch analysis of field test data guided item and scale refinement and provided evidence of the final SBQ-LCs measurement properties. The Rasch-derived SBQ-LC is composed of 17 independent scales with promising psychometric properties. Respondents rate symptom burden during the past 7-days using a dichotomous response or 4-point rating scale. Each scale provides coverage of a different symptom domain and returns a summed raw score that may be converted to a linear (0 - 100) score. Higher scores represent higher symptom burden. ConclusionsThe SBQ-LC is a comprehensive patient-reported assessment of Long COVID symptom burden developed using modern psychometric methods. It measures symptoms of Long COVID important to individuals with lived experience and may be used to evaluate the impact of interventions and inform best practice in clinical management.

Therapies for Long COVID in non-hospitalised individuals - from symptoms, patient-reported outcomes, and immunology to targeted therapies (The TLC Study): Study protocol (preprint)

Introduction Individuals with COVID-19 frequently experience symptoms and impaired quality of life beyond 4-12 weeks, commonly referred to as Long COVID. Whether Long COVID is one or several distinct syndromes is unknown. Establishing the evidence base for appropriate therapies is needed. We aim to evaluate the symptom burden and underlying pathophysiology of Long COVID syndromes in non-hospitalised individuals and evaluate potential therapies. Methods and analysis A cohort of 4000 non-hospitalised individuals with a past COVID-19 diagnosis and 1000 matched controls will be selected from anonymised primary care records from the Clinical Practice Research Datalink (CPRD) and invited by their general practitioners to participate on a digital platform (Atom5TM). Individuals will report symptoms, quality of life, work capability, and patient reported outcome measures. Data will be collected monthly for one year. Statistical clustering methods will be used to identify distinct Long COVID symptom clusters. Individuals from the four most prevalent clusters and two control groups will be invited to participate in the BioWear sub-study which will further phenotype Long COVID symptom clusters by measurement of immunological parameters and actigraphy. We will review existing evidence on interventions for post-viral syndromes and Long COVID to map and prioritise interventions for each newly characterised Long COVID syndrome. Recommendations will be made using the cumulated evidence in an expert consensus workshop. A virtual supportive intervention will be coproduced with patients and health service providers for future evaluation. Individuals with lived experience of Long COVID will be involved throughout this programme through a patient and public involvement group. Ethics and dissemination Ethical approval was obtained from the Solihull Research Ethics Committee, West Midlands (21/WM/0203). The study is registered on the ISRCTN Registry (1567490). Research findings will be presented at international conferences, in peer-reviewed journals, to Long COVID patient support groups and to policymakers.

Assessment and referral in suspected COVID-19: a community based observational study (preprint)

BackgroundThe COVID-19 pandemic presented new diagnostic and management challenges to primary care alongside rapid changes in service delivery. The purpose of this study was to describe the characteristics of patients with symptoms of COVID-19 in primary care, explore which characteristics were associated with a clinical diagnosis of COVID-19 and referrals to secondary care, and to describe secondary care referral decisions with reference to national guidance.MethodsAn observational study using routinely collected data from the Birmingham Out-of-hours Research Database. The study uses consultation data from the Birmingham and Solihull COVID Referral Centre (CRC) between 21st April and 24th July. All CRC consultations were examined to extract patient demographics, free text consultations, prescriptions, observation and onward referrals. The National Early Warning Score (NEWS2) was calculated and the clinical diagnosis of COVID-19 was established. The population was described and univariate logistic regression was used to identify characteristics associated with clinical diagnosis of COVID-19 and referral decisions.Results681 patients were seen at the CRC and 56.3% were identified to have a clinical diagnosis of COVID-19. 14.0% of all patients were referred to secondary care, but 59% of patients classified as most severe according to national criteria were not referred. Referral was associated with increasing age, shortness of breath, tachycardia, tachypnoea and hypoxia but patients with a clinical COVID-19 diagnosis were less likely to be referred than those with other diagnoses.ConclusionJust over half of patients seen in the CRC were clinically diagnosed with COVID-19 and most patients were managed in the community. Guidelines developed in the absence of service delivery data for the management of COVID-19 were inconsistent with community urgent care delivery.

Renin-Angiotensin System Inhibitors and Susceptibility to COVID-19 in Patients With Hypertension: A Propensity Score-Matched Cohort Study in Primary Care (preprint)

Introduction: Renin-angiotensin system (RAS) inhibitors have been postulated to influence susceptibility to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This study investigated whether there is an association between their prescription and the incidence of COVID-19 and all-cause mortality. Methods: We conducted a propensity-score matched cohort study comparing the incidence of COVID-19 among patients with hypertension prescribed ACE inhibitors or ARBs to those treated with calcium channel blockers (CCBs) in a large UK-based primary care database (The Health Improvement Network). We estimated crude incidence rates for confirmed/suspected COVID-19 in each drug exposure group. We used Cox proportional hazards models to produce adjusted hazard ratios for COVID-19. We assessed all-cause mortality as a secondary outcome. Results: The incidence rate of COVID-19 among users of ACE inhibitors and CCBs was 9.3 per 1000 person-years (83 of 18,895 users [0.44%]) and 9.5 per 1000 person-years (85 of 18,895 [0.45%]), respectively. The adjusted hazard ratio was 0.92 (95% CI 0.68 to 1.26). The incidence rate among users of ARBs was 15.8 per 1000 person-years (79 out of 10,623 users [0.74%]). The adjusted hazard ratio was 1.38 (95% CI 0.98 to 1.95). There were no significant associations between use of RAS inhibitors and all-cause mortality. Conclusion: Use of ACE inhibitors was not associated with the risk of COVID-19 whereas use of ARBs was associated with a statistically non-significant increase compared to the use of CCBs. However, no significant associations were observed between prescription of either ACE inhibitors or ARBs and all-cause mortality.

Renin-angiotensin system inhibitors and susceptibility to COVID-19 in patients with hypertension: a propensity score-matched cohort study in primary care (preprint)

Introduction A significant proportion of patients with Coronavirus Disease-19 (COVID-19) have hypertension and are treated with renin-angiotensin system (RAS) inhibitors, namely angiotensin-converting enzyme I inhibitors (ACE inhibitors) or angiotensin II type-1 receptor blockers (ARBs). These medications have been postulated to influence susceptibility to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The objective of this study was to assess a possible association between prescription of RAS inhibitors and the incidence of COVID-19 and all-cause mortality. Methods We conducted a propensity-score matched cohort study to assess the incidence of COVID-19 among patients with hypertension who were prescribed ACE inhibitors or ARBs compared to patients treated with calcium channel blockers (CCBs) in a large UK-based primary care database (The Health Improvement Network). We estimated crude incidence rates for confirmed/suspected COVID-19 among those prescribed ACE inhibitors, ARBs and CCBs. We used a Cox proportional hazards model to produce adjusted hazard ratios for COVID-19 comparing patients prescribed ACE inhibitors or ARBs to those prescribed CCBs. We further assessed all-cause mortality as a secondary outcome and a composite of accidents, trauma or fractures as a negative control outcome to assess for residual confounding. Results In the propensity score matched analysis, 83 of 18,895 users (0.44%) of ACE inhibitors developed COVID-19 over 8,923 person-years, an incidence rate of 9.3 per 1000 person-years. 85 of 18,895 (0.45%) users of CCBs developed COVID-19 over 8,932 person-years, an incidence rate of 9.5 per 1000 person-years. The adjusted hazard ratio for suspected/confirmed COVID-19 for users of ACE inhibitors compared to CCBs was 0.92 (95% CI 0.68 to 1.26). 79 out of 10,623 users (0.74%) of ARBs developed COVID-19 over 5010 person-years, an incidence rate of 15.8 per 1000 person-years, compared to 11.6 per 1000 person-years among users of CCBs. The adjusted hazard ratio for suspected/confirmed COVID-19 for users of ARBs compared to CCBs was 1.38 (95% CI 0.98 to 1.95). There were no significant associations between use of ACE inhibitors or ARBs and all-cause mortality, compared to use of CCBs. We found no evidence of significant residual confounding with the negative control analysis. Conclusion Current use of ACE inhibitors was not associated with the risk of suspected or confirmed COVID-19 whereas use of ARBs was associated with a statistically non-significant 38% relative increase in risk compared to use of CCBs. However, no significant associations were observed between prescription of either ACE inhibitors or ARBs and all-cause mortality during the peak of the pandemic.