Introduction

COVID-19 and its downstream effects are among the most pressing challenges to the long-term health and health care systems worldwide,1,2 with over half of adults in Canada infected by fall of 2022.3–5 Given on-going, widespread transmission of this airborne pathogen, there is growing recognition of considerable health impacts beyond the acute phase of COVID-19.6 This includes metabolic derangements, autoimmune conditions, and cardiovascular disease among others, occurring across the spectrums of age and severity of acute infection.7–12

Health care use during the acute phase of SARS-CoV-2 infection is higher than otherwise similar, uninfected individuals due largely to hospitalizations, although clinic visits, diagnostics and medications also contribute.13,14 Differences in post-acute (ie, delayed), direct health care costs after infection are, however, not well understood. Most people are expected to be experience at least one SARS-CoV-2 infection per year; thus, even small, sustained increases in health care costs after infection could impose significant strain on health care systems. Policy makers need detailed understanding of delayed health care burdens after SARS-CoV-2 infection so they can make informed policy decisions, and clinicians and patients need this information so they can weigh individual risks of infection.

The goal of this study was to test the hypothesis that health care costs were higher after the acute phase of SARS-CoV-2 infection, compared to otherwise similar adults who were not infected. We therefore compared total and component health care costs of community-dwelling adults in Ontario, Canada starting ≥56 days following a positive SARS-CoV-2 polymerase chain reaction (PCR) to matched individuals who tested negative for SARS-CoV-2.

Material and Methods Study Design

This retrospective cohort was constructed using population-level administrative and health care data linked and held at ICES, formerly known as the Institute for Clinical Evaluative Sciences. In accordance with Ontario’s Personal Health Information Protection Act (section 45), which permits collection and analysis of health care and demographic data for health system evaluation, individual consent was not obtained.15 ICES maintains and complies with rigorous security and quality control measures to ensure data privacy and accuracy. This study was conducted in accordance with the Declaration of Helsinki.

Cohort Construction and Matching

All community-dwelling adults (≥18 years of age) in Ontario, Canada with sufficient demographic information for data linkage (valid date of birth, sex, and death information) who underwent PCR testing for SARS-CoV-2 between January 1, 2020 and March 31, 2021 and were alive eight weeks (56 days) after the date of PCR test were eligible. Datasets used for cohort construction and variable definitions are listed in Supplementary Tables E1 and E2, respectively. At the time of the study, PCR testing was widely available and funded by the public health care system. Vaccination began in December of 2020, and by May of 2021 more than half of people in Ontario had received at least one COVID-19 vaccine dose.

The index date was defined as the date of first positive outpatient SARS-CoV-2 PCR test or, for individuals with only negative PCR test(s), the last test date. PCR results reported as pending or indeterminate (<0.02%) were excluded.

Individuals with a positive SARS-CoV-2 PCR test result were matched to those with only negative test results by 2-week pandemic periods, public health unit, vaccination status, and a propensity score computed from a large set of demographic, clinical, and health services factors, including component health care costs in year prior to the index PCR date (for details, see Supplementary Table E2).16 Subjects were matched on the logit of the propensity score using a caliper width equal to 0.05 times the standard deviation of the propensity score,17 and standardized difference <0.1 was considered as indicative of good balance between exposure groups.16,18

Outcome: Health Care Costs

Because symptoms of acute SARS-CoV-2 infection generally resolve within eight weeks,19–22 follow-up to assess post-acute health care costs began eight weeks (56 days) after the index date and ended on May 26, 2022, or death, whichever occurred first. The primary outcome was cost differences over the first year of follow-up for test-positive versus test-negative individuals, compared at the mean, median, 95th percentile, and 99th percentiles of component health care costs. We examined costs across their distribution because health care costs are highly skewed, with a small proportion of high costs.23 Note that mean costs are additive, but this is not the case for median, 95th percentile, or 99th percentile costs. Total person-specific costs of health care (ie, the amount of money spent by the Ontario Ministries of Health and Long Term Care) was comprised of 11 mutually exclusive component costs for the period starting 56 days after the index PCR test date (see Supplementary Table E1).24,25 Component costs were summed and divided by the number of days of follow-up (ie, exposure time), multiplied by 365 days to calculate annual per-person costs, and standardized to the Canadian dollar in 2020 (2020 CAD$). Only hospital-based costs that occurred during follow-up were included.

Secondary outcomes included the following dichotomous outcomes for outpatient cancer, rehabilitation, home care, mental health admission, complex continuing care, and long-term care costs, overall and stratified by sex: 1) being a high-cost health care user, defined as >95th percentile of total health care costs from the matched cohort,24,25 and 2) any reported post-acute health care cost.

Statistical Analyses

Baseline characteristics of the unmatched and matched cohorts were reported as means with standard deviations (SD), medians and interquartile ranges (IQR), or frequencies, as appropriate. Total and component annualized health care costs based on 1-year and 6-month follow-up were reported as means (SDs) and medians (Q1, Q3).

Analyses were performed for the overall cohort and stratified by sex based on prior work14,26,27 and evidence of interaction with some component costs (Supplementary Table E3; P-value threshold <0.10). To compare health care costs across a right-skewed distribution, person-specific annualized costs for matched test-positive versus negative individuals were compared at the mean (by paired T-test), median, 95th percentile, and 99th percentile (by Wilcoxon signed rank test),28 and 95% CI’s were generated by bootstrapping with 2000 bootstrap replicates.29 Sensitivity analyses censored at admission to long-term care and six months. Relative risks (RR) were computed for 6-month and 1-year high-cost health care use and any post-acute health care for six component costs (outpatient cancer care, rehabilitation, home care, mental health hospitalization, complex continuing care, and long-term care). The 95% CI RR were estimated using methods appropriate for matched data.30 All analyses were performed in SAS v. 9.04.

Results

Between January 1, 2020, and March 31, 2021, there were >11 million SARS-CoV-2 PCR tests completed for 3,777,451 unique adults. Of the 3,631,040 individuals in the unmatched cohort (Supplementary Table E4), 268,521 (7.4%) had a positive SARS-CoV-2 PCR test, 99% of whom were successfully matched to a test-negative person. The resulting matched cohort consisted of 531,182 individuals (Supplementary Figure E1 and Table 1). Compared to the unmatched cohort, the matched cohort was slightly younger and had higher proportion of males, urban, lower income, ethnically diverse neighborhoods with overall slightly lower prevalence of comorbid conditions and lower baseline health care costs. In addition, individuals in the matched cohort were less likely to have received any COVID vaccine dose, and they more often underwent PCR testing during late 2020 or early 2021 compared to the unmatched cohort.

Table 1 Baseline Demographics and Clinical Characteristics of the Matched Cohort and Characteristics Used for Matching*

Total Person-Specific Annualized Health Care Cost Differences

Differences in annual total and component health care costs per person, overall and stratified by sex, comparing matched test-positive and test-negative people are shown in Figure 1 (mean cost differences) and Figure 2 (99th percentile cost differences). Median and 95th percentiles cost differences are found in Supplementary Figures E2 and E3, respectively. Mean person-specific total health care costs in the first year of follow-up were $487.08 (95% CI $393.69, $593.28) higher for test-positive compared to test-negative matched individuals. For test-positive females, mean person-specific total health care costs were $513.83 (95% CI $387.37, $638.40) higher, and $459.10 (95% CI $304.60, $615.32) higher for test-positive males. At the 99th percentile, test-positive individuals had $13,306.00 (95% CI, $10,004.00, $16,965.50) greater annual total health care costs compared to test-negative people, with an increase of $12,533.00 (95% CI % $9008.50, $16,473.00) for test-positive females, and $14,604.00 (95% CI $9565.50, $19,506.50) for test-positive males.

Figure 1 Differences in person-specific annual mean health care costs* for test-positive versus test-negative matched individuals, overall and by sex (95% confidence intervals in 2020 CAD$; starting 56 days after polymerase chain reaction test).

Notes: $0 to +$600 range. * By paired T-test.

Figure 2 Differences in person-specific annual 99th percentile health care costs* for test-positive versus test-negative matched individuals, overall and by sex (95% confidence intervals in 2020 CAD$; starting 56 days after polymerase chain reaction test).

Note: $1000 to +$20,000 range. * By paired T-test.

Component Person-Specific Annualized Health Care Cost Differences

The largest differences in mean component costs in the first year of follow-up for test-positive individuals were for hospital-based care ($244.83, 95% CI $188.59, $301.22), long-term care ($102.16, 95% CI $90.09, $113.89), and complex continuing care ($79.28, 95% CI $49.98, $107.96). There were smaller but significantly higher costs for outpatient specialist, rehabilitation, emergency department, outpatient primary care (for females only, with no detected difference for males), and outpatient laboratory costs, and overall no detected differences in outpatient medication, mental health admission costs (no difference for males; decreased costs for test-positive females), or homecare (increased for females, no difference for males). Mean person-specific outpatient cancer care costs were lower (-$75.89, 95% CI -$96.71, -$54.45) for test-positive individuals.

At the 99th percentile, the largest cost differences for test-positive versus test-negative people were hospital-based care ($6035.00, 95% CI $4647.50, $7402.50) homecare ($937.00, 95% CI $389.50, $1508.00; higher only for females), and outpatient specialist care ($407.00, 95% CI $177.00, $731.00; higher only for males). ED costs were $170.00 (95% CI $96.00, $241.00) higher for test-positive individuals, while there were no differences in costs for outpatient primary care, medications, or laboratory tests, and zero costs for mental health admission, complex continuing care, or long-term care. Outpatient cancer care costs were lower over the first year of follow-up, -$521 (95% CI -$708.50, -$399.00) overall, but test-positive females had -$844.00, (95% CI -$1462.50, -$415.00) lower outpatient cancer care costs, with no detected difference for males.

Sensitivity Analyses

Censoring at entrance to long-term care produced similar results (Supplementary Figure E4), with slightly smaller outpatient primary care and hospitalization cost differences than in primary analyses. Annualized 6-month cost differences, overall and stratified by sex, (Supplementary Figure E5) were also similar, with some exceptions by sex, component cost, and distribution. RR’s for being a high-cost user generally decreased over time (Table 2 and Supplementaty Table E5 for risk differences), although women continued to have elevated risk for at 1-year for being a high-cost user of multiple types of high-intensity health care resources compared to matched, test-negative women. RR for any care also generally decreased over time, with differences by sex.

Table 2 Relative Risks* Comparing Test-Positive versus Test-Negative People, Overall and by Sex, for: (A) Being a High-Cost Health Care User (>95th Percentile) Within 6 Months and 1 Year of Follow-Up, and (B) Any Post-Acute Health Care Cost (>$0) Within 6 Months and 1 Year of Follow-Up

Discussion

Among 531,182 matched adults, post-acute (≥56 days after PCR testing) person-specific, annualized health care costs in the first year of follow-up were on average $487 higher ($513 for females, $459 for males) for individuals who had a positive SARS-CoV-2 PCR test compared to matched, test-negative individuals. Cost differences at the 99th percentile over the first year of follow-up were $13,306 higher ($12,533 for females, $14,604 for males) for test-positive individuals. With annual mean health care expenditures of $4800 per-person in Ontario for 2020,31 this >10% increase in mean health care costs over the first year of post-acute follow-up does not account for costs that may extend beyond a year of follow-up or for potential rising costs with re-infections.2 Cost differences did not returned to baseline over the first year of post-acute follow-up.

While hospital costs were the main driver of total cost, important costs were also incurred by long-term and complex continuing care, as well as homecare (for females), outpatient specialist (for males), and emergency department costs. Although mean cost differences for primary care and emergency department ($9.27 and $12.14, respectively) were relatively small, any sustained increase demand for these scarce resources has the potential for clinically important consequences in an already strained health care system.32–34

Notably, outpatient mean cancer care costs were lower for test-positive individuals, particularly for females, who were also less likely to have any outpatient cancer care costs but had increased risk of being a high-cost outpatient cancer care user over the first year of follow-up. Taken together, this raises the possibility that cancer diagnosis and/or treatment may have been impacted by SARS-CoV-2 infection, its complications, or changes in the health system.35

Post-acute symptoms and complications of SARS-CoV-2 infection are common and can be persistent.2,36–42 An estimated 10% of people meet criteria for long COVID following SARS-CoV-2 infection, with incidence and prevalence varying by case definition, outcome measures, pandemic phase, vaccination status, and follow-up duration.43–45 Vaccination in Ontario was administered entirely through the public health care system, with widespread, free access to vaccine clinics and strategic vaccination outreach programs; SARS-CoV-2 vaccination was required through March 1, 2022. Several previous studies addressing post-acute COVID-19 health care costs revealed higher hospital costs, as well as higher mortality and overall health care utilization.46–48 However, these studies were limited to 6-month follow-up of populations covered by specific health insurance programs early in the pandemic, used diagnosis codes to identify COVID-19 cases, were conducted in the US, which has the highest health care costs in the world, and they did not include home-based or other complex, long-term medical care not covered by health insurance in the US.

Our population-level data for a large, universal health care system reduces the risk of selection bias, differential follow-up, and recall bias. In Ontario, all hospitalizations and physician charges are funded by the public health care system. We were also able to examine outpatient costs for primary care, specialist, and cancer care separately. Use of PCR to identify cases likely biases our results towards the null by underestimating true burden infection,49,50 but we chose a highly specific case definition in order to fully examine post-acute health care costs with less risk of erroneously classifying people as having had SARS-CoV-2 infection. Our findings may further have been biased towards the null by likely overrepresentation of ill people in the test-negative population, eg, patients undergoing repeated PCR testing for chemotherapy, dialysis, etc.

We also add to existing literature regarding sex differences in COVID-1951–58 by identifying sex differences for component health care costs. Test-positive males had higher mean cost differences for rehabilitation and mental health care, while test-positive women had higher mean cost differences for outpatient medications, primary care, homecare, and long-term care. Further work is needed to examine the interplay between social factors (eg, caregiver availability for men versus women) and biological factors in order to appropriate plan for and allocate long COVID resources.

With few protective measures in place to prevent ongoing airborne spread and many people therefore expected to contract one or more SARS-CoV-2 infection annually,2 sustained health care cost increases of the magnitude we describe will require significant health care system restructuring, innovation, and investment of resources, particularly given existing prolonged wait times to access care, insufficient supply of acute and long-term care beds, and projected loss of health care workers.59–67 Health care workers appear to have higher risk of infection and developing post-acute complications, with 18% unable to return to pre-infection clinical workloads, including nearly half of whom were infected after been fully vaccinated.68–70 Further, our findings do not account for costs related to disability, unemployment, or reduced quality of life after acute COVID-19, which has been reported to be comparable to that of stage 4 lung cancer.68,71–75 Implementing protections and other measures to prepare for post-acute complications of SARS-CoV-2 infection could forestall considerable, avoidable health care and other costs.76

Limitations

Our findings may not generalize to people without similar access to medical care, who did not seek care, or who sought care outside the traditional health system. We could not adjust body mass index or symptoms severity and duration. However, control individuals may also not have had symptoms, and important post-acute complications occur following mild or asymptomatic acute infections.77 While this study was conducted prior to more recent variants, growing evidence indicates subsequent strains were not less severe, protection against post-acute complications from vaccination or previous infection wanes rapidly.78,79 New strains are so immune evasive that prior vaccination and/or infection have been deemed insufficient protection to recent strains, and a minimum of broad age-based annual vaccination is recommended.80 To date, there is no evidence to that longer-term complications of SARS-CoV-2 infection are completely prevented by vaccination or prior infection, and while vaccination may reduce risks, the duration of that protection is not yet known.81

Conclusion

Post-acute health care costs after a positive SARS-CoV-2 PCR test were significantly higher than matched test-negative individuals, and these increased costs persisted for at least one year. The largest increases health care costs came from hospitalizations, long-term care, complex continuing care, followed by outpatient specialists (for males) and homecare costs (for women). Policy makers should plan for sustained increases in health care costs for people infected with SARS-CoV-2. Clinicians and patients should be aware that health care costs may not return to normal within a year of infection. Future work should include cost effectiveness for strategies to prevent infections and treatment of long-term health impacts of SARS-CoV-2 infection.

Acknowledgments

This study was supported by the Sunnybrook Research Foundation, ICES, which is funded in part by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care (MOHLTC), and by the Ontario Ministry of Health COVID-19 and Health Equity Project. Part of this material is based on data and/or information compiled and provided by the Canadian Institute for Health Information (CIHI). The authors acknowledge that the clinical registry data used in this publications is from participating hospitals through CorHealth Ontario, which serves as an advisory body to the MOHLTC, is funded by the MOHLTC, and is dedicated to improving the quality, efficiency, access and equity in the delivery of the continuum of adult cardiac, vascular and stroke services in Ontario, Canada. The authors thank IQVIA Solutions Canada Inc. for use of their Drug Information File. We thank the Toronto Community Health Profiles Partnership for providing access to the Ontario Marginalization Index. Parts of this report are based on Ontario Registrar General (ORG) information on deaths, the original source of which is ServiceOntario. This study was supported by the Ontario Health Data Platform (OHDP), and Province of Ontario initiative to support Ontario’s ongoing response to COVID-19 and its related impacts. Parts of this material are based on data and/or information compiled and provided by CIHI and Cancer Care Ontario (CCO). The analyses, results, conclusions, opinions, and statements reported are those of the authors and are independent of the data and funding sources. No endorsements by ICES, the Ontario MOHLTC, Ontario Health, CIHI, OHDP or its partners, ORG or the Ministry of Government Services, CCO, or the Province of Ontario is intended or should be inferred.

This paper has been uploaded to Research Square as a preprint: https://www.medrxiv.org/content/10.1101/2023.08.02.23293563v1

Disclosure

Dr. McNaughton is supported by the Sunnybrook Research Institute, the Practice Plan of the Department of Emergency Services at Sunnybrook Health Sciences Centre, and the University of Toronto. Dr. Abdel-Qadir reports speaker honorarium from Astra Zeneca, outside the submitted work. Dr. Atzema is supported by the Sunnybrook Research Institute, the Practice Plan of the Department of Emergency Services at Sunnybrook Health Sciences Centre, and ICES. The authors report no other conflicts of interest in this work.

References

1. Government of Canada. Post COVID-19 condition (long COVID). https://www.canada.ca/en/public-health/services/diseases/2019-novel-coronavirus-infection/symptoms/post-covid-19-condition.html. Accessed July1, 2023.

2. Altmann DM, Whettlock EM, Liu S, Arachchillage DJ, Boyton RJ. The immunology of long COVID. Nat Rev Immunol. 2023;23(10):618–34.

3. Bergeri I, Whelan MG, Ware H, et al. Global SARS-CoV-2 seroprevalence from January 2020 to April 2022: a systematic review and meta-analysis of standardized population-based studies. PLoS Med. 2022;19(11):e1004107. doi:10.1371/journal.pmed.1004107

4. StatCan. Between April and August 2022, 98% of Canadians had antibodies against COVID-19 and 54% had antibodies from a previous infection. https://www150.statcan.gc.ca/n1/daily-quotidien/230327/dq230327b-eng.htm?fbclid=IwAR0jVe20IawIj2JDuAcDFkS30fjffEo04UHM9F281bVJxvBm_Sm0z7C0qvQ. Last accessed March20, 2023.

5. COVID-19 immunity task force. Seroprevalence against SARS-CoV-2 due to infection in Canada: results from the Government of Canada’s COVID-19 immunity task force and other partners’ funded studies through to May 31, 2022. https://www.covid19immunitytaskforce.ca/wp-content/uploads/2022/07/CITF_Bespoke-report_Omicron-tsunami_2022_FINAL_ENG.pdf. Accessed August29, 2022.

6. Tsui TCO, Zeitouny S, Bremner KE, et al. Initial health care costs for COVID-19 in British Columbia and Ontario, Canada: an interprovincial population-based cohort study. CMAJ Open. 2022;10(3):E818–E830. doi:10.9778/cmajo.20210328

7. Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med. 2022;28(3):583–590. doi:10.1038/s41591-022-01689-3

8. Alvarez-Garcia J, Jaladanki S, Rivas-Lasarte M, et al. New heart failure diagnoses among patients hospitalized for COVID-19. J Am Coll Cardiol. 2021;77(17):2260–2262. doi:10.1016/j.jacc.2021.03.006

9. O’Mahoney LL, Routen A, Gillies C, et al. The prevalence and long-term health effects of long covid among hospitalised and non-hospitalised populations: a systematic review and meta-analysis. EClinicalMedicine. 2023;55:101762. doi:10.1016/j.eclinm.2022.101762

10. Xie Y, Al-Aly Z. Risks and burdens of incident diabetes in long COVID: a cohort study. Lancet Diabetes Endocrinol. 2022;10(5):311–321. doi:10.1016/S2213-8587(22)00044-4

11. Xu E, Xie Y, Al-Aly Z. Long-term gastrointestinal outcomes of COVID-19. Nat Commun. 2023;14(1):983. doi:10.1038/s41467-023-36223-7

12. Xu E, Xie Y, Al-Aly Z. Risks and burdens of incident dyslipidaemia in long COVID: a cohort study. Lancet Diabetes Endocrinol. 2023;11(2):120–128. doi:10.1016/S2213-8587(22)00355-2

13. Tartof SY, Malden DE, Liu IA, et al. Health care utilization in the 6 months following SARS-CoV-2 infection. JAMA Network Open. 2022;5(8):e2225657. doi:10.1001/jamanetworkopen.2022.25657

14. McNaughton CD, Austin PC, Sivaswamy A, et al. Post-acute health care burden after SARS-CoV-2 infection: a retrospective cohort study. CMAJ. 2022;194(40):E1368–E1376. doi:10.1503/cmaj.220728

15. Schull MJ, Azimaee M, Marra M, et al. ICES: data, discovery, better health. Int J Popul Data Sci. 2020;4(2):1135. doi:10.23889/ijpds.v4i2.1135

16. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res. 2011;46(3):399–424. doi:10.1080/00273171.2011.568786

17. Austin PC. Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat. 2011;10(2):150–161. doi:10.1002/pst.433

18. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28(25):3083–3107. doi:10.1002/sim.3697

19. Fernandez-de-Las-Penas C, Palacios-Cena D, Gomez-Mayordomo V, Cuadrado ML, Florencio LL. Defining post-COVID symptoms (post-acute COVID, long COVID, persistent post-COVID): an integrative classification. Int J Environ Res Public Health. 2021;18(5):2621. doi:10.3390/ijerph18052621

20. Akbarialiabad H, Taghrir MH, Abdollahi A, et al. Long COVID, a comprehensive systematic scoping review. Infection. 2021;49(6):1163–1186. doi:10.1007/s15010-021-01666-x

21. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601–615. doi:10.1038/s41591-021-01283-z

22. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JVWHO; Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2021;22:e102–e107. doi:10.1016/S1473-3099(21)00703-9

23. Briggs A, Gray A. The distribution of health care costs and their statistical analysis for economic evaluation. J Health Serv Res Policy. 1998;3(4):233–245. doi:10.1177/135581969800300410

24. Guilcher SJ, Bronskill SE, Guan J, Wodchis WP. Who are the high-cost users? A method for person-centred attribution of health care spending. PLoS One. 2016;11(3):e0149179. doi:10.1371/journal.pone.0149179

25. Wodchis WP, Austin PC, Henry DA. A 3-year study of high-cost users of health care. CMAJ. 2016;188(3):182–188. doi:10.1503/cmaj.150064

26. Tharakan T, Khoo CC, Giwercman A, et al. Are sex disparities in COVID-19 a predictable outcome of failing men’s health provision? Nat Rev Urol. 2022;19(1):47–63. doi:10.1038/s41585-021-00535-4

27. Gebhard C, Regitz-Zagrosek V, Neuhauser HK, Morgan R, Klein SL. Impact of sex and gender on COVID-19 outcomes in Europe. Biol Sex Differ. 2020;11(1):29. doi:10.1186/s13293-020-00304-9

28. Austin PC, Tu JV, Daly PA, Alter DA. The use of quantile regression in health care research: a case study examining gender differences in the timeliness of thrombolytic therapy. Stat Med. 2005;24(5):791–816. doi:10.1002/sim.1851

29. Austin PC, Small DS. The use of bootstrapping when using propensity-score matching without replacement: a simulation study. Stat Med. 2014;33(24):4306–4319. doi:10.1002/sim.6276

30. Austin PC. The performance of different propensity-score methods for estimating relative risks. J Clin Epidemiol. 2008;61(6):537–545. doi:10.1016/j.jclinepi.2007.07.011

31. Financial Accountability Office of Ontario. 2020-21 Interprovincial Comparison: comparing Ontario’s fiscal position with other provinces after the first year of the COVID-19 pandemic. https://www.fao-on.org/en/Blog/Publications/interprovincial-comparison-2022. Accessed July4, 2023.

32. Duong D, Vogel L. National survey highlights worsening primary care access. CMAJ. 2023;195(16):E592–E593. doi:10.1503/cmaj.1096049

33. Duffy J, Jones P, McNaughton CD, et al. Emergency department utilization, admissions, and revisits in the United States (New York), Canada (Ontario), and New Zealand: a retrospective cross-sectional analysis. Acad Emerg Med. 2023;30:946–954. doi:10.1111/acem.14738

34. Varner C. Emergency departments are in crisis now and for the foreseeable future. CMAJ. 2023;195(24):E851–E852. doi:10.1503/cmaj.230719

35. Eskander A, Li Q, Yu J, et al. Incident cancer detection during the COVID-19 pandemic. J Natl Compr Canc Netw. 2022;20(3):276–284. doi:10.6004/jnccn.2021.7114

36. Wu Q, Ailshire JA, Crimmins EM. Long COVID and symptom trajectory in a representative sample of Americans in the first year of the pandemic. Sci Rep. 2022;12(1):11647. doi:10.1038/s41598-022-15727-0

37. Whitaker M, Elliott J, Chadeau-Hyam M, et al. Persistent COVID-19 symptoms in a community study of 606,434 people in England. Nat Commun. 2022;13(1):1957. doi:10.1038/s41467-022-29521-z

38. Servier C, Porcher R, Pane I, Ravaud P, Tran VT. Trajectories of the evolution of post-COVID-19 condition, up to two years after symptoms onset. Int J Infect Dis. 2023;133:67–74. doi:10.1016/j.ijid.2023.05.007

39. Ballouz T, Menges D, Anagnostopoulos A, et al. Recovery and symptom trajectories up to two years after SARS-CoV-2 infection: population based, longitudinal cohort study. BMJ. 2023;381:e074425. doi:10.1136/bmj-2022-074425

40. Kim Y, Bae S, Chang HH, Kim SW. Long COVID prevalence and impact on quality of life 2 years after acute COVID-19. Sci Rep. 2023;13(1):11207. doi:10.1038/s41598-023-36995-4

41. Peter RS, Nieters A, Krausslich HG, et al. Post-acute sequelae of covid-19 six to 12 months after infection: population based study. BMJ. 2022;379:e071050.

42. Al-Aly Z. Long-term neurological sequelae of SARS-CoV-2 infection. Nat Med. 2022;28(11):2269–2270. doi:10.1038/s41591-022-02018-4

43. Thaweethai T, Jolley SE, Karlson EW, et al. Development of a definition of postacute sequelae of SARS-CoV-2 infection. JAMA. 2023;329(22):1934–46.

44. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133–146. doi:10.1038/s41579-022-00846-2

45. Abu Hamdh B, Nazzal Z. A prospective cohort study assessing the relationship between long-COVID symptom incidence in COVID-19 patients and COVID-19 vaccination. Sci Rep. 2023;13(1):4896. doi:10.1038/s41598-023-30583-2

46. Pike J, Kompaniyets L, Lindley MC, Saydah S, Miller G. Direct medical costs associated with post-COVID-19 conditions among privately insured children and adults. Preventing Chronic Dis. 2023;20:E06. doi:10.5888/pcd20.220292

47. DeMartino JK, Swallow E, Goldschmidt D, et al. Direct health care costs associated with COVID-19 in the United States. J Manag Care Spec Pharm. 2022;28(9):936–947. doi:10.18553/jmcp.2022.22050

48. DeVries A, Shambhu S, Sloop S, Overhage JM. One-year adverse outcomes among US adults with post-COVID-19 condition vs those without COVID-19 in a large commercial insurance database. JAMA Health Forum. 2023;4(3):e230010. doi:10.1001/jamahealthforum.2023.0010

49. Axell-House DB, Lavingia R, Rafferty M, Clark E, Amirian ES, Chiao EY. The estimation of diagnostic accuracy of tests for COVID-19: a scoping review. J Infect. 2020;81(5):681–697. doi:10.1016/j.jinf.2020.08.043

50. Sundaram ME, Calzavara A, Mishra S, et al. Individual and social determinants of SARS-CoV-2 testing and positivity in Ontario, Canada: a population-wide study. CMAJ. 2021;193(20):E723–E734. doi:10.1503/cmaj.202608

51. Bienvenu LA, Noonan J, Wang X, Peter K. Higher mortality of COVID-19 in males: sex differences in immune response and cardiovascular comorbidities. Cardiovasc Res. 2020;116(14):2197–2206. doi:10.1093/cvr/cvaa284

52. Takahashi T, Ellingson MK, Wong P, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature. 2020;588(7837):315–320. doi:10.1038/s41586-020-2700-3

53. Förster C, Colombo MG, Wetzel AJ, Martus P, Joos S. Persisting symptoms after COVID-19-prevalence and risk factors in a population-based cohort. Dtsch Arztebl Int. 2022;119:167–174. doi:10.3238/arztebl.m2022.0147

54. Kashif A, Chaudhry M, Fayyaz T, et al. Follow-up of COVID-19 recovered patients with mild disease. Sci Rep. 2021;11(1):13414. doi:10.1038/s41598-021-92717-8

55. Bliddal S, Banasik K, Pedersen OB, et al. Acute and persistent symptoms in non-hospitalized PCR-confirmed COVID-19 patients. Sci Rep. 2021;11(1):13153. doi:10.1038/s41598-021-92045-x

56. Augustin M, Schommers P, Stecher M, et al. Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study. Lancet Reg Health Eur. 2021;6:100122. doi:10.1016/j.lanepe.2021.100122

57. Stavem K, Ghanima W, Olsen MK, Gilboe HM, Einvik G. Persistent symptoms 1.5-6 months after COVID-19 in non-hospitalised subjects: a population-based cohort study. Thorax. 2021;76(4):405–407. doi:10.1136/thoraxjnl-2020-216377

58. Wynberg E, van Willigen HDG, Dijkstra M, et al. Evolution of COVID-19 symptoms during the first 12 months after illness onset. Clin Infect Dis. 2021;10:1.

59. Financial Accountability Office of Ontario. Ministry of health: 2021 spending plan review. https://www.fao-on.org/en/Blog/Publications/2021-health-estimates. Last accessed March4, 2022.

60. Canadian Institute for Health Information. The Impact of COVID-19 on Long-Term Care in Canada: Focus on the First 6 Months. Ottawa, ON: CIHI; 2021.

61. Barrett KA, Vande Vyvere C, Haque N, et al. Critical care capacity during the COVID-19 pandemic. Science Briefs of the Ontario COVID-19 Science Advisory Table. 2021;2(51). doi:10.47326/ocsat.2021.02.51.1.0.

62. Brophy JT, Keith MM, Hurley M, McArthur JE. Sacrificed: Ontario healthcare workers in the time of COVID-19. New Solut. 2021;30(4):267–281. doi:10.1177/1048291120974358

63. Cantor J, Whaley C, Simon K, Nguyen T. US Health Care Workforce Changes During the First and Second Years of the COVID-19 Pandemic. JAMA Health Forum. 2022;3(2):e215217. doi:10.1001/jamahealthforum.2021.5217

64. Wilensky GR. The COVID-19 pandemic and the US health care workforce. JAMA Health Forum. 2022;3(1):e220001–e220001. doi:10.1001/jamahealthforum.2022.0001

65. Wang J, Vahid S, Eberg M, et al. Clearing the surgical backlog caused by COVID-19 in Ontario: a time series modelling study. CMAJ. 2020;192(44):E1347–E1356. doi:10.1503/cmaj.201521

66. Salenger R, Etchill EW, Ad N, et al. The surge after the surge: cardiac surgery post-COVID-19. Ann Thorac Surg. 2020;110(6):2020–2025. doi:10.1016/j.athoracsur.2020.04.018

67. Khan JR, Awan N, Islam MM, Healthcare Capacity MO. Health expenditure, and civil society as predictors of COVID-19 case fatalities: a global analysis. Front Public Health. 2020;8:347. doi:10.3389/fpubh.2020.00347

68. British Medical Association. Over-exposed and under-protected: the long-term impact of COVID-19 on doctors. https://www.bma.org.uk/media/7318/bma-long-covid-report040723.pdf. Accessed July14, 2023.

69. Peters C, Dulon M, Westermann C, Kozak A, Nienhaus A. Long-term effects of COVID-19 on workers in health and social services in Germany. Int J Environ Res Public Health. 2022;19(12):6983. doi:10.3390/ijerph19126983

70. Marra AR, Sampaio VS, Ozahata MC, et al. Risk factors for long coronavirus disease 2019 (long COVID) among healthcare personnel, Brazil, 2020-2022. Infect Control Hosp Epidemiol. 2023. 1–7.

71. U.S. Beureau of labor statistics, compiled by FRED economic data. Population with a disability, 16 years and over. https://fred.stlouisfed.org/series/LNU00074597. Accessed July14, 2023.

72. U.S. Health and Human Services. Health+ Long COVID report. 2022. https://www.hhs.gov/sites/default/files/healthplus-long-covid-report.pdf. Accessed July14, 2023.

73. Cutler DM The economic cost of Long COVID: an update. Harvard University. https://scholar.harvard.edu/files/cutler/files/long_covid_update_7-22.pdf. 2022. Access July14, 2023.

74. New York State Insurance Fund report on Long-term impacts of COVID-19. https://ww3.nysif.com/en/FooterPages/Column1/AboutNYSIF/NYSIF_News/2023/20230124LongCovid. Accessed July14, 2023.

75. Walker S, Goodfellow H, Pookarnjanamorakot P, et al. Impact of fatigue as the primary determinant of functional limitations among patients with post-COVID-19 syndrome: a cross-sectional observational study. BMJ open. 2023;13(6):e069217. doi:10.1136/bmjopen-2022-069217

76. Peng A, Simmons A, Amoako A, Tuite A, Fisman D. Relative pandemic severity in Canada and four peer nations during the SARS-CoV-2 pandemic. Can Commun Des Rep. 2023;49(5):197–205. doi:10.14745/ccdr.v49i05a05

77. Iuliano AD, Brunkard JM, Boehmer TK, et al. Trends in disease severity and health care utilization during the early omicron variant period compared with previous SARS-CoV-2 high transmission periods - United States, December 2020-January 2022. MMWR Morb Mortal Wkly Rep. 2022;71(4):146–152. doi:10.15585/mmwr.mm7104e4

78. Menegale F, Manica M, Zardini A, et al. Evaluation of waning of SARS-CoV-2 vaccine-induced immunity: a systematic review and meta-analysis. JAMA Network Open. 2023;6(5):e2310650. doi:10.1001/jamanetworkopen.2023.10650

79. Goldberg Y, Mandel M, Bar-On YM, et al. Protection and waning of natural and hybrid immunity to SARS-CoV-2. N Engl J Med. 2022;386(23):2201–2212. doi:10.1056/NEJMoa2118946

80. Tartof SY, Slezak JM, Frankland TB, et al. Estimated effectiveness of the BNT162b2 XBB vaccine against COVID-19. JAMA Intern Med. 2024;184(8):932. doi:10.1001/jamainternmed.2024.1640

81. Al-Aly Z, Bowe B, Xie Y. Long COVID after breakthrough SARS-CoV-2 infection. Nat Med. 2022;28(7):1461–1467. doi:10.1038/s41591-022-01840-0