The COVID-19 Hospitalization Metric in the Pre- and Post-vaccination Eras as a Measure of Pandemic Severity: A Retrospective, Nationwide Cohort Study

doi:10.21203/rs.3.rs-898254/v2

Background: COVID-19 hospitalization definitions do not include a disease severity assessment. Thus, we sought to identify a simple and objective mechanism for identifying hospitalized severe cases and to measure the impact of vaccination on trends.

Methods: All admissions to a Veterans Affairs (VA) hospital, where routine screening is recommended, between 3/1/2020-11/22/2021 with SARS-CoV-2 were included. Moderate-to-severe COVID-19 was defined as any oxygen supplementation or any SpO2 <94% between one day before and two weeks after the positive SARS-CoV-2 test. Admissions with moderate-to-severe disease were divided by the total number of admissions, and the proportion of admissions with moderate-to-severe COVID-19 was modelled using a penalized spline in a Poisson regression and stratified by vaccination status. Dexamethasone receipt and its correlation with moderate-to-severe cases was also assessed.

Results: Among 67,025 admissions with SARS-CoV-2, the proportion with hypoxemia or supplemental oxygen fell from 64% prior to vaccine availability to 56% by November 2021, driven in part by lower rates in vaccinated patients (vaccinated, 52% versus unvaccinated, 58%). The proportion of cases of moderate-to-severe disease identified using SpO2 levels and oxygen supplementation was highly correlated with dexamethasone receipt (correlation coefficient, 0.95), and increased after 7/1/2021, concurrent with delta variant predominance.

Conclusions: A simple and objective definition of COVID-19 hospitalizations using SpO2 levels and oxygen supplementation can be used to track pandemic severity. This metric could be used to identify risk factors for severe breakthrough infections, to guide clinical treatment algorithms, and to detect trends in changes in vaccine effectiveness over time and against new variants.

Infectious Diseases

COVID19

SARS-CoV-2

hospitalization

metrics

disease severity

surveillance

COVID-19 hospitalization rates are used to track the community burden of SARS-CoV-2. The CDC’s COVID-Net defines a COVID hospitalization as any patient admitted to the hospital within 14-days of a laboratory-confirmed diagnosis of SARS-CoV-2 infection, regardless of the reason for the admission.¹

Vaccination impacts the association between SARS-CoV-2 case rates and hospitalization rates, because vaccinated patients develop less severe disease and unvaccinated patients tend to be younger and healthier.² Thus, reporting metrics designed to determine the level of risk in a community, and in turn inform policy-making decisions about restrictions and mitigation strategies, should increasingly focus on hospitalizations rather than cases. However, after vaccines became available,^{3, 4} routine inpatient screening, common or mandated in many facilities, may identify incidental cases, and thus additional data about disease severity is needed to inform policy and practice.

Although many patients are hospitalized for management of severe disease, patients with asymptomatic or mild COVID-19 may be in the hospital for three main reasons: (1) admission for reasons unrelated to COVID-19 but infection identified as part of routine admission, inpatient, or pre-discharge screening (e.g., prior to admission to a long-term care facility), (2) admission for reasons unrelated to COVID-19 and subsequently develop symptoms during hospitalization and are therefore tested, but never develop severe illness, or (3) admission for mild COVID-19 for observation due to underlying co-morbidities, or to avoid exposing household contacts. If hospitalizations are to guide policy decisions, patients hospitalized for the management of COVID-19 disease must be distinguished from patients who are hospitalized and incidentally found to be infected with SARS-CoV-2.

Thus, the aim of this retrospective, national cohort study was to measure trends in severity of respiratory disease among inpatients with SARS-CoV-2 and how vaccination status has impacted these trends. This analysis is completed to inform the creation of a simple, objective metric comprised of variables easily extracted from the electronic health record (EHR) that could be used to improve the value of the hospitalization metric for reflecting cases of severe disease in the post-vaccine era.

All inpatient admissions to a Veterans Affairs (VA) hospital between 3/1/2020-11/22/2021 with a laboratory-confirmed diagnosis of SARS-CoV-2 up to 14-days prior to or during the admission were included, and data were extracted electronically from the VA Corporate Data Warehouse and the VA COVID-19 Shared Data Resource.⁵ Within the VA, screening for SARS-CoV-2 infection has been recommended for all inpatient admissions regardless of the presence of symptoms since 5/12/2020, and the recommendation is included in the VA COVID-19 testing manual.⁶ Some facilities, particularly those impacted early during the first wave, implemented routine screening of all inpatients earlier than 5/12/2021. At least one VA facility tests all inpatients 72 hours after admission, regardless of symptoms. In VA New England Healthcare, genetic sequencing of a sample of cases found that the delta variant was predominant by 7/1/2021 but not for most of June 2021 (unpublished data).

Patients were considered fully vaccinated if ≥14 days had elapsed after receipt of a single dose of an adenovirus vaccine or after receipt of both doses of either mRNA-1273 (Moderna) or BNT162b2 (Pfizer) vaccines. Data on third doses was not available for inclusion in the analysis. Patient-level comorbidities were measured using the CMS Medicare and Medicaid Chronic Conditions Data Warehouse definitions.⁷

Moderate-to-severe COVID-19 was defined as receipt of any oxygen supplementation (within the VA, any supplementation ≥ 0.5 L/min is recorded) or any documented SpO2 <94% recorded in the vital signs domain during an inpatient admission at any time between one day before and two weeks after the positive SARS-CoV-2 test. These criteria were adapted from the most stringent cut-offs for respiratory distress included in the National Institutes of Health (NIH) COVID-19 severity score and selected based on their objective and reproducible nature and ability to reliably capture them from the EHR without the need for manual chart review.⁸ A secondary analysis was conducted using a clinical definition of respiratory distress (oxygen supplementation ≥2L NC or any documented SpO2 <90%). In addition, several sensitivity analyses were conducted: one using only SpO2 levels and not oxygen supplementation, another stratified by region, one excluding patients with COPD or related conditions, and one excluding patients with lung cancer, both defined using CCW definitions.

Admissions meeting criteria for moderate-to-severe disease were divided by the total numbers of admissions in the cohort over different calendar periods. The changing proportion of admissions with moderate-to-severe COVID-19 was modelled as a smooth function of time using a penalized spline in a Poisson regression and stratified by vaccination status. A chi-squared test of proportion was completed to assess whether severe breakthrough infections increased during the post-delta period.

As an additional assessment of severity of illness, the proportion of cases receiving treatment with dexamethasone, which was demonstrated in a clinical trial to improve outcomes among patients receiving supplemental oxygen, and is therefore used to treat severe COVID-19 but not mild disease,⁹ was also evaluated as a function of time. Dexamethasone, rather than other therapeutic options, was chosen given its relatively consistent use for severe disease, when compared to other therapeutic options, such as remdesivir, prescription of which is highly variable by facility within the VA.^{10, 11} A Pearson test of correlation was performed between the series of weekly proportions of COVID-19 hospitalizations with moderate-to-severe COVID-19 and the series of weekly proportions of COVID-19 hospitalizations during which dexamethasone was received.

The study was approved by the VA Boston R&D committee with a waiver for informed consent (protocol # 3328-X).

Among 67,025 admissions (33,166 before 1/24/2021, when the first patient in the cohort was fully vaccinated, and 33,859 after) representing 53,607 unique patients admitted with laboratory-confirmed SARS-CoV-2, 40,331 admissions had moderate-to-severe disease as measured by SpO2 levels and/or receipt of supplemental oxygen. The median age among all hospitalized patients was 70.9 (mean, 68.5, SD, 14.1); 41,897 (62.5%) were white; and 63,208 (94.3%) were male. Among hospitalized patients, 24 percent had heart failure, 27.6% percent had COPD, and 29.9% were obese (Table 1).

The total number of COVID-19 hospitalizations in the VA tracks with the national data from CDC COVID-Net (Figure 1).¹ The proportion of inpatients with any documented SpO2 <94% or oxygen supplementation changed over time (P<0.001, Figure 2). From 3/1/2020-1/23/2021, the proportion of hospitalized patients with moderate-to-severe disease was 64.0% (95% CI, 63.1-64.9%) and from 1/21/2021-11/21/2021, was 56.4% (95% CI, 55.6-57.2%).

Among 33,859 admissions on or after 1/24/2021 (unvaccinated, 24,524; vaccinated, 9,335), 19,097 met the case definition for moderate-to-severe disease (unvaccinated, 14,277; vaccinated, 4,820). Among unvaccinated inpatients during this period, 58.2% (95% CI, 57.3-59.2%) had at least one documented SpO2 <94%, versus 51.6% (95% CI, 50.2-53.1%) in vaccinated inpatients (Figure 2). Proportions of COVID-19 admissions receiving treatment with dexamethasone dropped in parallel with reduction in proportion of cases with moderate-to-severe disease (Pearson correlation coefficient, 0.95). After 7/1/2021, when the delta variant became predominant, the proportion of breakthrough infections with moderate to severe disease increased as measured by either SpO2 and/or oxygen supplementation or receipt of dexamethasone (p<0.05); the increase is evident in all regions, although peaked earlier in the Southeast (Supplementary Figure 1).

Findings from the secondary analysis using a clinical definition of respiratory distress (SpO2 <90 and/or ≥2L oxygen supplementation) were similar. N=20,737 admissions met the stricter case definition, including 32.4% (95% CI, 31.8-33.0%) of COVID-19 admissions prior to 1/24/2021 and 29.5% (95% CI, 29.0-30.1%) afterward (unvaccinated patients, 31.2%, 95% CI, 30.5-31.9% versus vaccinated, 25.0%, 95% CI, 24.0-26.1%, Figure 3).

In the sensitivity analyses, the metric performed similarly with or without inclusion of the oxygen supplementation criterion in addition to SpO2 cut-offs (Supplementary Figure 2). When patients with lung cancer or COPD were excluded, the proportion of cases with moderate to severe disease decreased, but overall trends were similar (Supplementary Figures 3 and 4).

Early in the pandemic, SARS-COV-2 cases were strongly correlated with hospitalizations, and both were reflective of community risk. Since widespread vaccine availability, these metrics are uncoupled, as reflected by the falling proportion of SARS-CoV-2 admissions with moderate-to-severe COVID-19.² The uncoupling is more pronounced in fully vaccinated individuals, who continue to be strongly protected against severe disease, although during the period after June 2021, when the delta variant became predominant, there appeared to be an increasing proportion of severe breakthrough cases. ^{12, 13} The changes in frequency of admissions with moderate-to-severe disease as defined using SpO2 levels and/or oxygen supplementation are strongly correlated with the changes in proportions of cases receiving dexamethasone, which is recommended for patients with severe but not mild disease,⁹ supporting an objective and reproducible approach that uses SpO2 values and supplemental oxygenation receipt to identify patients hospitalized for COVID-19.

For the purposes of monitoring hospital capacity and estimating resource needs, such as personal protective equipment, reporting all COVID-19 hospitalizations will continue to be important for the foreseeable future. Our findings suggest that reporting definitions should be revised to also include disease severity metrics to reflect the changing nature of the pandemic, particularly among vaccinated patients and in regions with high levels of vaccine uptake to identify severe cases. Definitions that include a measure of disease severity are also important for identifying patients at high-risk of severe disease despite vaccination and could be used as part of an early monitoring system to identify waning vaccine effectiveness for preventing critical illness,¹⁴ or to alert to the possibility of viral evolution, such as the emergence of new variants, that cause clinically severe disease despite vaccination. Early identification of an increase in the proportion of cases with severe disease would allow for rapid response, such as deployment of genetic testing, recommendations for booster vaccinations, or need for new vaccine formulations. Early identification of the most clinically significant problems is therefore likely to translate into improved pandemic responses and better clinical outcomes.

Our definition was adapted from the NIH criteria, but includes some adjustments. Specifically, our definition does not include patients who may have severe COVID-19 symptoms that are non-respiratory in nature, such as severe gastrointestinal distress. In addition, we did not include imaging findings, which are included in NIH criteria, in our electronic surveillance definition. Imaging findings were not included for two reasons. First, imaging results are not structured or standardized and are thus not ideal for inclusion in a simple and easy to program and reproduce electronic surveillance tool. Second, during the conduct of a multi-center COVID-19 therapeutics trial in which we screened hundreds of inpatients for severe disease, we found no cases that met imaging criteria for severe disease that did not also have other objective criteria of clinical respiratory illness.¹⁵ Thus, while it is possible that including imaging results would change severe hospitalization estimates somewhat, the impact is likely to be extremely small, and including imaging results would substantially impact the feasibility of the simple approach for measuring severe cases.

In the adapted NIH definition, we included any oxygen supplementation to ensure all cases with any degree of respiratory discomfort were captured. Depending upon the goals of the surveillance, the more typical clinical cut-offs, which appear to track closely with prescribed treatment for severe disease, may be preferred over the cut-offs using the adapted NIH criteria, which may over-estimate cases of severe disease. This is particularly true of the oxygen supplementation metric, which may include individuals with very low levels of oxygen support being provided for comfort rather than therapeutic effect.

The current definition of COVID-19 hospitalizations includes progressively more mild or incidental diagnoses, for example, cases identified due to institutional screening practices prior to admission or discharge, rather than hospitalizations due to severe COVID-19, particularly in vaccinated patients.¹⁶ Other recent studies similarly found that current definitions of “COVID-19 hospitalizations” combined with routine, and often mandatory, screening testing of all inpatient admissions may substantially overestimate the number of hospitalizations caused by SARS-CoV-2 infection.^{17, 18} In a pediatric population, 41% of reported admissions associated with SARS-CoV-2 infection were for reasons other than COVID-19, rates similar to those found when the simple definition of moderate to severe disease was applied in our cohort.¹⁸

Limitations:

Our study has several limitations. The VA population is not representative of the US population as a whole, having few women and no children. Screening at the time of admission is recommended throughout the VA, and findings may be different in hospitals that do not test all admissions. We did not control for baseline hypoxemia or oxygen requirement (common among VA patients) or for altitude, and thus some mild cases may have been misclassified as moderate-to-severe. However, to ensure that severe cases are captured, a sensitive definition is preferable to one that favors specificity and we found similar results when patients with lung cancer and COPD were excluded. Measured changes in overall incidence of severe hospitalizations may be due to several factors independent of vaccination, such as the increasing availability of different therapeutic options, like monoclonal antibody treatments, during the study period.¹⁹ Variable clinical practices, common in the VA and elsewhere, may also contribute to observed differences in rates of hospitalization severity.¹⁰ Severe COVID-19 cases may have been admitted non-differentially to non-VA hospitals. Some Veterans may have been vaccinated outside of the VA, however, vaccines were typically available earliest within the VA, thus mitigating the impact of this limitation somewhat.

In this large, national cohort, the proportion of hospitalizations due to moderate-to-severe COVID-19 decreased following vaccine availability, particularly among vaccinated patients. Consideration should be given to updating definition of COVID-19 hospitalizations for tracking pandemic burden to improve differentiation between hospitalization caused by COVID-19 and those associated with detection of SARS-CoV-2 through the addition of straightforward and objective disease severity measures.

Funding:

This work was supported by the VA Office of Research and Development, Cooperative Studies Program.

Role of the Funder:

The funder had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript, or the decision to submit the manuscript for publication.

Access to Data and Data Analysis:

Dr. Fillmore had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Author Contributions:

Concept and design: WBE, NF, PM, SD

Acquisition, analysis, or interpretation of data: All authors

Drafting of the manuscript: WBE, PM, NF

Critical revision of the manuscript for important intellectual content: All authors

Statistical analysis: CZ, JL, NF

Competing Interest Declaration:

WBE and PM are site investigators for a study funded by Gilead pharmaceuticals (funds to institution). WBE is the recipient of VA HSRD funding. All other authors report no competing interests. American Heart Association grant #857078 (NRF).

1. US Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19)-Associated Hospitalization Surveillance Network (COVID-NET). 2020.

2. Vaccine Breakthrough Case Investigations Team. COVID-19 vaccine breakthrough infections reported to CDC-United States, January. 1:792-3.

3. Oliver SE, Gargano JW, Marin M, et al. The advisory committee on immunization practices’ interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine—United States, December 2020. Morbidity and Mortality Weekly Report. 2020;69(50):1922.

4. Allen H, MSc AV, MFPH JF, MSc KA. Increased household transmission of COVID-19 cases associated with SARS-CoV-2 Variant of Concern B. 1.617. 2: a national casecontrol study. Public Health England. 2021;

5. COVID-19 Shared Data Resource (2020). VA Healthcare System. Access date 12/7/2021

6. Gelman, M. VA Guidebook on COVID-19 Testing v1.2 27 (2021).

7. Centers for Medicare and Medicaid Services. Chronic Conditions Data Warehouse. Accessed 11/30/2021, 2021. https://www2.ccwdata.org/web/guest/condition-categories

8. National Institutes of Health. Clinical Spectrum of SARS-CoV-2 Infection. Updated 9/3/2021. Accessed September 6, 2021. https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/

9. National Institutes of Health. Therapeutic Management of Hospitalized Adults With COVID-19. Accessed September 17, 2021. https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/hospitalized-adults--therapeutic-management/

10. Asundi A, Resnik J, Benedict PA, Shin M, Rani Elwy A, Branch-Elliman W. How Are Emerging Data Translated Into Clinical Practice? A Mixed Methods Investigation of Coronavirus Disease 2019 Institutional Treatment Protocols. Oxford University Press US; 2021:ofab072.

11. Ohl ME, Miller DR, Lund BC, et al. Association of remdesivir treatment with survival and length of hospital stay among US veterans hospitalized with COVID-19. JAMA network open. 2021;4(7):e2114741-e2114741.

12. US Centers for Disease Control and Prevention. COVID-19 vaccine breakthrough case investigation and reporting. 2021.

13. Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. New England Journal of Medicine. 2021;doi:10.1056/NEJMoa2108891

14. Bar-On YM, Goldberg Y, Mandel M, et al. Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel. New England Journal of Medicine. 2021;385(15):1393-1400. doi:10.1056/NEJMoa2114255

15. Branch-Elliman W, Ferguson R, Doros G, et al. Subcutaneous Sarilumab for the Treatment of Hospitalized Patients with Severe COVID-19 Disease: A Pragmatic, Embedded, Randomized Controlled Trial. IDSA; 2021:

16. Calderwood MS, Deloney VM, Anderson DJ, et al. Policies and practices of SHEA Research Network hospitals during the COVID-19 pandemic. Infection control and hospital epidemiology. 2020;41(10):1127-1135. doi:10.1017/ice.2020.303

17. Webb NE, Osburn TS. Characteristics of Hospitalized Children Positive for SARS-CoV-2: Experience of a Large Center. Hospital Pediatrics. 2021;

18. Kushner LE, Schroeder AR, Kim J, Mathew R. “For COVID” or “With COVID”: Classification of SARS-CoV-2 Hospitalizations in Children. Hospital Pediatrics. 2021;

19. National Institutes of Health. COVID-19 Treatment Guidelines. Updated 10/27/2021. Accessed November 30, 2021, 2021. https://www.covid19treatmentguidelines.nih.gov/about-the-guidelines/whats-new/

Table 1. Comorbidities of Veteran Patients Hospitalized with SARS-CoV-2 Infection

Comorbidity	All Hospitalizations (N, %)	Moderate-to-Severe COVID-19 (N, %)	Cases without low SpO2 or oxygen supplementation (N, %)
Age (Median, IQR)	70.7 (60.7, 76.6)	71.6 (62.4, 77.4)	68.3 (57.3, 75.1)
Hypertension	42,410 (79.1%)	28,348 (81.3)	14,062 (75.1)
Hyperlipidemia	36,321 (67.8)	24,265 (69.6)	12,056 (64.4)
Chronic Kidney Disease	29,455 (54.9)	20,034 (57.4)	8,279 (44.2)
Diabetes	25,70 (48.1)	17,491 (50.1)	8,279 (44.2)
Ischemic Heart Disease	19,177 (35.8)	12,965 (37.2)	6,212 (33.2)
Benign Prostatic Hypertrophy	16,865 (31.5)	11,594 (33.2)	5,271 (28.2)
Obesity	16,019 (29.9)	11,292 (32.4)	4,727 (25.2)
Chronic Obstructive Pulmonary Disease and related conditions	14,772 (27.6)	10,682 (30.6)	4,090 (21.8)
Arthritis (Rheumatoid or osteoarthritis)	13,960 (26.0)	9,323 (26.7)	4,637 (24.8)
Heart Failure	12,856 (24.0)	8,866 (25.4)	3,990 (21.3)
Peripheral Neuropathy	12,467 (23.3)	8,291 (23.8)	4,176 (22.3)
Atrial Fibrillation	10,940 (20.4)	7,490 (21.5)	3,450 (18.4)
Alzheimer’s Disease and Related Conditions	9,397 (17.5)	6,665 (19.1)	2,732 (14.6)
Sensory Deafness and Hearing Loss	7,954 (14.8)	5,465 (15.7)	2,489 (13.3)
Acquired Hypothyroidism	6,705 (12.5)	4,678 (13.4)	2,027 (10.8)
Peripheral Vascular Disease	6,605 (12.3)	4,442 (12.7)	2,163 (11.6)
Pressure and Chronic Ulcers	5,257 (9.8)	3,556 (10.2)	1,701 (9.1)
Lung Cancer	1,469 (2.7)	1,052 (3.0)	417 (2.2)
Leukemias and Lymphomas	1,347 (2.5)	947 (2.7)	400 (2.1)
Alzheimer’s disease	1,208 (2.3)	8,47 ( 2.4)	361 (1.9)
Sensory Blindness and Visual Impairment	1,110 (2.1)	784 (2.2)	326 (1.7)

*Co-morbidities calculated using the CMS Chronic Conditions Warehouse definitions and are reported on a per-person, rather than per-hospitalization basis. Conditions that are not associated at a level of p<0.001 with increased risk of hospitalization with hypoxemia are not listed.

SuppFig1Allpanels.pdf
Supplementary Figure 1 - All Panels
SuppFig1PanelAnorthatlanticregion.pdf
Supplementary Figure 1A- North Atlantic Region
SuppFig1PanelBMidwesternregion.pdf
Supplementary Figure 1B - Midwestern Region
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Supplementary Figure 1C - Continental Region
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Supplementary Figure 1D - Southeast Region
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Supplementary Figure E- Pacific Region
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Supplementary Figure 2 - Oxygen supplementation excluded
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Supplementary Figure 3 - Sensitivity Analysis (Patients with Lung Cancer Diagnosis Excluded)
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Supplementary Figure 4 - Sensitivity Analysis (Patients with COPD excluded)
SupplementaryFigureLegends.docx

The COVID-19 Hospitalization Metric in the Pre- and Post-vaccination Eras as a Measure of Pandemic Severity: A Retrospective, Nationwide Cohort Study

Status:

Journal Publication

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Abstract

Figures

Background

Methods

Results

Discussion

Conclusions

Declarations

References

Tables

Supplementary Files

Status:

Journal Publication

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