Letters

RESEARCH LETTER
Mortality in Patients Hospitalized for COVID-19
vs Influenza in Fall-Winter 2023-2024
In the first year of the COVID-19 pandemic, risk of death in
people hospitalized for COVID-19 was substantially higher than
in people hospitalized for seasonal influenza.1,2 The risk of
death due to COVID-19 has since declined. In fall-winter 2022-
2023, people hospitalized for
COVID-19 had a 60% higher
Supplemental content
risk of death compared with
those hospitalized for seasonal influenza.3 New variants of
SARS-CoV-2 have continued to appear, including the emer-
gence of JN.1, the predominant variant in the US since Decem-
ber 24, 2023.4 This study evaluated the risk of death in a co-
hort of people hospitalized for COVID-19 or seasonal influenza
in fall-winter 2023-2024.
Methods | Based on US Department of Veterans Affairs elec-
tronic health records from all 50 states, we identified people
who were admitted to the hospital with a diagnosis of COVID-19
or seasonal influenza between October 1, 2023, and March 27,
2024, and within 2 days before and 10 days after a positive test
result for SARS-CoV-2 or influenza. Patients with either infec-
tion hospitalized for another reason or those hospitalized for
both COVID-19 and seasonal influenza were excluded. The co-
hort was followed up for 30 days, until death, or until March
31, 2024. Baseline characteristics between patients hospital-
ized for COVID-19 vs influenza were compared using abso-
lute standardized differences; a standardized difference less
than .01 suggests good balance.
We adjusted for differences in baseline characteristics
between the groups using inverse probability weighting.
Logistic regression was used to calculate a propensity score
(probability of being assigned to the COVID-19 group) that
was then applied to balance the 2 groups; covariates are
listed in Supplement 1. Weighted Cox survival models were
used to estimate the difference in risk of death between
COVID-19 and seasonal influenza groups. Results were
reported as adjusted death rates and hazard ratios (HRs)
with 95% CIs in the COVID-19 group compared with the sea-
sonal influenza group.

Table 1. Characteristics of the Seasonal Influenza and COVID-19 Groups Before and After Propensity Score Weighting

Before propensity score weighting After propensity score weightinga

Seasonal influenza COVID-19 Seasonal influenza COVID-19
(n = 2647) (n = 8625) SMDb (n = 2647) (n = 8625) SMDb
Baseline characteristics
Age, mean (SD), y 70.21 (12.66) 73.90 (11.97) 0.30 73.86 (11.88) 73.90 (11.97) 0.003
Race, No. (%)c
Black 677 (25.58) 1672 (19.39) 0.15 511 (19.29) 1672 (19.39) 0.002
White 1606 (60.67) 5570 (64.58) 0.08 1696 (64.09) 5570 (64.58) 0.01
Other 364 (13.75) 1383 (16.03) 0.06 440 (16.62) 1383 (16.03) 0.02
Sex, No. (%)
Male 2455 (92.75) 8207 (95.15) 0.10 2526 (95.43) 8207 (95.15) 0.01
Female 192 (7.25) 418 (4.85) 0.10 121 (4.57) 418 (4.85) 0.01
Smoking status, No. (%)
Never 862 (32.57) 3099 (35.93) 0.07 969 (36.60) 3099 (35.93) 0.01
Former 963 (36.38) 3520 (40.81) 0.09 1071 (40.48) 3520 (40.81) 0.007
Current 822 (31.05) 2006 (23.26) 0.18 607 (22.92) 2006 (23.26) 0.008
Area Deprivation Index, mean (SD)d 53.64 (18.49) 52.64 (19.24) 0.05 52.86 (19.27) 52.64 (19.24) 0.01
BMI, mean (SD) 28.94 (7.27) 28.37 (7.57) 0.08 28.38 (7.30) 28.37 (7.57) 0.001
eGFR, mean (SD), mL/min/1.73 m2 66.41 (26.00) 64.04 (26.60) 0.09 64.32 (26.65) 64.04 (26.60) 0.01
Systolic blood pressure, mean (SD), 134.06 (12.92) 133.42 (12.86) 0.05 133.32 (12.69) 133.42 (12.86) 0.007
mm Hg
Diastolic blood pressure, 76.56 (7.43) 75.02 (7.32) 0.21 75.07 (7.18) 75.02 (7.32) 0.007
mean (SD), mm Hg
No. of outpatient visits, mean (SD) 3.79 (1.69) 4.13 (1.69) 0.20 4.12 (1.67) 4.13 (1.69) 0.004
No. of outpatient visits from 0.18 (0.71) 0.22 (0.75) 0.06 0.22 (0.80) 0.22 (0.75) 0.008
Medicare, mean (SD)
Infected before JN.1, No. (%) NA 4085 (47.36) NA NA 4085 (47.36) NA
Infected during JN.1, No. (%) NA 4540 (52.64) NA NA 4540 (52.64) NA
Follow-up, median (IQR), d 30 (30-30) 30 (30-30) 0.03 30 (30-30) 30 (30- 30) 0.04

(continued)

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 Letters

Table 1. Characteristics of the Seasonal Influenza and COVID-19 Groups Before and After Propensity Score Weighting (continued)

Before propensity score weighting After propensity score weightinga

Seasonal influenza COVID-19 Seasonal influenza COVID-19
(n = 2647) (n = 8625) SMDb (n = 2647) (n = 8625) SMDb
COVID-19 vaccination status, No. (%)
Without COVID-19 vaccination 524 (19.80) 1265 (14.67) 0.14 379 (14.32) 1265 (14.67) 0.01
With 1 shot of COVID-19 vaccine 115 (4.34) 311 (3.61) 0.04 94 (3.57) 311 (3.61) 0.002
With 2 shots of COVID-19 vaccine 513 (19.38) 1443 (16.73) 0.07 472 (17.85) 1443 (16.73) 0.03
With 3 or more shots of COVID-19 1495 (56.48) 5606 (65.00) 0.18 1701 (64.27) 5606 (65.00) 0.02
vaccine
Influenza vaccination status
Influenza vaccine, No. (%)e 932 (35.21) 3801 (44.07) 0.18 1160 (43.84) 3801 (44.07) 0.005
Treatment status
Outpatient nirmatrelvir-ritonavir, NA 456 (5.29) NA NA 456 (5.29) NA
molnupiravir, or remdesivir, No. (%)
Outpatient oseltamivir, No. (%) 277 (8.58) NA NA 212 (8.01) NA NA
Characteristics during hospitalization
SOFA score, mean (SD)f 1.30 (1.49) 1.37 (1.50) 0.03 1.39 (1.51) 1.37 (1.50) 0.009
ICU admission, No. (%) 491 (18.55) 1886 (21.87) 0.08 506 (19.10) 1886 (21.87) 0.07
Acute kidney injury, No. (%) 454 (17.15) 1736 (20.13) 0.08 542 (20.46) 1736 (20.13) 0.008
b
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided An absolute standardized mean difference of less than 0.1 was considered
by height in meters squared); eGFR, estimated glomerular filtration rate; evidence of good balance.
NA, not applicable; SMD, standardized mean difference; SOFA, Sequential c
Self-reported race information was collected from electronic health records and
Organ Failure Assessment. used in the study in accordance with the requirements of the funding agency
a
Propensity score weights were estimated based on age, self-reported race, (US Department of Veterans Affairs) and the Office of Management and Budget,
sex, Area Deprivation Index, BMI, smoking status, use of long-term care, which defines standards for maintaining, collecting, and presenting data on race
COVID-19 vaccination status, influenza vaccination status, eGFR, systolic and and ethnicity for all federal reporting agencies. Other race included American
diastolic blood pressure, cancer, cardiovascular disease, chronic lung disease, Indian and Alaska Native, Asian, or Native Hawaiian and Other Pacific Islander.
coronary artery disease, dementia, diabetes, hyperlipidemia, HIV, immune The categories in this classification are social-political constructs and should not
dysfunction, liver diseases and peripheral artery diseases, number of be interpreted as being anthropological in nature.
outpatient visits and hospital admissions, number of blood panel tests, d
Area Deprivation Index is a measure of socioeconomic disadvantage, with
number of medications received and number of Medicare outpatient visits and a range from low to high disadvantage of 0 to 100.
hospital admissions, the calendar date of the admission, hospital bed capacity, e
Receipt of influenza vaccine for this influenza season and before the infection.
and hospital bed occupancy at the participants’ health care facility within the
f
week of the admission. SOFA scores range from 0 to 24, where higher scores mean greater severity.

We also examined the difference in risk of death between
people hospitalized for COVID-19 before and during the JN.1-
predominant era (before vs on or after December 24, 2023).
Analyses were performed with SAS Enterprise Guide version
8.3 (SAS Institute Inc). We defined statistical significance as a
95% CI that did not cross 1.00. The study was approved with
a waiver of informed consent by the VA St Louis Health Care
System Institutional Review Board.
Results | The cohort included 8625 participants hospitalized for
COVID-19 (unadjusted death rate, 5.70% at 30 days) and 2647
participants hospitalized for seasonal influenza (unadjusted
death rate, 3.04% at 30 days). The COVID-19 and seasonal in-
fluenza groups were balanced after propensity score weight-
ing (Table 1).
Patients hospitalized for COVID-19 had a higher risk of death
compared with those hospitalized for seasonal influenza (ad-
justed death rate, 5.70% vs 4.24% at 30 days; adjusted HR, 1.35
[95% CI, 1.10-1.66]). There was no statistically significant dif-
ference in the risk of death among people hospitalized for
COVID-19 before and during the JN.1-predominant era (ad-
justed death rate, 5.46% vs 5.82% at 30 days; adjusted HR, 1.07
[95% CI, 0.89-1.28]) (Table 2).
Discussion | The study found that in fall-winter 2023-2024, the
risk of death in patients hospitalized for COVID-19 was greater
than the risk of death in patients hospitalized for seasonal in-
fluenza. Compared with a study using the same database and
methods,3 the death rate at 30 days was 5.97% in 2022-2023 vs
5.70% in 2023-2024 for COVID-19 and 3.75% in 2022-2023 vs
4.24% in 2023-2024 for influenza. Both adjusted HRs were sta-
tistically significant, with an HR of 1.61 in 2022-2023 and 1.35
in 2023-2024, with overlapping 95% CIs. Changes in either the
SARS-CoV-2 or influenza viruses or in their care (eg, use of vac-
cines or antivirals) may influence the comparative risk of death
each season. The findings should be interpreted in the context
of nearly twice as many hospitalizations for COVID-19 com-
pared with seasonal influenza during 2023-2024.5,6
The results also showed that at the level of statistical power
available in this study, there was no significant difference in
risk of death among those hospitalized for COVID-19 before and
during the JN.1-predominant era—suggesting that JN.1 may not
have a materially different severity profile than the variants
that immediately preceded it.
Study limitations include that the Veterans Affairs popula-
tion (older age and predominantly male) may not represent the
general population and causes of death were not examined.

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Table 2. Risk of Death in People Hospitalized for COVID-19 Compared With Seasonal Influenza and in Those Hospitalized for COVID-19
Before vs During the JN.1-Predominant Era
Death rate at 30 d, % (95% CI)
Unadjusted
Hospitalized for COVID-19 compared with hospitalized for seasonal influenza
COVID-19 5.70 (5.20-6.19)
Seasonal influenza 3.04 (2.40-3.79)
Hospitalized for COVID-19 before compared with during JN.1-predominant erab
Before JN.1-predominant era 5.77 (5.05-6.48)
During JN.1-predominant era 5.64 (4.95-6.33)
a
Model adjusting through inverse probability weights where the overall
COVID-19 group is the target population. Variables adjusted for included age,
self-reported race, sex, Area Deprivation Index, smoking, use of long-term
care, BMI, eGFR, systolic and diastolic blood pressure, COVID-19 vaccination
status, influenza vaccination status, cancer, cardiovascular disease, chronic
lung disease, coronary artery disease, dementia, diabetes, hyperlipidemia,
HIV, immune dysfunction, liver diseases, peripheral artery diseases, number of
outpatient visits and hospital admissions, number of blood panel tests,
Yan Xie, PhD
Taeyoung Choi, MS
Ziyad Al-Aly, MD
Author Affiliations: Clinical Epidemiology Center, VA St Louis Health Care
System, St Louis, Missouri.
Accepted for Publication: April 10, 2024.
Published Online: May 15, 2024. doi:10.1001/jama.2024.7395
Corresponding Author: Ziyad Al-Aly, MD, VA St Louis Health Care System,
915 N Grand Blvd, 151-JC, St Louis, MO 63106 (ziyad.alaly@va.gov; zalaly@
gmail.com).
Author Contributions: Dr Al-Aly 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.
Concept and design: Al-Aly, Xie.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Al-Aly, Xie.
Critical review of the manuscript for important intellectual content: All authors.
Statistical analysis: All authors.
Obtained funding: Al-Aly.
Administrative, technical, or material support: Al-Aly.
Supervision: Al-Aly.
Other - visualization: Choi.
Conflict of Interest Disclosures: Dr Al-Aly reported receiving grants from US
Department of Veterans Affairs during the conduct of the study. Dr Xie reported
receiving personal fees from Guidepoint outside the submitted work. No other
disclosures were reported.
Funding/Support: This research was funded by the US Department of Veterans
Affairs (Dr Al-Aly).
Role of the Funder/Sponsor: The funders of this study had no role in the
design and conduct of the study; collection, management, analysis, and
interpretation of the data; preparation, review, or approval of the manuscript;
and decision to submit the manuscript for publication.
Disclaimer: The contents do not represent the views of the US Department of
Veterans Affairs or the US government.
Data Sharing Statement: See Supplement 2.
1. Xie Y, Bowe B, Maddukuri G, Al-Aly Z. Comparative evaluation of clinical
manifestations and risk of death in patients admitted to hospital with covid-19
and seasonal influenza: cohort study. BMJ. 2020;371:m4677. doi:10.1136/bmj.
m4677
2. Cates J, Lucero-Obusan C, Dahl RM, et al. Risk for in-hospital complications
associated with COVID-19 and influenza—Veterans Health Administration,
United States, October 1, 2018-May 31, 2020. MMWR Morb Mortal Wkly Rep.
2020;69(42):1528-1534. doi:10.15585/mmwr.mm6942e3
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Letters
Adjusteda Adjusted hazard ratio (95% CI)a
5.70 (5.20-6.19) 1.35 (1.10-1.66)
4.24 (3.47-5.01)
5.46 (4.76-6.16) 1.07 (0.89-1.28)
5.82 (5.12-6.51)
number of medications received, number of Medicare outpatient visits and
hospital admissions within 1 year before beginning of follow-up, hospital bed
capacity, and hospital bed occupancy at the participants’ health care facility
within the week of the admission. The calendar date of the admission was
additionally adjusted for in COVID-19 vs seasonal influenza.
b
JN.1-predominant era defined as beginning on December 24, 2023.
3. Xie Y, Choi T, Al-Aly Z. Risk of death in patients hospitalized for COVID-19 vs
seasonal influenza in fall-winter 2022-2023. JAMA. 2023;329(19):1697-1699.
doi:10.1001/jama.2023.5348
4. Centers for Disease Control and Prevention. COVID data tracker. Accessed
February 23, 2024. https://covid.cdc.gov/covid-data-tracker/#variant-
proportions
5. Centers for Disease Control and Prevention. COVID-19–associated
hospitalizations. Accessed February 23, 2024. https://gis.cdc.gov/grasp/
covidnet/covid19_3.html
6. Centers for Disease Control and Prevention. Influenza Hospitalization
Surveillance Network (FluSurv-NET). Accessed February 23, 2024. https://www.
cdc.gov/flu/weekly/influenza-hospitalization-surveillance.htm
COMMENT & RESPONSE
Apixaban to Prevent Recurrence
After Cryptogenic Stroke
To the Editor The recent Atrial Cardiopathy and Antithrombotic
Drugs in Prevention After Cryptogenic Stroke (ARCADIA)
trial1 did not demonstrate superiority of apixaban over aspi-
rin for secondary prevention in patients with cryptogenic
stroke and atrial cardiopathy. In this study, atrial cardiopathy
was defined by meeting any of the following criteria: serum
N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels
greater than 250 pg/mL, P-wave terminal force in electrocar-
diography lead V1 greater than 5000 μV × ms, or left atrial
diameter index of 3 cm/m2 or greater. Notably, approximately
46% of participants were enrolled based on the serum
NT-proBNP criterion alone. While serum NT-proBNP levels
are positively correlated with left atrial remodeling and dys-
function, they are not robust predictors of atrial fibrillation
and are influenced by various noncardiac factors such as age,
obesity, and kidney function.2 Thus, use of this criterion
alone may not have accurately represented atrial cardiopathy
and may have affected the precision of effect estimates of
desired interventions. We speculate that the negative results
in ARCADIA may be partially attributed to within-study vari-
ance because participants could be enrolled solely based on
the NT-proBNP criterion. It would be helpful if the authors
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