Articles
Rates of infection with other pathogens after a positive COVID-19 test versus a negative test in US veterans (November, 2021, to December, 2023): a retrospective cohort study
Miao Cai, Evan Xu, Yan Xie, et al
Lancet Infect Dis 2025; 25: 847-860
Summary
Background
SARS-CoV-2 infection leads to post-acute sequelae that can affect nearly every organ system, including the immune system. However, whether an infection with SARS-CoV-2 is associated with increased risk of future infections with other pathogens is not yet fully characterised. In this study, we aimed to test the association between a positive test for COVID-19, compared with a negative test, and rates of future infections with other pathogens.
Methods
We used the US Department of Veterans Affairs health-care databases to build a spatiotemporally aligned cohort of 231 899 people with a positive COVID-19 test and 605 014 with a negative COVID-19 test (test-negative control group) between Nov 1, 2021, and Dec 31, 2023. We first did a discovery approach to map the associations between those with a positive COVID-19 test versus a negative test and laboratory-based outcomes of infectious illnesses. We then compared rates of a prespecified set of infectious disease outcomes between those with and without a positive COVID-19 test. To evaluate the specificity of the findings to COVID-19, we compared the rates of a prespecified set of infectious disease outcomes in a spatiotemporally aligned cohort of people admitted to hospital for COVID-19 (n=12 450) versus those admitted for seasonal influenza (n=3293). Outcomes were ascertained 30 days after the date of the first test until the end of follow-up (365 days after the first test plus 30 days, death, or July 18, 2024, whichever came first). An inverse probability weighting approach was used to balance demographic and health characteristics across cohorts. Log-binomial regression models were used to estimate risk ratios (RRs) and 95% CIs.
Findings
In the 12 months of follow-up, compared with participants who had a negative test for COVID-19, people with COVID-19 who did not require admission to hospital during the acute phase of infection had increased test positivity rates for bacterial infections (in blood, urine, and respiratory cultures) and viral diseases (including Epstein–Barr virus, herpes simplex virus reactivation, and respiratory viral infections). People who were positive for COVID-19 and admitted to hospital also had increased rates of bacterial infections in blood, respiratory, and urine biospecimens, and viral infections in blood and respiratory biospecimens. Analyses of prespecified outcomes showed that, compared with the test-negative control group, participants with a positive COVID-19 test who were not admitted to hospital had significantly increased rates of outpatient diagnosis of infectious illnesses (RR 1·17 [95% CI 1·15–1·19]), including bacterial, fungal, and viral infections; outpatient respiratory infections (1·46 [1·43–1·50]); and admission to hospital for infectious illnesses (1·41 [1·37–1·45]), including for sepsis and respiratory infections; the rates of prespecified outcomes were generally higher among those who were admitted to hospital for COVID-19 during the acute phase. Compared with people admitted to hospital for seasonal influenza, those admitted for COVID-19 had higher rates of admission to hospital for infectious illnesses (1·24 [1·10–1·40]), admission to hospital for sepsis (RR 1·35 [1·11–1·63]), and in-hospital use of antimicrobials (1·23 [1·10–1·37]).
Table. Weighted demographic and health characteristics for the COVID-19-positive versus test-negative cohorts
| Test-negative control cohort (n=605 014) | COVID-19 positive cohort (n=231 899) | |||||
|---|---|---|---|---|---|---|
| Not admitted to hospital (n=196 941) | Weighted SMD* | Admitted to hospital (n=34 958) | Weighted SMD* | |||
| Age, years | ||||||
| Mean (SD) | 64·48 (13·91) | 64·50 (13·92) | 0·002 | 64·61 (13·97) | 0·009 | |
| Median (IQR) | 67·04 (55·54–74·67) | 67·00 (55·77–74·77) | NA | 67·10 (55·51–74·64) | NA | |
| Sex | ||||||
| Male | 535 008 (88·43%) | 174 213 (88·46%) | 0·001 | 31 032 (88·77%) | 0·011 | |
| Female | 70 006 (11·57%) | 22 728 (11·54%) | 0·001 | 3926 (11·23%) | 0·011 | |
| Race | ||||||
| White | 403 470 (66·69%) | 131 466 (66·75%) | 0·001 | 23 377 (66·87%) | 0·004 | |
| Black | 130 753 (21·61%) | 42 440 (21·55%) | 0·002 | 7408 (21·19%) | 0·01 | |
| Other | 48 653 (8·04%) | 15 835 (8·04%) | 0 | 2993 (8·56%) | 0·019 | |
| Asian | 8829 (1·46%) | 2865 (1·45%) | 0 | 443 (1·27%) | 0·017 | |
| American Indian or Alaska Native | 7380 (1·22%) | 2409 (1·22%) | 0 | 404 (1·16%) | 0·006 | |
| Native Hawaiian or Pacific Islander | 5929 (0·98%) | 1926 (0·98%) | 0 | 333 (0·95%) | 0·003 | |
| Smoking status | ||||||
| Never smoker | 239 311 (39·55%) | 77 831 (39·52%) | 0·001 | 13 938 (39·87%) | 0·006 | |
| Former smoker | 238 767 (39·46%) | 77 883 (39·55%) | 0·002 | 13 519 (38·67%) | 0·016 | |
| Current smoker | 126 936 (20·98%) | 41 227 (20·93%) | 0·001 | 7501 (21·46%) | 0·012 | |
| Area deprivation index† | ||||||
| Mean (SD) | 53·90 (19·60) | 53·91 (19·59) | 0 | 53·73 (19·62) | 0·009 | |
| Median (IQR) | 55·35 (41·06–68·53) | 55·35 (40·98–68·62) | NA | 55·26 (41·29–68·42) | NA | |
| BMI,‡ kg/m2 | ||||||
| Mean (SD) | 30·64 (6·02) | 30·64 (6·01) | 0 | 30·63 (6·12) | 0·002 | |
| Median (IQR) | 30·05 (26·47–34·20) | 30·05 (26·46–34·18) | NA | 29·98 (26·45–34·00) | NA | |
| COVID-19 vaccination | ||||||
| Unvaccinated | 100 505 (16·61%) | 32 774 (16·64%) | 0·001 | 5815 (16·63%) | 0·001 | |
| 1 dose | 28 249 (4·67%) | 9189 (4·67%) | 0 | 1646 (4·71%) | 0·002 | |
| 2 doses | 140 125 (23·16%) | 45 516 (23·11%) | 0·001 | 7878 (22·53%) | 0·015 | |
| ≥3 doses | 336 135 (55·56%) | 109 462 (55·58%) | 0 | 19 619 (56·12%) | 0·011 | |
| Seasonal influenza vaccine | ||||||
| Unvaccinated | 263 932 (43·62%) | 85 695 (43·51%) | 0·002 | 14 954 (42·78%) | 0·017 | |
| 1 dose | 192 277 (31·78%) | 62 789 (31·88%) | 0·002 | 11 627 (33·26%) | 0·032 | |
| ≥2 doses | 148 805 (24·60%) | 48 457 (24·61%) | 0 | 8377 (23·96%) | 0·015 | |
| HPV vaccine | ||||||
| Unvaccinated | 603 504 (99·75%) | 196 445 (99·75%) | 0·001 | 34 843 (99·67%) | 0·015 | |
| 1 dose | 1330 (0·22%) | 437 (0·22%) | 0·001 | 111 (0·32%) | 0·019 | |
| ≥2 doses | 180 (0·03%) | 59 (0·03%) | 0 | 4 (0·01%) | 0·012 | |
| RSV vaccine | ||||||
| Unvaccinated | 604 046 (99·84%) | 196 623 (99·84%) | 0 | 34 899 (99·83%) | 0·002 | |
| ≥1 dose | 968 (0·16%) | 318 (0·16%) | 0 | 59 (0·17%) | 0·002 | |
| Pneumococcal vaccine | ||||||
| Unvaccinated | 508 882 (84·11%) | 165 646 (84·11%) | 0 | 29 367 (84·01%) | 0·003 | |
| 1 dose | 92 079 (15·22%) | 29 971 (15·22%) | 0 | 5351 (15·31%) | 0·002 | |
| ≥2 doses | 4053 (0·67%) | 1324 (0·67%) | 0 | 240 (0·69%) | 0·002 | |
| Comorbidities | ||||||
| Autoimmune diseases | 36 982 (6·11%) | 12 036 (6·11%) | 0 | 2260 (6·46%) | 0·015 | |
| Anxiety | 135 849 (22·45%) | 44 180 (22·43%) | 0·001 | 7915 (22·64%) | 0·004 | |
| Cancer | 66 252 (10·95%) | 21 579 (10·96%) | 0 | 3911 (11·19%) | 0·008 | |
| Cardiovascular disease | 141 833 (23·44%) | 46 262 (23·49%) | 0·001 | 8461 (24·20%) | 0·018 | |
| Cerebrovascular disease | 65 270 (10·79%) | 21 329 (10·83%) | 0·001 | 3936 (11·26%) | 0·015 | |
| Dementia | 43 724 (7·23%) | 14 344 (7·28%) | 0·002 | 2632 (7·53%) | 0·012 | |
| Depression | 88 490 (14·63%) | 28 830 (14·64%) | 0 | 5190 (14·85%) | 0·006 | |
| Type 2 diabetes | 218 944 (36·19%) | 71 326 (36·22%) | 0·001 | 12 770 (36·53%) | 0·007 | |
| Immunocompromised status | 88 098 (14·56%) | 28 707 (14·58%) | 0 | 5242 (15·00%) | 0·012 | |
| Lung disease | 132 749 (21·94%) | 43 250 (21·96%) | 0 | 7789 (22·28%) | 0·008 | |
| Peripheral artery disease | 20 493 (3·39%) | 6705 (3·40%) | 0·001 | 1264 (3·62%) | 0·012 | |
| Prescription of prednisone | 125 253 (20·70%) | 40 847 (20·74%) | 0·001 | 7453 (21·32%) | 0·015 | |
| Care Assessment Need score§ | ||||||
| Mean (SD) | 0·19 (0·16) | 0·19 (0·16) | 0·003 | 0·2 (0·17) | 0·037 | |
| Median (IQR) | 0·14 (0·08–0·25) | 0·14 (0·08–0·25) | NA | 0·14 (0·08–0·26) | NA | |
| Veterans Affairs electronic health record frailty index | ||||||
| Mean (SD) | 0·20 (0·12) | 0·20 (0·12) | 0·002 | 0·20 (0·12) | 0·025 | |
| Median (IQR) | 0·16 (0·10–0·26) | 0·16 (0·10–0·26) | NA | 0·16 (0·10–0·26) | NA | |
| Estimated glomerular filtration rate‡, mL/min per 1·73 m2 | ||||||
| Mean (SD) | 78·25 (21·65) | 78·23 (21·65) | 0·001 | 77·71 (21·85) | 0·025 | |
| Median (IQR) | 80·54 (64·63–93·90) | 80·53 (64·62–93·88) | NA | 80·23 (64·18–93·81) | NA | |
| Diastolic blood pressure,‡ (mm Hg) | ||||||
| Mean (SD) | 77·49 (10·21) | 77·48 (10·23) | 0·001 | 77·49 (10·27) | 0 | |
| Median (IQR) | 78·00 (71–84) | 78·00 (71–84) | NA | 78 (71–84) | NA | |
| Systolic blood pressure,‡ (mm Hg) | ||||||
| Mean (SD) | 132·63 (17·35) | 132·63 (17·37) | 0 | 132·92 (17·62) | 0·016 | |
| Median (IQR) | 132 (121–143) | 132 (121–143) | NA | 132·00 (121–143) | NA | |
| Long-term care use¶ | 18 997 (3·14%) | 6259 (3·18%) | 0·002 | 1241 (3·55%) | 0·023 | |
| Number of Medicare inpatient visits | ||||||
| Mean (SD) | 0·04 (0·29) | 0·04 (0·31) | 0 | 0·04 (0·30) | 0·004 | |
| Median (IQR) | 0 (0–0) | 0 (0–0) | NA | 0 (0–0) | NA | |
| Number of Medicare outpatient visits | ||||||
| Mean (SD) | 0·15 (0·62) | 0·15 (0·63) | 0·001 | 0·15 (0·61) | 0·005 | |
| Median (IQR) | 0 (0–0) | 0 (0–0) | NA | 0 (0–0) | NA | |
| Number of SARS-CoV-2 tests within 1 year before T0 | ||||||
| Mean (SD) | 1·16 (2·45) | 1·17 (2·35) | 0·002 | 1·19 (2·53) | 0·01 | |
| Median (IQR) | 0 (0–1) | 0 (0–1) | NA | 0 (0–1) | NA | |
| Number of SARS-CoV-2 tests within 1–2 years before T0 | ||||||
| Mean (SD) | 0·72 (1·34) | 0·72 (1·31) | 0·002 | 0·74 (1·35) | 0·016 | |
| Median (IQR) | 0 (0–1) | 0 (0–1) | NA | 0 (0–1) | NA | |
| Number of seasonal influenza tests within 1 year before T0 | ||||||
| Mean (SD) | 0·29 (0·71) | 0·29 (0·68) | 0·003 | 0·31 (0·70) | 0·03 | |
| Median (IQR) | 0 (0–0) | 0 (0–0) | NA | 0 (0–0) | NA | |
| Number of seasonal influenza infections within 1 year before T0 | ||||||
| Mean (SD) | 0·16 (0·48) | 0·16 (0·47) | 0·001 | 0·17 (0·49) | 0·015 | |
| Median (IQR) | 0 (0–0) | 0 (0–0) | NA | 0 (0–0) | NA | |
| Rurality | ||||||
| Urban | 429 879 (71·05%) | 139 855 (71·01%) | 0·001 | 24 949 (71·37%) | 0·007 | |
| Rural | 157 462 (26·03%) | 51 311 (26·05%) | 0·001 | 9027 (25·82%) | 0·005 | |
| Highly rural | 17 491 (2·89%) | 5712 (2·90%) | 0·001 | 978 (2·80%) | 0·006 | |
| Insular island | 182 (0·03%) | 63 (0·03%) | 0·001 | 4 (0·01%) | 0·014 | |
Versus the test-negative control group.†
Area Deprivation Index is a measure of socioeconomic disadvantage, with a range of disadvantage from 0 (least disadvantaged) to 100 (most disadvantaged).‡
2·29% of the estimated glomerular filtration rate, 0·36% of the systolic and diastolic blood pressure, and 5·44% of the BMI values were missing and were imputed using multivariate imputation by chained equations in different exposure groups.§
Score ranges from 0 to 1, where a higher values indicates a higher risk.¶
Defined in the appendix (p 5).
Interpretation
Our results suggest that a positive test for COVID-19 (vs a negative test) was associated with increased rates of diagnosis of various infections in the 12 months following an acute SARS-CoV-2 infection. The putative long-term effects of COVID-19 on the immune system and the propensity for infection with other pathogens should be further evaluated in future studies.
Funding
US Department of Veterans Affairs.
