The study involved 225,723 children and adolescents with COVID-19 and 677,448 without COVID-19. The COVID-19-positive cohort comprised 109,022 NHW patients (48.3%), 45,823 NHB patients (20.3%), 60,012 Hispanic patients (26.6%), and 10,866 AAPI patients (4.8%) with SARS-CoV-2 infection from March 2020 to October 2022. Of these, 50.2% were female. Baseline comorbidities by race/ethnicity and severity are in Table 1. The COVID-19-negative cohort included 365,113 NHW patients (53.9%), 130,465 NHB patients (19.3%), 149,686 Hispanic patients (22.1%), and 32,184 AAPI patients (4.8%) without SARS-CoV-2 infection or MIS-C diagnosis.
Table 1
Baseline characteristics of COVID-19 positive patients, by race/ethnicity and severity status.
| Severe | Non-severe |
| NHW (N = 9,140) | AAPI (N = 590) | Hispanic (N = 3,786) | NHB (N = 3,346) | NHW (N = 99,882) | AAPI (N = 10,276) | Hispanic (N = 56,226) | NHB (N = 42,477) |
Age categories (%) | | | | | | | | |
< 1 years | 1601 (17.5%) | 122 (20.7%) | 767 (20.3%) | 733 (21.9%) | 9655 (9.7%) | 965 (9.4%) | 6154 (10.9%) | 4686 (11.0%) |
1 to < 5 years | 2811 (30.8%) | 197 (33.4%) | 1174 (31.0%) | 910 (27.2%) | 22018 (22.0%) | 2802 (27.3%) | 11892 (21.2%) | 9147 (21.5%) |
5 to < 12 years | 1893 (20.7%) | 133 (22.5%) | 773 (20.4%) | 568 (17.0%) | 27547 (27.6%) | 3191 (31.1%) | 17205 (30.6%) | 12991 (30.6%) |
12 to < 16 years | 1243 (13.6%) | 60 (10.2%) | 489 (12.9%) | 482 (14.4%) | 18276 (18.3%) | 1433 (13.9%) | 10430 (18.6%) | 7721 (18.2%) |
16 to < 21 years | 1592 (17.4%) | 78 (13.2%) | 583 (15.4%) | 653 (19.5%) | 22386 (22.4%) | 1885 (18.3%) | 10545 (18.8%) | 7932 (18.7%) |
Gender | | | | | | | | |
Female | 4208 (46.0%) | 255 (43.2%) | 1728 (45.6%) | 1580 (47.2%) | 50682 (50.7%) | 4968 (48.3%) | 28412 (50.5%) | 21408 (50.4%) |
Male | 4932 (54.0%) | 335 (56.8%) | 2058 (54.4%) | 1766 (52.8%) | 49200 (49.3%) | 5308 (51.7%) | 27814 (49.5%) | 21069 (49.6%) |
Hospital | | | | | | | | |
A | 1459 (16.0%) | 37 (6.3%) | 154 (4.1%) | 389 (11.6%) | 14323 (14.3%) | 530 (5.2%) | 1226 (2.2%) | 6069 (14.3%) |
B | 1113 (12.2%) | 95 (16.1%) | 317 (8.4%) | 646 (19.3%) | 24713 (24.7%) | 1960 (19.1%) | 4289 (7.6%) | 9949 (23.4%) |
C | 1031 (11.3%) | 57 (9.7%) | 801 (21.2%) | 163 (4.9%) | 4415 (4.4%) | 242 (2.4%) | 3880 (6.9%) | 848 (2.0%) |
D | 390 (4.3%) | 29 (4.9%) | 159 (4.2%) | 257 (7.7%) | 4647 (4.7%) | 471 (4.6%) | 2245 (4.0%) | 4443 (10.5%) |
E | 420 (4.6%) | 13 (2.2%) | 60 (1.6%) | 48 (1.4%) | 7581 (7.6%) | 322 (3.1%) | 1094 (1.9%) | 1047 (2.5%) |
F | 712 (7.8%) | 71 (12.0%) | 595 (15.7%) | 250 (7.5%) | 1907 (1.9%) | 239 (2.3%) | 1833 (3.3%) | 661 (1.6%) |
G | 754 (8.2%) | 28 (4.7%) | 92 (2.4%) | 153 (4.6%) | 7547 (7.6%) | 742 (7.2%) | 768 (1.4%) | 1314 (3.1%) |
H | 232 (2.5%) | 1 (0.2%) | 16 (0.4%) | 35 (1.0%) | 4529 (4.5%) | 109 (1.1%) | 283 (0.5%) | 710 (1.7%) |
I | 1156 (12.6%) | 85 (14.4%) | 183 (4.8%) | 517 (15.5%) | 8530 (8.5%) | 1098 (10.7%) | 1801 (3.2%) | 5844 (13.8%) |
J | 882 (9.6%) | 33 (5.6%) | 643 (17.0%) | 501 (15.0%) | 8173 (8.2%) | 526 (5.1%) | 5824 (10.4%) | 3404 (8.0%) |
K | 105 (1.1%) | 25 (4.2%) | 273 (7.2%) | 64 (1.9%) | 6783 (6.8%) | 2568 (25.0%) | 28574 (50.8%) | 5440 (12.8%) |
L | 182 (2.0%) | 88 (14.9%) | 320 (8.5%) | 100 (3.0%) | 1942 (1.9%) | 1151 (11.2%) | 3170 (5.6%) | 1057 (2.5%) |
M | 704 (7.7%) | 28 (4.7%) | 173 (4.6%) | 223 (6.7%) | 4792 (4.8%) | 318 (3.1%) | 1239 (2.2%) | 1691 (4.0%) |
Entry time | | | | | | | | |
03/2020–06/2020 | 136 (1.5%) | 17 (2.9%) | 163 (4.3%) | 122 (3.6%) | 907 (0.9%) | 190 (1.8%) | 1935 (3.4%) | 891 (2.1%) |
07/2020–10/2020 | 241 (2.6%) | 19 (3.2%) | 166 (4.4%) | 108 (3.2%) | 5454 (5.5%) | 433 (4.2%) | 4967 (8.8%) | 1760 (4.1%) |
11/2020–02/2021 | 753 (8.2%) | 47 (8.0%) | 346 (9.1%) | 291 (8.7%) | 16011 (16.0%) | 1240 (12.1%) | 10089 (17.9%) | 5262 (12.4%) |
03/2021–06/2021 | 720 (7.9%) | 32 (5.4%) | 277 (7.3%) | 309 (9.2%) | 7916 (7.9%) | 445 (4.3%) | 3007 (5.3%) | 4056 (9.5%) |
07/2021–10/2021 | 1063 (11.6%) | 37 (6.3%) | 394 (10.4%) | 485 (14.5%) | 13868 (13.9%) | 818 (8.0%) | 6095 (10.8%) | 6477 (15.2%) |
11/2021–02/2022 | 3050 (33.4%) | 193 (32.7%) | 1320 (34.9%) | 1136 (34.0%) | 33830 (33.9%) | 3746 (36.5%) | 19028 (33.8%) | 16290 (38.4%) |
03/2022–06/2022 | 1662 (18.2%) | 120 (20.3%) | 577 (15.2%) | 447 (13.4%) | 12030 (12.0%) | 1951 (19.0%) | 4939 (8.8%) | 3739 (8.8%) |
07/2022–10/2022 | 1515 (16.6%) | 125 (21.2%) | 543 (14.3%) | 448 (13.4%) | 9866 (9.9%) | 1453 (14.1%) | 6166 (11.0%) | 4002 (9.4%) |
Obesity | | | | | | | | |
0 | 6055 (66.2%) | 422 (71.5%) | 2230 (58.9%) | 1926 (57.6%) | 62750 (62.8%) | 6141 (59.8%) | 21525 (38.3%) | 21711 (51.1%) |
1 | 3085 (33.8%) | 168 (28.5%) | 1556 (41.1%) | 1420 (42.4%) | 37132 (37.2%) | 4135 (40.2%) | 34701 (61.7%) | 20766 (48.9%) |
PMCA | | | | | | | | |
0 | 4333 (47.4%) | 311 (52.7%) | 1938 (51.2%) | 1552 (46.4%) | 67424 (67.5%) | 7594 (73.9%) | 41294 (73.4%) | 27868 (65.6%) |
1 | 1435 (15.7%) | 79 (13.4%) | 534 (14.1%) | 524 (15.7%) | 18614 (18.6%) | 1564 (15.2%) | 8820 (15.7%) | 8692 (20.5%) |
2 | 3372 (36.9%) | 200 (33.9%) | 1314 (34.7%) | 1270 (38.0%) | 13844 (13.9%) | 1118 (10.9%) | 6112 (10.9%) | 5917 (13.9%) |
Negative tests prior entry | | | | | | | | |
0 | 6038 (66.1%) | 407 (69.0%) | 2671 (70.5%) | 2301 (68.8%) | 73195 (73.3%) | 7908 (77.0%) | 45852 (81.5%) | 32592 (76.7%) |
1 | 1445 (15.8%) | 97 (16.4%) | 521 (13.8%) | 497 (14.9%) | 15999 (16.0%) | 1440 (14.0%) | 6650 (11.8%) | 6233 (14.7%) |
2 | 641 (7.0%) | 32 (5.4%) | 225 (5.9%) | 238 (7.1%) | 5875 (5.9%) | 519 (5.1%) | 2169 (3.9%) | 2146 (5.1%) |
>=3 | 1016 (11.1%) | 54 (9.2%) | 369 (9.7%) | 310 (9.3%) | 4813 (4.8%) | 409 (4.0%) | 1555 (2.8%) | 1506 (3.5%) |
Vaccine dosage | | | | | | | | |
0 | 7860 (86.0%) | 469 (79.5%) | 3347 (88.4%) | 3015 (90.1%) | 82136 (82.2%) | 7256 (70.6%) | 46760 (83.2%) | 37252 (87.7%) |
1 | 240 (2.6%) | 22 (3.7%) | 80 (2.1%) | 71 (2.1%) | 2878 (2.9%) | 474 (4.6%) | 1667 (3.0%) | 1159 (2.7%) |
>=2 | 1040 (11.4%) | 99 (16.8%) | 359 (9.5%) | 260 (7.8%) | 14868 (14.9%) | 2546 (24.8%) | 7799 (13.9%) | 4066 (9.6%) |
Incidence of PASC symptoms and conditions for COVID-19 positive and negative patients
Table 2 presents the incidence for 24 potential PASC symptoms and conditions in the COVID-19 positive cohort compared with the COVID-19 negative cohort, stratified by acute COVID-19 severity status. The data in Table 2 reveal that the incidence rates of all listed PASC symptoms and conditions were significantly increased in COVID-19-positive patients as compared with the COVID-19-negative group during the follow-up period. For example, the incidence of respiratory signs and symptoms for COVID-19-positive patients was 9.68% while the incidence was 7.25% for the COVID-19-negative group (P < 0.001). Moreover, the incidence of the potential PASC symptoms and conditions in the severe group was increased compared to the incidence of these symptoms and conditions within the non-severe COVID-19 patient group.
Table 2
Raw incidence (%) of potential PASC symptoms and conditions comparing COVID-19 positive and negative patients.
| COVID-19 positive (%) | COVID-19 negative (%) |
All (N = 225,723) | Severe (N = 16,862) | Non-severe (N = 208,861) | All (N = 677,448) | Severe (N = 143,592) | Non-severe (N = 533,856) |
At least one condition | 26.86 | 34.17 | 26.42 | 21.44 | 19.8 | 21.84 |
Systematic conditions | 2.69 | 7.46 | 2.37 | 1.87 | 2.93 | 1.61 |
Syndromic conditions | 26.15 | 32.48 | 25.75 | 20.83 | 18.77 | 21.35 |
Abdominal pain | 3.04 | 3.66 | 2.99 | 2.27 | 2.15 | 2.31 |
Abnormal liver enzyme | 0.32 | 1.17 | 0.25 | 0.24 | 0.43 | 0.19 |
Acute kidney injury | 0.22 | 1.32 | 0.13 | 0.15 | 0.42 | 0.08 |
Acute respiratory distress syndrome | 0.03 | 0.24 | 0.01 | 0.01 | 0.03 | 0.01 |
Arrhythmias | 1.43 | 4.41 | 1.21 | 0.95 | 1.56 | 0.79 |
Cardiovascular signs and symptoms | 1.16 | 1.69 | 1.12 | 0.88 | 0.86 | 0.89 |
Changes in the taste and smell | 0.16 | 0.08 | 0.17 | 0.04 | 0.02 | 0.05 |
Chest pain | 1.39 | 1.69 | 1.37 | 0.74 | 0.68 | 0.75 |
Cognitive functions | 0.68 | 1 | 0.66 | 0.66 | 0.62 | 0.68 |
Fatigue and malaise | 1.74 | 3.22 | 1.63 | 1.3 | 1.74 | 1.18 |
Fever and chills | 5.67 | 9.15 | 5.41 | 3.73 | 3.31 | 3.84 |
Fluid and electrolyte | 0.56 | 3.33 | 0.36 | 0.39 | 0.92 | 0.24 |
Generalized pain | 1.26 | 1.78 | 1.22 | 0.91 | 1.02 | 0.88 |
Hair loss | 0.24 | 0.48 | 0.22 | 0.14 | 0.14 | 0.14 |
Headache | 2.2 | 2.33 | 2.19 | 1.51 | 1.23 | 1.59 |
Heart disease | 0.37 | 1.67 | 0.27 | 0.28 | 0.62 | 0.2 |
Mental health | 6.32 | 8.04 | 6.19 | 5.45 | 5.05 | 5.55 |
Musculoskeletal pain | 3.53 | 4.03 | 3.5 | 2.79 | 2.72 | 2.81 |
Myocarditis | 0.03 | 0.17 | 0.02 | 0.01 | 0.02 | 0 |
Myositis | 0.02 | 0.08 | 0.02 | 0.02 | 0.02 | 0.01 |
POTS/dysautonomia | 1.03 | 1.34 | 1.01 | 0.71 | 0.72 | 0.71 |
Respiratory signs and symptoms | 9.68 | 15.02 | 9.31 | 7.25 | 6.77 | 7.38 |
Skin symptoms | 3.62 | 4.99 | 3.51 | 2.7 | 2.66 | 2.71 |
Thrombophlebitis and thromboembolism | 0.13 | 1.02 | 0.06 | 0.11 | 0.33 | 0.05 |
Note: * indicates no evidence of statistical significance from the two-sample proportion test (see the Supplementary Materials) |
Red Symptom: COVID-19 positive higher incidence |
Blue Symptom: COVID-19 positive lower incidence (see the Supplementary Materials) |
Racial/ethnic differences in PASC symptoms and conditions
After achieving the balance of SMD (Section S8), Fig. 3 shows the racial/ethnic difference attributable to COVID-19 in potential PASC symptoms and conditions by the severity of COVID-19. Overall, we found moderate evidence of an increase in composite outcomes, i.e., at least one condition and any of the syndromic conditions, after SARS-CoV-2 infection among the AAPI group in both severe and non-severe COVID-19 group, but there was no strong evidence of increased racial differences among Hispanic and Non-Hispanic Black groups.
[Insert Fig. 3 Here]
For patients with severe COVID-19, AAPI patients showed a higher increase in any of the conditions (RR 1.24, 95% confidence interval (CI) 1.04 to 1.49, P = 0.019) and any of syndromic conditions (RR 1.22, 95% CI 1.01 to 1.47, P = 0.042) compared to NHW after SARS-CoV-2 infection. Hispanic patients showed no increase in any of the conditions (RR 0.99, 95% CI 0.91 to 1.08, P = 0.804), and NHB patients showed a minor decrease in any of the conditions (RR 0.93, 95% CI 0.85 to 1.24, P = 0.147) as compared to NHW patients. For patients with non-severe COVID-19, AAPI patients showed a higher increase in any of the conditions (RR 1.08, 95% CI 1.01 to 1.14, P = 0.015) and any of syndromic conditions (RR 1.08, 95% CI 1.01 to 1.08, P = 0.017) compared to NHW. Hispanic patients showed almost no increase in any of the conditions (RR 1.01, 95% CI 0.98 to 1.04, P = 0.498), and NHB patients also showed almost no decrease in any of the conditions (RR 0.99, 95% CI 0.89 to 1.11, P = 0.915) as compared to NHW patients.
However, there exist statistically significant differences among all minority groups across several PASC symptoms and conditions after SARS-CoV-2 infection. For example, for patients with severe COVID-19, the increased prevalence of hair loss among Hispanic patients was greater (RR 2.62, 95% CI 1.06 to 6.49, P = 0.038) than the increased prevalence among NHW patients. The corresponding increase in the prevalence of fever and chills among AAPI was greater (RR 1.41, 95% CI 1.01 to 1.97, P = 0.045). NHB patients had a smaller increase in skin symptoms (RR 0.74, 95% CI 0.58 to 0.96, P = 0.021) than NHW patients. For patients with non-severe COVID-19, AAPI patients had a greater increase concerning POTS/dysautonomia (RR 1.57, 95% CI 1.02 to 2.40, P = 0.037) and respiratory signs and symptoms (RR 1.11, 95% CI 1.00 to 1.23, P = 0.036) compared to NHW patients. NHB patients had a greater increase in cognitive functions (1.25, 95% CI 1.01 to 1.55, P = 0.037) than NHW patients.
Furthermore, we observed a differential increase by racial/ethnic group within both severe and non-severe groups. These racial/ethnic differences varied depending upon the severity of the acute phase of COVID-19 as well as the specific potential PASC symptoms and conditions being analyzed. For example, among the severe group, the differential increase in abdominal pain was more pronounced for all three minority groups compared to those in the non-severe category.
Sensitivity analysis
Figure S2 showed the results of the negative control outcome experiments and estimated systematic error, such as the unmeasured confounder bias. Figure S3 showed the racial/ethnic differences after SARS-CoV-2 infection stratified by severity of COVID-19, using standard regression models. Among COVID-19 patients within the severe group, NHB patients showed a greater incidence in any of the conditions (RR 1.16, 95% CI 1.02 to 1.32, P = 0.024) and any syndromic conditions (RR 1.14, 95% CI 1.00 to 1.30, P = 0.042) as compared to NHW patients. Hispanic patients also showed a greater incidence in any of the conditions (RR 1.12, 95% CI 0.99 to 1.27, P = 0.075) as compared to NHW patients.
Specifically, among COVID-19 patients with severe illness during the acute infection, Hispanic individuals exhibited a greater incidence of respiratory signs and symptoms (RR: 1.16, 95% CI 1.02 to 1.33, P = 0.024) and hair loss (RR: 1.84, 95% CI 1.02 to 3.31, P = 0.043) as compared with the NHW patient group. NHB had a greater incidence of respiratory signs and symptoms (RR: 1.19, 95% CI 1.03 to 1.36, P = 0.015) and heart disease (RR: 1.48, 95% CI 1.06 to 2.07, P = 0.022), but a lower incidence of arrhythmias (RR: 0.73, 95% CI 0.57 to 0.94, P = 0.013) and headache (RR: 0.66, 95% CI 0.48 to 0.93, P = 0.016) compared with the NHW group.
Among those with non-severe acute COVID-19, Hispanic patients displayed a higher incidence of myocarditis (RR 4.28, 95% CI 1.53 to 11.98, P = 0.006) and abnormal liver enzyme (RR 2.06, 95% CI 1.08 to 3.94, P = 0.029) compared with NHW patients. Meanwhile, AAPI patients demonstrated a greater incidence of hair loss (RR 3.32, 95% CI 1.43 to 7.72, P = 0.005) compared with the NHW patient group.
These findings revealed that our difference-in-differences approach identified fewer racial/ethnic differences compared to standard regression models. It is worth noting that the difference-in-differences approach adjusted for the baseline racial/ethnic difference before the SARS-CoV-2 infection, a step that a standard regression analysis failed to take into consideration. Consequently, some of the observed racial/ethnic differences with prior work might not be attributed to COVID-19. Nevertheless, given its adjustment for baseline racial/ethnic differences, the difference-in-differences approach holds greater robustness.
In the analysis including only those patients identified based on positive SARS-CoV-2 PCR or antigen testing (Section S4), differences among severe patients were diminished among some potential PASC symptoms and conditions, while among the non-severe patients, the differences that we identified were consistent in both sets of analyses. To account for the potential bias stemming from limited hospital capacity during the initial COVID-19 period, we performed a secondary analysis excluding COVID-19 patients from the first wave of the pandemic (March to May 2020). This exclusion did not significantly alter the results, as demonstrated in Section S5. Section S6 shows the results of subgroup analysis by age group. Section S7 shows the results of stratified analysis by virus variants.