Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex

Authors: Martina Patone, PhD; Xue W. Mei, PhD; Lahiru Handunnetthi, PhD; Sharon Dixon, MD; Francesco Zaccardi, PhD; Manu Shankar-Hari, PhD; Peter Watkinson, MD; Kamlesh Khunti, PhD; Anthony Harnden, PhD; Carol A.C. Coupland, PhD; Keith M. Channon, MD; Nicholas L. Mills, PhD; Aziz Sheikh, MD; Julia Hippisley-Cox, MD August 28, 2022 ORIGINAL RESEARCHARTICLECirculation. 2022;146:00–00. DOI: 10.1161/CIRCULATIONAHA.122.059970 xxx xxx, 20223Patone et al

BACKGROUND: Myocarditis is more common after severe acute respiratory syndrome coronavirus 2 infection than after COVID-19 vaccination, but the risks in younger people and after sequential vaccine doses are less certain.

METHODS:

A self-controlled case series study of people ages 13 years or older vaccinated for COVID-19 in England between December 1, 2020, and December 15, 2021, evaluated the association between vaccination and myocarditis, stratified by age and sex. The incidence rate ratio and excess number of hospital admissions or deaths from myocarditis per million people were estimated for the 1 to 28 days after sequential doses of adenovirus (ChAdOx1) or mRNA-based (BNT162b2, mRNA-1273) vaccines, or after a positive SARS-CoV-2 test.RESULTS: In 42842345 people receiving at least 1 dose of vaccine, 21242629 received 3 doses, and 5934153 had SARS-CoV-2 infection before or after vaccination. Myocarditis occurred in 2861 (0.007%) people, with 617 events 1 to 28 days after vaccination. Risk of myocarditis was increased in the 1 to 28 days after a first dose of ChAdOx1 (incidence rate ratio, 1.33 [95% CI, 1.09–1.62]) and a first, second, and booster dose of BNT162b2 (1.52 [95% CI, 1.24–1.85]; 1.57 [95% CI, 1.28–1.92], and 1.72 [95% CI, 1.33–2.22], respectively) but was lower than the risks after a positive SARS-CoV-2 test before or after vaccination (11.14 [95% CI, 8.64–14.36] and 5.97 [95% CI, 4.54–7.87], respectively). The risk of myocarditis was higher 1 to 28 days after a second dose of mRNA-1273 (11.76 [95% CI, 7.25–19.08]) and persisted after a booster dose (2.64 [95% CI, 1.25–5.58]). Associations were stronger in men younger than 40 years for all vaccines. In men younger than 40 years old, the number of excess myocarditis events per million people was higher after a second dose of mRNA-1273 than after a positive SARS-CoV-2 test (97 [95% CI, 91–99] versus 16 [95% CI, 12–18]). In women younger than 40 years, the number of excess events per million was similar after a second dose of mRNA-1273 and a positive test (7 [95% CI, 1–9] versus 8 [95% CI, 6–8]).CONCLUSIONS: Overall, the risk of myocarditis is greater after SARS-CoV-2 infection than after COVID-19 vaccination and remains modest after sequential doses including a booster dose of BNT162b2 mRNA vaccine. However, the risk of myocarditis after vaccination is higher in younger men, particularly after a second dose of the mRNA-1273 vaccine.

We recently reported an association between the first and second dose of COVID-19 vaccination and myocarditis, which generated considerable scientific, policy, and public interest.1 It added to evidence emerging from multiple countries that has linked exposure to BNT162b2 mRNA vaccine with acute myocarditis.2–8In the largest and most comprehensive analysis to date, we reported an increased risk of hospital admission or death from myocarditis after both adenoviral (ChAdOx1) vaccines and mRNA (BNT162b2 or mRNA-1273) vac-cines. It is important that we also demonstrated across the entire vaccinated population in England that the risk of myocarditis after vaccination was small compared with the risk after a positive SARS-CoV-2 test.1However, myocarditis is more common in younger people younger than the age of 40 years and in men in particular.9,10 Additional analyses stratified by age and sex are important because vaccine campaigns are rap-idly being extended to include children and young adults. Furthermore, given the consistent observation that the risk of myocarditis is higher after the second dose of vac-cine compared with the first dose,1,11 there is an urgent need to evaluate the risk associated with a booster dose because booster programs are accelerated internation-ally to combat the omicron variant.12Because new data were available, we have extended our analysis to include people ages 13 years or older and those receiving a booster dose to further evaluate the association between COVID-19 vaccination or infection and risk of myocarditis, stratified by age and sex.

METHODS

Transparency and Openness Promotion This analysis makes use of multiple routinely collected health care data sources that were linked, deidentified, and held in a trusted research environment that was accessible to approved individuals who had undertaken the necessary governance training. Because of the sensitive nature of the data collected for this study, requests to access the dataset from qualified researchers trained in human subject confidentiality proto-cols may be sent to National Health Service Digital and the United Kingdom Health Security Agency. Simulated data and the analysis code are available publicly at https://github.com/qresearchcode/COVID-19-vaccine-safety. National Health Service Research Ethics Committee approval was obtained from the East Midlands–Derby Research Ethics Committee (Reference 18/EM/0400]. Anonymized data are analyzed, so there is no requirement for written informed consent. Data Sources We used the National Immunisation Database of COVID-19 vaccination to identify vaccine exposure. This includes vaccine type, date, and doses for all people vaccinated in England. We linked National Immunisation Database vaccination data, at the individual level, to national data for mortality (Office for National Statistics), hospital admissions (Hospital Episode Statistics and Secondary User’s service data), and SARS-CoV-2 infection data (Second Generation Surveillance System).Study Design and Oversight We undertook a self-controlled case series design, originally developed to examine vaccine safety.12 The analyses are conditional on each case, so any fixed characteristics during the study period, such as sex, ethnicity, or chronic conditions, are inherently controlled for. Age was considered as a fixed variable because the study period was short. Any time-varying factors, such as seasonal variation, need to be adjusted for in the analy-ses. Hospital admissions were likely to be influenced by the pressure on the health systems because of COVID-19, which was not uniform during the pandemic study period. To allow for these underlying seasonal effects, we split the study observation period into weeks and adjusted for week as a factor vari-able in the statistical models.Study Period and Population We included all people ages 13 years or older who had received at least 1 dose of ChAdOx1 (AstraZeneca), BNT162b2 (Pfizer), and mRNA-1273 (Moderna) vaccine and were admit-ted to hospital or died from myocarditis between December 1, 2020, and December 15, 2021.OutcomeThe primary outcome of interest was the first hospital admis-sion caused by the myocarditis, or death recorded on the death Clinical PerspectiveWhat Is New?•We performed an evaluation of the risk of myocar-ditis after COVID-19 vaccine in >42 million vacci-nated people 13 years or older, including 21 million people receiving a booster dose, stratified by age and sex.•We extend our previous findings demonstrating that the risk of hospitalization or death from myo-carditis after SARS-CoV-2 infection is substantially higher than the risk associated with a first dose of ChAdOx1, and a first, second, or booster dose of BNT162b2 mRNA vaccine.

•Associations were stronger in younger men <40 years for all vaccines and after a second dose of mRNA-1273 vaccine, where the risk of myocarditis was higher after vaccination than SARS-CoV-2 infection. What Are the Clinical Implications?•Our findings will inform recommendations on the type of vaccine offered to younger people and will help to shape public health policy on booster pro-grams enabling an informed discussion of the risk of vaccine associated myocarditis when considering the net benefit of vaccination.

Myocarditis After COVID-19 Vaccine and Infection certificate with the International Classification of Diseases, Tenth Revision code (Table S1) related to myocarditis within the study period (December 1, 2020, to December 15, 2022). We used the earliest date of hospitalization or date of death as the event date.ExposuresThe exposure variables were a first, second, or booster dose of the ChAdOx1, BNT162b2, or mRNA-1273 vaccines, and SARS-CoV-2 infection, defined as the first SARS-CoV-2–positive test in the study period. All exposures were included in the same model. We defined the exposure risk intervals as the following prespecified time periods: 0, 1 to 7, 8 to 14, 15 to 21, and 22 to 28 days after each exposure date, under the assumption that the adverse events under consideration are unlikely to be related to exposure later than 28 days after expo-sure. A pre-risk interval of 1 to 28 days before each exposure date was included to account for potential bias that might arise if the occurrence of the outcome temporarily influenced the likelihood of exposure. The baseline period for the vaccination exposures was the remaining time from December 1, 2020, until 29 days before the first dose date and from 29 days after the first or second dose until 29 days before the second or booster dose (if applicable), and from 29 days after the booster dose until December 15, 2021, or the censored date if earlier. We assumed that the risks might be different after each vac-cine dose, and hence we allowed for a dose effect, by defining a separate risk interval after each dose: 0, 1 to 7, 8 to 14, 15 to 21, or 22 to 28 days after the first, second, or booster dose. To avoid overlapping risk periods, we assumed that later expo-sures take precedence over earlier ones, except for the 1- to 28-day pre-risk period for the second or booster dose. A posi-tive SARS-CoV-2 test was considered as a separate exposure in the models, which allowed overlapping risk windows with vaccination exposure.Statistical AnalysisWe described the characteristics of the whole study population by vaccine dose and type, and in those with myocarditis strati-fied by age and sex.In vaccinated people with myocarditis, the self-controlled case series models were fitted using a conditional Poisson regression model with an offset for the length of the expo-sure risk period. Incidence rate ratios (IRR), the relative rate of hospital admissions or deaths caused by myocarditis in expo-sure risk periods relative to baseline periods, and their 95% CIs were estimated by the self-controlled case series model adjusted for calendar time. We investigated if associations between vaccine exposure and the myocarditis outcome were sex- or age-dependent by performing subgroup analyses strati-fied by sex and age (men age <40 years, men age≥ 40 years, women age <40 years, and women age ≥40 years). We also conducted analyses stratified by vaccination history, restricted to those who had the same type of vaccine in the first and sec-ond dose and by lag in days between the first and second dose (≤65, 66 to 79, and ≥80 days).We conducted sensitivity analyses to assess the robustness of results to assumptions, such as that the occurrence of an outcome event did not influence the probability of subsequent exposures by (1) excluding those who died from the outcome and (2) restricting analysis to the period after the first dose and (3) after the second dose, without censoring at death; and to assess potential reporting delays in the data by (4) restricting the study to the period up to December 1, 2021.We also performed sensitivity analyses (5) removing patients who had outcomes in the 28 days after a first dose, but before a second dose, and (6) removing patients who had outcomes in the 28 days after a second dose, but before a booster dose, because they are less likely to have a second dose if they experienced an adverse event after the first. Last, we conducted a sensitivity analysis (7) restricted to those with-out a positive SARS-CoV-2 test during the observation period.We used Stata (version 17) for these analyses.

RESULTS

Between December 1, 2020, and December 15, 2021, there were 42 842 345 people vaccinated with at least 1 dose of ChAdOx1 (n=20 650 685), BNT162b2 (n=20 979 704), or mRNA-1273 (n=1 211 956) (Table 1). Of these, 39 118 282 received a sec-ond dose of ChAdOx1 (n=20 080 976), BNT162b2 (n=17 950 086), or mRNA-1273 (n=1 087 220), and 21 242 629 people received a third vaccine dose: ChAdOx1 (n=53 606), BNT162b2 (n=17 517 692), and mRNA-1273 (n=3 671 331).Among people receiving at least 1 vaccine dose, 5 934 153 (13.9%) tested positive for SARS-CoV-2, including 2 958 026 (49.8%) before their first vac-cination.Of the 42 842 345 people in the study population, 2861 (0.007%) were hospitalized or died from myocar-ditis during the study period; 345 (<0.001%) patients died within 28 days from a hospital admission with myo-carditis or with myocarditis as cause of death recorded in the death certificate. A total of 617 (0.001%) of these events occurred 1 to 28 days after any dose of vaccine (Table 2). Of the 524 patients admitted to the hospital with myocarditis in the 1 to 28 days after any first or sec-ond vaccine dose, 151 (28.8%) had received a booster dose: 34.4% (79/230) of those who had ChAdOx1 in the first or second dose and 29.7% (72/243) of those who had BNT162b2 in the first or second dose (Table 2). Of the 5 934 153 patients with a SARS-CoV-2 infection, 195 (0.003%) were hospitalized or died with myocarditis in the 1 to 28 days after the positive test; 114 (58.5%) of these events occurred before vaccination (Table S2).Vaccine-Associated MyocarditisIn the study period, we observed 140 and 90 patients who were admitted to the hospital or died of myocardi-tis after a first and second dose of ChAdOx1 vaccine, respectively. Of these, 40 (28.6%) and 11 (12.2%)‚ re-spectively, died with myocarditis or within 28 days from hospital admission. Similarly, there were 124, 119, and 85 patients who were admitted to the hospital or died

After COVID-19 Vaccine and Infection Table 1.Baseline Demographic Characteristics of People Receiving ChAdOx1, BNT162b2, or mRNA-1273 Vaccines or Testing Positive for SARS-CoV-2 Virus (in Those Vaccinated) in England Between December 1, 2020, and December 15, 2021 ChAdOx1BNT162b2mRNA-1273ChAdOx1BNT162b2mRNA-1273ChAdOx1BNT162b2mRNA-1273SARS- CoV-2 positive*One dose (n=42 842 345)Two doses (n=39 118 282)Booster doses (n=21 242 629)(n= 5 934 153)% (n)% (n) % (n)% (n)% (n)% (n)% (n)% (n)% (n)% (n)Total no. of people20 650 68520 979 7041 211 95620 080 97617 950 0861 087 22053 60617 517 6923 671 3315 934 153SexWomen49.5(10 215 079)49.1(10 295 561)38.7(469 114)49.5(9 945 533)50.1(9 000 748)39.5(429 705)61.2(32 792)54.2(9 489 364)48.4(1 778 317)52.3(3 103 168)Men43.3(8 933 572)40.4(8 476 032)42.0(508 416)43.3(8 697 560)39.8(7 148 539)42.1(457 629)34.8(18 674)41.4(7 244 858)44.2(1 623 230)40.5(2 405 336)Not recorded7. 3(1 502 034)10.5(2 208 110)19.3(234 426)7. 2(1 437 882)10.0(1 800 799)18.4(199 886)4.0(2140)4.5(783 471)7. 3(269 784)7. 2(425 649)Age, yMean age (SD)54.9 (14.8)43.0 (22.4)32.3 (9.7)55.0 (14.7)46.5 (21.7)32.7 (9.8)63.1 (17.0)61.8 (15.9)53.7 (12.4)41.4 (18.0)13–17 <0.1(10 214)10.6(2 219 006)0.1(838)<0.1(9105)2.6(468 569)0.1 (623)0.1 (31)0.1(23 826)0.1(2961)8.3(493 728)18–29 5.2(1 081 177)24.4(5 127 151)43.1(521 916)5.1(1 022 847)24.9(4 472 159)41.3(449 436)3.7(1964)3.6(624 465)4.0(146 688)21.6(1 279 933)30–39 7. 9(1 634 841)21.5(4 517 781)35.6(431 515)7. 8(1 556 785)23.1(4 146 117)36.1(392 581)5.8(3102)6.1(1 067 916)8.6(315 936)18.3(1 084 406)40–49 22.1(4 564 393)8.5(1 784 664)18.4(222 849)22.0(4 414 864)9.3(1 665 983)19.5(212 187)11.5 (6171)11.1(1 949 092)19.2(706 004)19.4(1 152 196)50–59 2 7. 5(5 673 878)8.0(1 684 013)1.8(22 320)2 7. 6(5 549 187)9.1(1 636 430)1.9(20 463)19.9(10 644)20.8(3 635 337)35.3(1 295 168)16.7(989 499)60–69 19.8(4 083 887)8.5(1 777 370)0.7(8330)20.0(4 013 588)9.8(1 753 552)0.7(8145)19.3(10 371)22.5(3 938 515)24.8(910 586)8.5(505 389)70–79 13.4(2 763 041)9.4(1 979 901)0.3(3241)13.5(2 717 638)10.9(1 959 318)0.3(2789)22.6(12 090)23.1(4 049 042)6.5(237 287)4.2(248 415)80–89 3.1(630 457)7. 7(1 621 129)0.1(842)3.0(604 788)8.9(1 591 216)0.1(837)12.5 (6710)10.8(1 888 973)1.3(47 228)2.2(132 459)90+ 1.0(208 753)1.3(268 563)<0.1(103)1.0(192 162)1.4(256 698)<0.1(158)4.7(2523)1.9(340 498)0.3(9473)0.8(48 117)Not recorded<0.1 (44)<0.1 (125)<0.1 (2)<0.1 (11)<0.1 (44)<0.0 (1)0<0.1 (29)0<0.1 (11)Women age groups, y <40 14.8(1 510 119)51.7(5 325 910)7 7. 9(365 443)14.4(1 437 517)45.9(4 131 123)76.4(328 311)9.2(3020)10.9(1 032 366)14.2(252 054)4 7. 6(1 477 776)≥40 85.2(8 704 960)48.3(4 969 651)22.1(103 671)85.5(8 508 009)54.1(4 869 604)23.6(101 394)90.8(29 772)89.1(8 456 981)85.8(1 526 263)52.4(1 625 385) Not recorded<0.1 (16)<0.1 (59)0<0.1 (7)<0.1 (21)0000<0.1 (7)Men age groups, y<40 11.2(998 025)56.2(4 762 038)78.2(397 521)10.9(949 865)49.4(3 533 806)76.7(35 074)8.8(1650)7. 5(541 432)10.5(171 132)46.2(1 110 723)≥40 88.8(7 935 546)43.8(3 712 994)21.8(110 895)89.1(7 747 692)50.8(3 614 721)23.3(106 834)91.2(17 024)92.5(6 703 416)89.5(1 452 098)53.8(1 294 609) Not recorded<0.1 (21)<0.1 (42)<0.1 (2)<0.1 (3)<0.1 (12)<0.1 (1)000<0.1 (4)EthnicityWhite6 7. 9(14 012 353)63.6(13 344 722)53.0(642 168)68.0(13 656 716)64.2(11 530 182)54.0(587 123)74.3(39 827)73.6(12 891 303)69.6(2 553 453)66.9(3 971 366)Indian2.0(406 066)2.2(469 302)1.1(13 385)2.0(395 171)2.2(394 274)1.1(11 902)2.1(1141)2.0(354 433)1.4(51 193)2.6(153 403)Pakistani1.2(253 523)1.6(335 100)1.0(12 213)1.2(239 511)1.4(249 446)0.9(9732)0.9(477)0.6(109 038)0.5(19 186)2.0(118 522)Bangladeshi0.5 (96 392)0.5 (111 314)0.5 (5966)0.5 (92 835)0.5 (83 524)0.5 (4902)0.4 (217)0.2 (43 360)0.3 (10 775)0.7 (40 093)Other Asian0.9 (177 629)1.1 (238 245)1.0 (11 859)0.9 (171 863)1.1 (191 996)1.0 (10 365)0.8 (436)0.7 (128 434)0.6 (23 284)1.1 (67 392)Caribbean0.6 (117 507)0.5 (96 994)0.4 (4265)0.6 (110 470)0.4 (80 146)0.3 (3296)1.3 (706)0.4 (77 095)0.3 (11 820)0.5 (28 327)(Continued)ORIGINAL RESEARCHARTICLECirculation. 2022;146:00–00. DOI: 10.1161/CIRCULATIONAHA.122.059970xxx xxx, 20225Patone et alMyocarditis After COVID-19 Vaccine and Infectionof myocarditis after a first, second, and third dose of BNT162b2 vaccine, respectively. Of these, 22 (17.7%), 14 (11.8%), and 13 (15.3%) patients died with myo-carditis or within 28 days from hospital admission. Last, there were 11, 40, and 8 patients who were admitted to the hospital for myocarditis after, respectively, a first, second, and third dose of mRNA-1273 vaccine. None of these patients died with myocarditis or within 28 days from hospital admission with myocarditis (Table2).In the overall population, we confirmed our previous findings that the risk of hospitalization or death from myocarditis was higher after SARS-CoV-2 infection than vaccination and was greater after the first 2 doses of mRNA vaccine than after adenovirus vaccine (Table3; Table S3; Figure). There was an increased risk of myo-carditis at 1 to 28 days after the first dose of ChAdOx1 (IRR, 1.33 [95% CI, 1.09–1.62]) and BNT162b2 (IRR, 1.52 [95% CI, 1.24–1.85]).There was an increased risk of myocarditis at 1 to 28 days after a second dose of BNT162b2 (IRR, 1.57 [95% CI, 1.28–1.92]) and mRNA-1273 (IRR, 11.76 [95% CI, 7.25–19.08]); and after a booster dose of BNT162b2 (IRR, 1.72 [95% CI, 1.33–2.22]) and mRNA-1273 (IRR, 2.64 [95% CI, 1.25–5.58]).Vaccine-Associated Myocarditis in MenOf the 17918020 men vaccinated in England in the study period, 6158584 (34.4%) were younger than 40 years, and 11759 436 (65.6%) were 40 years or older (Table1). Analysis restricted to younger men age younger than 40 years showed an increased risk of myocarditis Black African0.9 (185 852)1.0 (218 158)1.0 (12 121)0.9 (176 094)0.9 (164 260)0.9 (9258)1.1 (588)0.6 (98 216)0.5 (16 997)1.0 (57 157)Chinese0.3 (63 180)0.3 (70 206)0.4 (5176)0.3 (61 902)0.3 (58 438)0.5 (4902)0.3 (149)0.3 (47 390)0.3 (11 899)0.2 (11 732)Other1.8 (378 719)2.4 (502 815)2.6 (31 811)1.8 (363 257)2.2 (388 674)2.5 (27 107)1.7 (902)1.4 (245 301)1.4 (50 501)2.3 (138 024)Not recorded24.0(4 959 464)26.7(5 592 847)39.0(472 992)24.0(4 813 156)26.8(4 809 146)38.5(418 633)1 7. 1(9163)20.1(3 523 123)25.1(922 223)22.7(1 348 137)History of myocarditis Previous myo-carditis<0.1 (1837)<0.1 (1632)<0.1 (69)<0.1 (1778)<0.1 (1511)<0.1 (56)<0.1 (18)<0.1 (1885)<0.1 (272)<0.1 (687)COVID-19 status†No COVID-1986.3(17 815 732)86.0(18 052 842)85.8(1 039 833)86.3(17 334 448)8 7. 3(15 674 125)86.2(937 147)88.4(47 367)90.5(15 846 583)88.0(3 230 055)…COVID-19 previous vac-cination5.9(1 227 131)7. 8(1 629 334)8.4(101 484)5.9(1 183 882)6.5(1 170 434)7. 8(85 166)6.3(3398)4.7 (815 805)5.3(194 056)49.8(2 958 026)COVID-19 after first dose0.7(143 526)2.8(594 914)3.2(38 200)0.5(99 981)2.2(401 516)3.0(32 222)0.9(456)0.6 (108 097)0.4(15 316)13.1(776 725)COVID-19 after second dose6.7(1 383 490)3.0(638 578)2.7(32 215)6.9(1 381 868)3.6(639 976)3.0(32 452)1.8(969)3.5 (621 836)5.8(213 627)34.6(2 054 331)COVID-19 after booster dose0.4(80 807)0.3(64 035)<0.1(224)0.4(80 796)0.4(64 035)<0.1(233)2.6(1416)0.7(125 372)0.5(18 277)2.4(145 071)No. of dosesOne dose only2.3(467 328)14.8(3 114 034)11.9(144 026)………………12.8(761 515)Two doses only36.0(7 430 747)45.1(9 464 269)80.8(979 495)36.5(7 328 422)53.2(9 550 989)91.7(996 599)………51.5(3 054 000)Two doses + booster61.8(12 752 610)40.0(8 401 400)7. 3(88 435)63.5(12 752 553)46.8(8 399 097)8.3 (90 621)100.0(53 606)100.0(17 517 692)100.0(3 671 331)35.7(2 118 638)Type of vaccinesTwo doses of ChAdOx19 7. 0(20 040 458)……99.8(20 040 458)……83.0(44 472)55.8(9 780 549)79.1(2 903 545)46.2(2 741 419)Two doses of BNT162b2…84.9(17 815 058)……99.2(17 815 058)…5.1(2760)43.7(7 653 274)19.6(720 535)38.0(2 256 069)Two doses of mRNA-1273……8 7. 5(1 060 277)……9 7. 5(1 060 277)<0.1(8)0.3(45 269)1.2(42 783)2.5(146 385)*Among vaccinated individuals. †Determined by a SARS-CoV-2 test. Table 1.ContinuedChAdOx1BNT162b2mRNA-1273ChAdOx1BNT162b2mRNA-1273ChAdOx1BNT162b2mRNA-1273SARS- CoV-2 positive*One dose (n=42 842 345)Two doses (n=39 118 282)Booster doses (n=21 242 629)(n= 5 934 153)% (n)% (n) % (n)% (n)% (n)% (n)% (n)% (n)% (n)% (n)

After COVID-19 Vaccine and Infectionafter a first dose of BNT162b2 (IRR, 1.85 [95% CI, 1.30–2.62]) and mRNA-1273 (IRR, 3.06 [95% CI, 1.33–7.03]); and a second dose of ChAdOx1 (IRR, 2.73 [95% CI, 1.62–4.60]), BNT162b2 (IRR, 3.08 [95% CI, 2.24–4.24]), and mRNA-1273 (IRR, 16.83 [95% CI, 9.11–31.11]). The risk of myocarditis for older men 40 years or more was associated with a booster dose of both mRNA vaccines, BNT162b2 (IRR, 2.15 [95% CI, 1.46–3.17]) and mRNA-1273 (IRR, 3.76 [95% CI, 1.41–10.02]) (Table 3).Vaccine-Associated Myocarditis in WomenOf the 20 979 754 women vaccinated in England in the study period, 7 201 472 (34.3%) were younger than 40 Table 2. Demographic and Clinical Characteristics of Patients Who Were Admitted to the Hospital for Myocarditis in the 1 to 28 Days After a COVID-19 Vaccine First Dose, Second Dose, and Booster Dose or SARS-CoV-2 Infection Among the Vaccinated Population in England from December 1, 2020, Until December 15, 2021VariableBaselineRisk set (1–28 days after exposure)ChAdOx1BNT162b2mRNA-1273 First dose Second dose Booster dose First dose Second dose Booster dose First dose Second dose Booster dose Total no. of people22441409001241198511408Sex Women40.4 (907)40.7 (57)26.7 (24)…41.1 (51)28.6 (34)45.9 (39)*** Men59.4 (1333)59.3 (83)73.3 (66)…58.1 (72)70.6 (84)54.1 (46)>5>5>5 Not recorded0.2 (4)00…0.8 (1)0.8 (1)0000Age Mean age (SD)53.8 (19.7)57.5 (17.5)54.2 (18.0)…48.7 (24.3)45.0 (24.8)67.2 (15.8)27.0 (9.5)24.9 (6.3)61.8 (14.8) <40 y26.3 (590)14.3 (20)25.6 (23)…46.8 (58)58.8 (70)7.1 (6)>5>5≥40 y73.7 (1654)85.7 (120)74.4 (67)…53.2 (66)41.2 (49)92.9 (79)>5Deaths with myocarditis or within 28 days of hospital admission with myocarditis No. of deaths10.9 (245)28.6 (40)12.2 (11)…17.7 (22)11.8 (14)15.3 (13)……… Mean age of death (SD), y68.7 (14.3)62.1 (17.4)65.2 (10.4)…67.8 (20.4)69.2 (21.6)78 (8.7)……… No. of deaths Women38.2 (92)35.0 (14)…57.1 (12)46.1 (6)……… Men61.8 (149)65.0 (26)>5…42.9 (9)53.9 (7)> 5……… Not recorded0.2 (4)000.8 (1)0.8 (1)0COVID-19 status (positive SARS-CoV-2 test) No COVID-19…72.9 (102)82.2 (74)…71.8 (89)88.2 (105)81.2 (69)54.5 (6)90.0 (36)100.0 (8) COVID-19 previous vac-cination…12.9 (18)11.1 (10)…10.5 (13)8.2 (7)… COVID-19 after first dose…11.4 (16)…15.3 (19)… COVID-19 after second dose…5.6 (5)…5.0 (6)… COVID-19 after booster dose…7.1 (6)…No. of doses One …45.7 (64)…53.2 (66)90.9 (10)* Two …23.6 (33)60.0 (54)…16.9 (21)70.6 (84)97.5 (39)* Two + booster…30.7 (43)40.0 (36)…29.8 (37)29.4 (35)100.0 (85)100.0 (8)Type of first 2 doses received ChAdOx1…50.7 (71)98.9 (89)………49.4 (42)……62.5 (5) BNT162b2…………43.5 (54)99.2 (118)50.6 (43)……* mRNA-1273………………100.0 (40)Lag between first and second doses (days)≤655.7 (8)16.7 (15)…8.1 (10)47.9 (57)24.7 (21)55.0 (22)* 6 6–7931.4 (44)55.6 (50)…25.8 (32)32.8 (39)54.1 (46)…22.5 (9)*≥8017.1 (24)27.8 (25)…12.9 (16)19.3 (23)21.2 (18)…22.5 (9)Cells with counts <5 are suppressed. ORIGINAL RESEARCH

After COVID-19 Vaccine and Infection Table 3. Incidence Rate Ratios (IRR [95% CI]) for Main Analysis and by Age Group (Age 40 Years or Older, Younger Than 40 Years) and Sex (Female and Male) for Myocarditis in Predefined Risk Periods Immediately Before and After Exposure to Vacci-nation and Before and After a Positive SARS-CoV-2 Test Result, Adjusted for Calendar Time From December 1, 2020, to December 15, 2021 (if 1 or no events, IRR has not been estimated and reported as n/a).Time periodChAdOx1 nCoV-19 vaccineBNT162b2 mRNA vaccinemRNA-1273 vaccine Positive SARS-CoV-2 test (before vaccine)Positive SARS-CoV-2 test (vaccinated) Events I RR (95% CI) Events I RR (95% CI)Events IRR (95% CI)Events IRR (95% CI)Events IRR (95% CI)Main analysis 1–28 days: first dose/positive test before any vaccination1401.33 (1.09–1.62)1241.52 (1.24–1.85)111.85 (0.93–3.66)11411.14 (8.64–14.36)815.97 (4.54–7.87) 1–28 days: second dose900.93 (0.74–1.17)1191.57 (1.28–1.92)4011.76 (7.25–19.08) 1–28 days: booster dose*n/a851.72 (1.33–2.22)82.64 (1.25–5.58)Women 1–28 days: first dose/positive test before any vaccination571.32 (0.97–1.81)511.59 (1.16–2.20)*1.07 (0.23–4.90)4714.23 (9.34–21.68)326.87 (4.38–10.78) 1–28 days: second dose240.54 (0.35–0.83)341.04 (0.72–1.50)*3.95 (1.20–13.04) 1–28 days: booster dose*n/a391.55 (1.06–2.27)*1.51 (0.35–6.47)Men 1–28 days: first dose/positive test before any vaccination831.33 (1.03–1.72)721.47 (1.14–1.90)92.35 (1.09–5.08)679.71 (7.03–13.40)495.55 (3.91–7.88) 1–28 days: second dose661.26 (0.96–1.65)841.93 (1.51–2.45)3614.98 (8.61–26.07) 1–28 days: booster dose*n/a461.89 (1.34–2.67)63.57 (1.48–8.64)Age <40 y 1–28 days: first dose/positive test before any vaccination201.31 (0.79–2.16)581.79 (1.33–2.41)102.76 (1.32–5.75)205.25 (3.11–8.86)81.18 (0.56–2.48) 1–28 days: second dose231.69 (1.06–2.71)702.59 (1.96–3.44)3913.97 (8.07–24.19) 1–28 days: booster dose*n/a61.53 (0.64–3.64)*n/aAge ≥40 y 1–28 days: first dose/positive test before any vaccination1201.21 (0.97–1.51)661.28 (0.97–1.71)*n/a9414.87 (10.98–20.14)7310.52 (7.61–14.54) 1–28 days: second dose670.72 (0.55–0.93)490.85 (0.62–1.16)*n/a 1–28 days: booster dose*n/a791.96 (1.48–2.59)72.97 (1.32–6.69)Women age <40 y 1–28 days: first dose/positive test before any vaccination71.20 (0.51–2.84)141.65 (0.91–2.97)*2.68 (0.54–13.25)79.80 (3.70–25.97)63.98 (1.52–10.42) 1–28 days: second dose/posi-tive test after any vaccination*0.32 (0.08–1.37)91.16 (0.57–2.34)*4.75 (1.11–20.40) 1–28 days: booster dose*n/a*0.83 (0.19–3.64)*n/aMen age <40 y 1–28 days: first dose/positive test before any vaccination131.34 (0.72–2.48)431.85 (1.30–2.62)83.06 (1.33–7.03)134.35 (2.31–8.21)*0.39 (0.09–1.60) 1–28 days: second dose212.73 (1.62–4.60)603.08 (2.24–4.24)3616.83 (9.11–31.11) 1–28 days: booster dose*n/a*2.28 (0.77–6.80)*n/a(Continued )ORIGINAL

After COVID-19 Vaccine and Infection years, and 13 778 282 (65.7%) were 40 years or older (Table 1). Analysis restricted to women younger than 40 years showed an increased risk of myocarditis after a second dose of mRNA-1273 (IRR, 4.75 [95% CI, 1.11–20.40]). For women 40 years or older, there was an in-creased risk of myocarditis associated with a first (IRR, 1.57 [95% CI, 1.05–2.33]) and third (IRR, 1.76 [95% CI, 1.17–2.65]) dose of BNT162b2 vaccine. It is important that for all subgroups, the higher risk of myocarditis was found in the 1 to 7 days or 8 to 14 days after vaccination (Table S4).Vaccine-Associated Myocarditis by Vaccination History Analyses restricted to people who had the same type of vaccine for the first and second doses (Table S5) showed that for patients having a first and second dose of ChAdOx1, there was an increased risk of myocarditis associated with a booster dose of BNT162b2 (IRR, 1.78 [95% CI, 1.22–2.60]) and mRNA-1273 (IRR, 2.97 [95% CI, 1.13–7.82]). For patients who had a first and second dose of BNT162b2 vaccine, there was an increased risk of myocarditis after the second dose of BNT162b2 (IRR, 1.53 [95% CI, 1.24–1.88]). Last, for patients who had a first and second dose of mRNA-1273 vaccine, there was an increased risk of myocarditis after a second dose of mRNA-1273 (IRR, 8.63 [95% CI, 3.98–18.75]).The risk after a second dose of BNT162b2 was higher for people who received the first 2 doses within 65 days of each other (IRR, 2.16 [95% CI, 1.60–2.91]) compared with people who received the first 2 doses with a longer lag: between 66 and 79 days (IRR, 1.01 [95% CI, 0.71–1.44]) and 80 days or more (IRR, 1.40 [95% CI, 0.88–2.21]). The risk after a second dose of mRNA-1273 was higher when the lag was of 80 or more days (IRR, 22.80 [95% CI, 7.48–69.48]) compared with when the lag was 65 days or less (IRR, 7.41 [95% CI, 3.98–13.77) (Table S6).SARS-CoV-2 Infection–Associated Myocarditis There was an increased risk of myocarditis in the 1 to 28 days after a SARS-CoV-2–positive test, which was higher if infection occurred before vaccination (IRR, 11.14 [95% CI, 8.64–14.36]) than in vaccinated individuals (IRR, 5.97 [95% CI, 4.54–7.87]). The risk of myocarditis associated with a SARS-CoV-2–positive test before vaccination was higher in people 40 years or older (IRR, 14.87 [95% CI, 10.98–20.14]) than in-dividuals younger than 40 years (IRR, 5.25 [95% CI, 3.11–8.86]), but no significant difference was observed between risks in women (IRR, 14.23 [95% CI, 9.34–21.68]) and men (IRR, 9.71 [95% CI, 7.03–13.40), al-though the point estimate for women was higher than the equivalent for men. A similar pattern of risk of myo-carditis was associated with a SARS-CoV-2–positive test occurring in vaccinated individuals; however, in this case, the increased risk was substantially lower and in particular was not observed for individuals younger than 40 years (IRR, 1.18 [95% CI, 0.56–2.48]) (Table 3).Absolute and Excess Risks After the first dose of the ChAdOx1 and BNT162b2 vaccines, an additional 2 (95% CI, 1–3) and 2 (95% CI, 1–3) myocarditis events per million people vaccinated would be anticipated, respectively. After the second dose of BNT162b2 and mRNA-1273, an additional 2 (95% CI, 2–3) and 34 (95% CI, 32–35) myocar-ditis events per million people would be anticipated, Women age ≥40 y 1–28 days: first dose/positive test before any vaccination501.30 (0.92–1.84)371.57 (1.05–2.33)*n/a4017.29 (10.70–27.96)268.65 (5.13–14.59) 1–28 days: second dose220.55 (0.35–0.86)250.98 (0.63–1.52)*n/a 1–28 days: booster dose*n/a371.76 (1.17–2.65)*2.00 (0.46–8.72)Men age ≥40 y 1–28 days: 1st dose/positive test before any vaccination701.16 (0.87–1.54)291.05 (0.69–1.59)*n/a5413.40 (9.04–19.88)4711.77 (7.77–17.85) 1–28 days: second dose450.85 (0.61–1.19)240.77 (0.49–1.18)*n/a 1–28 days: booster dose*n/a422.15 (1.46–3.17)53.76 (1.41–10.02)Day 0 of each exposure has been removed because of small numbers.*Cells with counts <5 are suppressed. Table 3. Continued Time periodChAdOx1 nCoV-19 vaccineBNT162b2 mRNA vaccinemRNA-1273 vaccine Positive SARS-CoV-2 test (before vaccine)Positive SARS-CoV-2 test (vaccinated) Events IRR (95% CI)Events IRR (95% CI)Events IRR (95% CI)Events IRR (95% CI) EventsIRR (95%

After COVID-19 Vaccine and Infectionres pectively. After a booster dose of BNT162b2 and mRNA-1273, an additional 2 (95% CI, 1–3) and 1 (95% CI, 0–2) myocarditis events per million people would be anticipated, respectively. These estimates compare with an additional 35 (95% CI, 34–36) and 23 (95% CI, 21–24) myocarditis events per million people in the 1 to 28 days after a SARS-CoV-2–posi-tive test before vaccination and in vaccinated individu-als, respectively (Table 4; Figure).In men younger than 40 years, we estimate an additional 4 (95% CI, 2–6) and 14 (95% CI, 5–17) myocarditis events per million in the 1 to 28 days after a first dose of BNT162b2 and mRNA-1273, respectively; and an additional 14 (95% CI, 8–17), 11 (95% CI, 9–13) and 97 (95% CI, 91–99) myocarditis events after a second dose of ChAdOx1, BNT162b2, and mRNA-1273, respectively. These estimates compare with an additional 16 (95% CI, 12–18) myocarditis events per million men younger than 40 years in the 1 to 28 days after a SARS-CoV-2–positive test before vaccination (Table 4; Figure).Robustness of the ResultsOverall, our main findings were not sensitive to censoring because of death (Table S7, sensitivity analyses 1 through 3), and IRRs for the second dose of vaccination agreed with main results when we removed those who had the outcome after the first dose of any vaccine, but before the second dose (Table S7, sensitivity analysis 5). Similarly, IRRs for the booster dose of vaccination agreed with main results when we removed those who had the outcome af-ter the second dose of any vaccine, but before the booster dose (Table S7, sensitivity analysis 6). There was no bias caused by possibly not complete data near the end of the study period (Table S7, sensitivity analysis 4). Estimates for vaccines exposures agreed with the main analysis when restricted to patients who never tested positive to SARS-CoV-2 (Table S8, sensitivity analysis 7).

DISCUSSIONIn

a population of >42 million vaccinated individuals, we re-port several new findings that could influence public health Figure. Risk of myocarditis in the 1 to 28 days after COVID-19 vaccines or SARS-CoV-2.(Left) Incidence rate ratios with 95% CIs and (right) number of excess myocarditis events for million people with 95% CIs in the 1 to 28 day risk periods after the first, second, and booster doses of ChAdOx1, BNT162b2,and mRNA-1273 vaccine or a positive SARS-CoV-2 test in (top) a population of 42 842 345 vaccinated individuals and (bottom) younger men (age <40 years), older men (age ≥40 years), younger women (age <40 years), and older women (aged ≥40 years).ORIGINAL

First, the risk of myocar-ditis is substantially higher after SARS-CoV-2 infection in unvaccinated individuals than the increase in risk observed after a first dose of ChAdOx1nCoV-19 vaccine, and a first, second, or booster dose of BNT162b2 vaccine. Second, although the risk of myocarditis with SARS-CoV-2 infec-tion remains after vaccination, it was substantially reduced, suggesting vaccination provides some protection from the cardiovascular consequences of SARS-CoV-2. Third, in contrast with other vaccines, the risk of myocarditis ob-served 1 to 28 days after a second dose of mRNA-1273 vaccine was higher and similar to the risk after infection. Last, vaccine-associated myocarditis was largely restrict-ed to men younger than 40 years with 1 exception; both younger men and women were at increased risk of myo-carditis after a second dose of mRNA-1273.Vaccination against COVID-19 has both major public health and economic benefits. Although the net benefit of vaccination for the individual or on a population level should not be framed exclusively around the risks of myocarditis, quantifying this risk is important, particularly in young people who are less likely to have a severe ill-ness with SARS-CoV-2 infection. Multiple studies have identified an increase in myocarditis after exposure to the BNT162b2 mRNA vaccine.1–8,13 Some of our find-ings are confirmatory, but we also demonstrate that the risk of myocarditis is not restricted to this vaccine but is observed after vaccination with adenovirus and other mRNA vaccines and after a booster dose.It is important to place our findings into context. One of the strengths of our analysis is that we quantify the risk of myocarditis associated with both vaccination and SARS-CoV-2 infection in the same population. Myocarditis is an uncommon condition. The risk of vaccine-associated myocarditis is small, with up to an additional 2 events per million people in the 28-day period after exposure to all vaccine doses other than mRNA-1273. This is substan-tially lower than the 35 additional myocarditis events observed with SARS-CoV-2 infection before vaccination. Furthermore, vaccination reduced the risk of infection associated myocarditis by approximately half, suggest-ing that the prevention of infection associated myocarditis may be an additional longer-term benefit of vaccination.The risk of vaccine-associated myocarditis is con-sistently higher in younger men, particularly after a second dose of mRNA-1273, where the number of additional events during 28 days was estimated to be 97 per million people exposed. An important consid-eration for this group is that the risk of myocarditis after a second dose of mRNA-1273 was higher than the risk after infection. Indeed, in younger women, although the relative risks of myocarditis were lower than in younger men, the number of additional events per million after a second dose of mRNA-1273 was similar to the number after infection. These findings may justify some reconsideration of the selection of vaccine type, the timing of vaccine doses, and the net benefit of booster doses in young people, particularly in young men. However, there are some important caveats that need to be considered. First, the num-ber of people vaccinated with mRNA-1273 was small compared with those receiving other types of vaccine, Table 4. Measures of the Effect of Vaccinations and SARS-CoV-2 Infections Presented as Excess Events Per 1 Million Exposed Excess myocarditis events per 1 000 000 exposed (95% CI)Main analysis Age <40 yAge ≥40 y Women Men Age <40 yAge ≥40 y Women Men Women Men ChAdOx1 First dose2 (1–3)………2 (0–4)………… Second dose…4 (0–6)…………14 (8–17)…… Booster dose………………………BNT162b2 First dose2 (1–3)2 (1–3)…2 (1–3)3 (1–4)…4 (2–6)3 (0–4)… Second dose2 (1–3)5 (4–5)……6 (4–7)…11 (9–13)…… Booster dose2 (1–3)…2 (2–3)1 (0–2)3 (2–4)……2 (1–3)3 (2–4)mRNA-1273 First dose…7 (3–9)……10 (1–14)…14 (5–17)…… Second dose34 (32–35)43 (41–44)…7 (2–9)73 (70–76)7 (1–9)97 (91–99)…… Booster dose1 (0–2)…1 (1–2)…3 (1–3)………3 (1–3)SARS-CoV-2 Positive test (before vaccine)35 (34–36)10 (9–11)63 (62–64)28 (27–29)50 (48–51)8 (6–8)16 (12–18)51 (49–52)85 (82–87) Positive test (vaccinated)23 (21–24)…39 (38–40)17 (16–19)34 (30–36)7 (3–8)…26 (24–27)61 (58–63)Only significant increased risks were reported during the 1 to 28 days after exposure. When incidence rate ratios were not significant during the 1 to 28 days after vaccine, absolute measures are not given.

Second, the average age of those receiving this vaccine was younger at 32 years compared with other vaccines where recipients were in their mid-40s and 50s. The observed excess risk related to mRNA-1273 may in part be a result of the higher probability of myocarditis in this younger age group. Our findings are consistent with 2 recent studies from the United States and Denmark in which the risks of myocarditis after mRNA-1273 and BNT162b2 were compared.7,14 In the Vaccine Adverse Event Reporting System, 1991 cases of myocarditis were reported to August 31, 2021, with a median age of 21 years and 82% male.14 Although our findings are not directly com-parable because the Vaccine Adverse Event Reporting System dataset relies on clinician reporting, the risks of myocarditis were higher after a second dose of both BNT162b2 and mRNA-1273 and were greater for mRNA-1273 in most younger age groups. In Denmark, a population-based study that applied both case-control and self-controlled case series study methods observed a greater increase in the risk of myocarditis or myopericarditis 1 to 28 days after mRNA-1273 (adjusted hazard ratio, 3.92 [95% CI, 2.30–6.68]) than after BNT162b2 (adjusted hazard ratio, 1.34 [95% CI, 0.90–2.00]).7 They also observed the risk was largely confined to those younger than 40 years and was present for both younger men and women for mRNA-1273. The reasons for male predominance in myocarditis is not known but may relate to sex hormone differences in both the immune response and myocarditis, or to the underdiagnosis of cardiac dis-ease in women.15,16This study has several strengths. First, the United Kingdom offered an ideal place to carry out this study given that 3 types of COVID-19 vaccination have been rolled out at the same speed and scale as each other. Second, this was a population-based study of data recorded prospectively and avoided recall and selection biases linked to case reports. Third, the large sample size provided sufficient power to investigate these rare outcomes, which could not be assessed through clini-cal trials. Fourth, the self-controlled case series study design removes potential confounding from fixed char-acteristics, and the breakdown of our study period into weekly blocks accounted for temporal confounding. Of note, the estimated IRRs were consistently <1 in the pre-exposure period before vaccination and >1 in the pre-risk period before a SARS-CoV-2–positive test. This was expected because events are unlikely to happen shortly before vaccination (relatively healthy people are receiving the vaccine) and more likely to happen before a SARS-CoV-2–positive test (as a standard procedure, patients admitted to the hospital are tested for SARS-CoV-2). We also assessed the robustness of our results through several sensitivity analyses.There are some limitations to consider. First, the number of people receiving a booster dose of ChAdOx1 or mRNA-1273 vaccine was too small to evaluate the risk of myocar-ditis. Second, we relied on hospital admission codes and death certification to define myocarditis, and it is possible that we might have over- or underestimated risk because of misclassification. Third, although we were able to include 2 230 058 children age 13 to 17 years in this analysis, the number of myocarditis events was small (56 events in all periods and 16 events in the 1 to 28 days after vac-cination) in this subpopulation and precluded a separate evaluation of risk. It should also be noted that only the first occurrence of myocarditis in the study period is used in this analysis. Therefore, the results found for the risk of myo-carditis after a third dose do not include repeated instances of myocarditis in the same individual. A comparison of rates of death with myocarditis between those infected with SARS-CoV-2 or vaccinated was not possible, given that for this analysis, we have included only people who had been vaccinated. Therefore, a patient with COVID-19 who died after myocarditis before receiving a vaccination will not be included, and rates of myocarditis death after SARS-CoV-2 will be under estimated.In summary, the risk of hospital admission or death from myocarditis is greater after SARS- CoV2 infection than COVID-19 vaccination and remains modest after sequential doses including a booster dose of BNT162b2 mRNA vaccine. However, the risk of myocarditis after vaccination is higher in younger men, particularly after a second dose of the mRNA-1273 vaccine.

ARTICLE INFORMATIONReceived March 10, 2022; accepted June 7, 2022.AffiliationsNuffield Department of Primary Health Care Sciences (M.P., X.W.M., S.D., A.H., C.A.C.C., J.H.-C.), Wellcome Centre for Human Genetics (L.H.), British Heart Foundation Centre of Research Excellence, National Institute for Health Research, Oxford Biomedical Research Centre, Radcliffe Department of Medicine, John Rad-cliffe Hospital (K.M.C.): National Institute for Health Research Biomedical Research Centre, Oxford University Hospitals National Health Service Trust (P.W.); University of Oxford. School of Immunology and Microbial Sciences, King’s College London, Centre for Inflammation Research (M.S.-H.). Leicester Real World Evidence Unit, Diabetes Research Centre (F.Z., K.K.), University of Leicester. Usher Institute (M.S.-H., N.L.M., A.S.), British Heart Foundation University Centre for Cardiovascular Sci-ence (N.L.M.), University of Edinburgh. Centre for Academic Primary Care, School of Medicine, University of Nottingham (C.A.C.C.)

How COVID Could Screw You Worse With Each Reinfection

Authors: David Axe Tue, July 5, 2022

The more times you catch COVID, the sicker you’re likely to get with each reinfection. That’s the worrying conclusion of a new study drawing on data from the U.S. Veterans Administration.

Scientists stressed they need more data before they can say for sure whether, and why, COVID might get worse the second, third, or fourth time around. But with more and more people getting reinfected as the pandemic lurches toward its fourth year, the study hints at some of the possible long-term risks.

To get a handle on the health impact of reinfection, re-reinfection and even re-re-reinfection, three researchers—Ziyad Al-Aly from the Washington University School of Medicine plus Benjamin Bowe and Yan Xie, both from the V.A. St. Louis Health Care System—scrutinized the health records of 5.7 million American veterans.

Some 260,000 had caught COVID just once, and 40,000 had been reinfected at least one more time. The control group included 5.4 million people who never got COVID at all. Al-Aly, Bowe and Xie tracked health outcomes over a six-month period and came to a startling conclusion. “We show that, compared to people with first infection, reinfection contributes additional risks,” they wrote in their study, which hasn’t been peer-reviewed yet but is under consideration for publication in Nature.

Every time you catch COVID, your chance of getting really sick with somethinglikely COVID-related—seems to go up, Al-Aly, Bowe and Xie found. The risk of cardiovascular disorders, problems with blood-clotting, diabetes, fatigue, gastrointestinal and kidney disorders, mental health problems, musculoskeletal disorders and neurologic damage all increase with reinfection—this despite the antibodies that should result from repeat infections.

All of the conditions are directly associated with COVID or have been shown to get worse with COVID. “The constellation of findings show that reinfection adds non-trivial risks,” the researchers warned.

This risk could become a bigger deal as more people get reinfected. Globally, the death rate from COVID is going down, thanks in large part to growing population-wide immunity from past infection and vaccines.

But at the same time, non-fatal reinfections are piling up. Around half a billion people all over the world have caught COVID more than once, according to Al-Aly, Bowe and Xie’s study, citing data from the Johns Hopkins Coronavirus Resource Center. Many more reinfections, including “breakthrough” infections in the fully vaccinated, are likely as new variants and subvariants of COVID evolve to partially evade our antibodies.

The exact increase in risk from reinfection depends on the particular disorder in question—and whether you’ve been vaccinated and boosted. Broadly speaking, however, the likelihood of heart and clotting problems, fatigue and lung damage roughly doubles each time you catch COVID, Al-Aly, Bowe and Xie found.

Ali Mokdad, a professor of health metrics sciences at the University of Washington Institute for Health, offered one important caveat: time. “In general, one would expect that COVID will do more damage with a longer infection,” he told The Daily Beast. A short-lasting COVID infection followed by another short case of COVID should be less damaging than, say, back-to-back long illnesses.

The longer your infections drag on, the greater the stress on your organs. “These are two blows instead of one,” Mokdad said.

But it’s possible the worsening outcomes resulting from reinfection have little or nothing to do with the cumulative stress of successive long illnesses. According to Peter Hotez, an expert in vaccine development at Baylor College, the escalating risk could result from a poorly-understood phenomenon called “immune enhancement.”

A virus undergoes immune enhancement when a person’s immune system, after initial exposure to the pathogen, backfires during reinfection. Someone suffering immune enhancement with regards to a particular disease is likely to get sicker and sicker each time they’re exposed.

Immune enhancement could explain Al-Aly, Bow and Xie’s observation of escalating risk from COVID reinfection. “If the observation is true,” Hotez stressed. But it’s possible the observation is inaccurate. Hotez said he’s “not convinced that reinfection is actually more severe.”

Anthony Alberg, a University of South Carolina epidemiologist, told The Daily Beast he, too, is somewhat skeptical. Just how much more risk you might accumulate with each case of COVID is really hard to predict. And Al-Aly, Bow and Xie’s study is too cursory to totally settle the uncertainty all on its own.

The main problem, Alberg explained, is tied to a classic logical dilemma: causation versus correlation. Just because veterans got sicker with each COVID infection doesn’t necessarily mean COVID is definitely to blame, he pointed out. The vets in the study who came down with COVID more than once maybe tended to belong to groups with overall worse health outcomes whether or not they caught COVID twice, thrice or never.

The Massive Screwup That Could Let COVID Bypass Our Vaccines

“Compared with veterans who were infected once with SARS-CoV-2, those who were infected two times or more were more likely to be older [or] Black people, reside in long-term care, be immunocompromised, have anxiety, depression and dementia and to have had cerebrovascular disease, cardiovascular disease diabetes and lung disease,” Alberg said.

COVID, in other words, might be beside the point. It’s possible the worsening outcomes in Al-Aly, Bow and Xie’s study are due to the fact that the reinfected patients “were on average older and with much poorer health status than those with one infection,” Alberg said, “not because of having been infected more than once.”

Untangling causation and correlation in a study of this scale could be tricky. “More evidence [is] needed on this topic before definitive conclusions can be reached,” Alberg said.

In the meantime, it should be easy for us to mitigate the potential risk. Anyone who comes down with COVID a second time shouldn’t hesitate to take a course of paxlovid or some other antiviral drug that’s approved for the disease. “We should continue to focus on making sure people are aware of the benefits of early treatment,” Jeffrey Klausner, an infectious diseases expert at the University of Southern California Keck School of Medicine, told The Daily Beast.

Better yet, we could focus on developing “strategies for reinfection prevention,” Al-Aly, Bow and Xie wrote.

The top priority, of course, should be vaccinating the unvaccinated. Even the best COVID vaccines aren’t 100-percent effective at preventing infection or reinfection—and they’re getting somewhat worse as SARS-CoV-2 evolves for greater immune-escape.

But even with cleverer viral mutations, the jabs are still pretty effective. You can’t get sicker and sicker with reinfection… if you never get infected in the first place.

COVID-19 outcomes and the human genome

Authors: Michael F. Murray MDEimear E. Kenny PhDMarylyn D. RitchiePhDDaniel J. Rader MDAllen E. Bale MDMonica A. Giovanni MS, CGC & Noura S. Abul-Husn MD, PhD Genetics in Medicine  volume 22, pages1175–1177

BACKGROUND

In the COVID-19 pandemic, the opportunity to link host genomic factors to the highly variable clinical manifestations of SARS-CoV-2 infection has been widely recognized.1,2 The overt motivation for this research is the clinical implementation of any new insights to improve clinical management and foster better patient outcomes.

Human infection is a complex interaction between the microbe, the environment, and the human host.3 Variation in the human genome has only rarely been linked to complete resistance to infection by a specific microbe; far more commonly host genomic variability has been linked to complications associated with infections (see Table 1).3,4,5 In this pandemic, the ability to identify host genomic factors that increase susceptibility or resistance to the complications of COVID-19 and to translate these findings to improved patient care should be the goal.Table 1 Sample characteristics.

Full size table

Several approaches can be taken to uncover relevant host genomic factors. Familial and population-based linkage analyses and analyses of extreme phenotypes can uncover monogenic variants contributing to COVID-19 clinical outcomes.6 Genome-wide association studies (GWAS)7,8 and multiomic-based approaches can be used to uncover common variants and biological networks underlying host-pathogen interactions. Likewise, data derived from genomes, such as HLA haplotypes, ABO blood groups, and polygenic risk scores (PRS),9 can be used to understand COVID-19 susceptibility, resistance, and complications. Furthermore, biobanks linking genomic data to electronic health records (EHRs)10 can be leveraged to investigate the impact of these genomic factors on the clinical course of SARS-CoV-2 infected patients.

Many recognize that this area of research needs to go forward in a manner that is proactively inclusive of traditionally underserved populations to both avoid the exacerbation of existing health-care disparities and to optimize discovery. Past efforts have demonstrated the value of this type of inclusion, as was seen in the extension of a CCR5-associated delta 32 correlation to HIV-1 infection in individuals with European ancestry to a promoter variant in CCR5 linked to perinatal HIV-1 transmission in individuals with African ancestry.11,12,13

As host genomic factors are discovered, new strategies supporting rapid clinical implementation should be trialed to realize improvement in outcomes for SARS-CoV-2 infected patients. Implementation will require an infrastructure to deliver relevant genomic results to infected patients and their health-care providers to guide clinical management. This commentary examines the types of genomic factors that might be identified in emerging COVID-19 discovery and implementation research, based on decades of genomic discovery, research into other human infections, and advances in genomic medicine.

PHASES OF PHENOTYPE ASCERTAINMENT IN THE COVID PANDEMIC

In this fast-moving pandemic, we believe there will be at least two phases to defining COVID-19 related phenotypes. Currently in the United States, we are in an initial phase when important limitations influence the ability of research teams to ascertain and appropriately define phenotypes of interest. These limitations include (1) the absence of widespread viral and serologic testing to accurately distinguish those who have been infected from those who have not, (2) the lack of knowledge about infection exposure at a community level, and (3) institutional limits to recruiting human subjects in a time of social distancing. Heterogeneity of testing strategies and their sensitivity, and nascent regulatory oversight may pose challenges in clear and reproducible definitions of COVID-19-related phenotypes. In the second phase, adequate serologic testing may allow for increased numbers and more accurate discrimination of cases and controls, as well as the ability to define additional clinical phenotypes of interest (e.g., asymptomatic seropositive individuals). The use of telemedicine, which has expanded for health-care delivery during the pandemic, in addition to community outreach efforts, can overcome barriers to recruitment in this infectious disease outbreak.

To find important genotype–phenotype correlations, there will need to be phenotypes that are ascertained in a manner that is clear, quantitative, and reproducible, and there will need to be adequate sampling from well-defined cases and controls. One rubric that can be used for phenotyping during this initial phase of COVID-19 host genomic research is the Ordinal Scale for Clinical Improvement proposed by the World Health Organization (WHO) in their blueprint for therapeutic trials (see Supplemental Table 1).14 For instance, this scale can be applied across research groups and across health systems in order to allow phenotypic groupings of COVID-19 patients based on (1) need for hospitalization, (2) need for oxygen supplementation, (3) progression to respiratory failure, or (4) mortality, and these phenotypes could be readily extracted from EHRs. In the current initial phase of the COVID-19 pandemic, difficulties with the enrollment and appropriate scoring of uninfected, asymptomatic, or mildly affected patients (categories 0–2 in Supplemental Table 1) are anticipated. Specifically, asymptomatic positives will be mistakenly scored as 0 instead of 1 without either viral screening or serologic testing. In addition, patients who would be scored 0–2 are difficult to recruit and consent given the social distancing limitations that are currently in place. As serologic testing becomes more sophisticated, widespread, and robust, it is anticipated that COVID-19-related phenotyping will become more standard, facilitating reproducible and scalable COVID-19 research.

CANDIDATE GENES AND PATHWAYS

At least three lines of inquiry might inform the nomination of candidate genes for intensive interrogation with COVID-19 phenotypes: (1) what do we know about the microbial life cycle, (2) what do clinical observations in patients suggest with regard to biological pathways that are likely being triggered, and (3) what does the literature teach us about host genetics in infection that could apply to this novel infection. For example, the cellular surface receptor for SARS-CoV-2 virus is encoded by the ACE2 gene, and critical amino acid residues in the binding interaction have been described.15,16 This and other insights into host–pathogen interactions will elucidate specific variants, genes, and pathways underlying interindividual COVID-19 susceptibility and response. Genes and pathways related to COVID-19 could also include other viral receptor genes (e.g., TMPRSS2) (unpublished data: https://doi.org/10.1101/2020.03.30.20047878), inflammatory and immune response pathways (e.g., IL-6 pathway), and genes involved in hypercoagulability and acute respiratory distress syndrome.17 Other genes that may be of interest include genes associated with ABO blood group (e.g., FUT2) in light of a report on an association between blood groups and COVID-19 in China (unpublished data: https://doi.org/10.1101/2020.03.11.20031096) as well as similar associations in the past.18 Research into the genetics of the interplay between viral infection and common diseases (e.g., diabetes and heart disease) is also of interest to many investigators. As our understanding of genes underlying SARS-CoV-2 infectivity and biological mechanisms grows, we will better elucidate their potential involvement in disease susceptibility and clinical outcomes.

GENOME-SCALE APPROACHES FOR DISCOVERY AND RISK PREDICTION

In tandem, the global scientific community has rapidly mobilized collaborative efforts to advance unbiased genome-wide COVID-19 host genomic discovery through large-scale genomic studies. For example, the COVID-19 Host Genetics Initiative is organizing analytical activities across a growing network of over 120 studies to identify genomic determinants of COVID-19 susceptibility and severity.1 It is difficult at this stage to estimate the number of research participants needed to identify host genomic factors related to the COVID-19 novel pathogenic exposure. If we assume that the effect size and allele frequency of genetic variants important for COVID-19 susceptibility, resistance, and/or complications are as variable as other host factors in infectious conditions (i.e., Supplemental Table 1), then the number of cases and controls needed to have statistical power to identify associations could vary widely. Collaborative efforts like the COVID-19 Host Genetics Initiative should be well-powered for the unbiased discovery of novel genes and pathways. Such efforts foster data aggregation and sharing broadly among the research community and are likely to greatly impact the speed with which COVID-19 discoveries can be made and disseminated worldwide.

In aggregate, knowledge of host genomic factors could lead to improved care for patients with COVID-19, through risk stratification, as well as targeted prevention and treatment options. For example, GWAS discovery efforts could yield PRS for COVID-19 clinical outcomes, which could be used in the context of other clinical data to risk stratify patients early in the disease course. Host genomic factors could be linked to variability in the protective immune response and have implications for vaccination strategies, or could be used to optimally select patients for novel therapeutic treatments and trials. However, as it can take many years for genomic discoveries to directly benefit patients,10 in parallel we need to prepare our health systems with infrastructure to rapidly integrate high quality, clinically relevant COVID-19 host genomic findings into the care of individuals with SARS-CoV-2 infection.

CONCLUSIONS

The COVID-19 pandemic currently threatens to overwhelm health-care systems and undermine economies. There is no proven therapeutic and no vaccine for the novel coronavirus causing this pandemic. In this moment, we emphasize the sentiments voiced by the COVID-19 Host Genetics Initiative, namely that “[i]nsights into how to better understand and treat COVID-19 are desperately needed. Given the importance and urgency in obtaining these insights, it is critical for the scientific community to come together around this shared purpose.” 1

As the community works together to develop a COVID-19 host genomics research engine, we are poised for novel discovery and advances in genomic medicine. A model to understand human genomic variants linked to COVID-19 outcomes can be conceived as a continuum from ultrarare to common. We offer Supplemental Table 2 as a way to think about findings that can be expected from this research.19,20 It is imperative that the research community prioritize high-quality and reproducible findings, even under the pressure for expediency, and be mindful of ethical, legal, or social issues that could emerge related to the COVID-19 impact among different groups within society.

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COVID long-haulers: Study shows who is most at risk, impact on local communities

Authors:  Hiroshima University Medical Express Posted June 9. 2022

A Japanese research team looking at COVID-19’s lingering impacts on survivors and local communities found that having a mild case of COVID-19, smoking status, comorbidities, or your sex aren’t significant predictors to tell if you are less likely to develop long-term symptoms, but age is.

“The prevalence of sequelae did not significantly differ by sex, severity of COVID-19, place of medical care, smoking status, or comorbidities,” the research team, led by Hiroshima University Professor and Executive Vice President Junko Tanaka, said in their findings published in Scientific Reports.

The cross-sectional study explored four areas to investigate what recovery and community life are like for COVID-19 survivors. These areas are the persistence of symptoms, psychological distress, impairments in work performance, and experiences of stigma and discrimination. Some 127 patients who recovered from COVID-19 at two hospitals in Hiroshima Prefecture, Japan participated in the study between August 2020 to March 2021.

Although they found that smoking history and comorbidities were not significantly related to the frequency of long-term symptoms in the multivariate analysis, the researchers believe that these factors should be continued to be examined in the future since only 18 were smokers among the study participants. As for comorbidities, hypertension was reported only in 19 of the participants and diabetes in 13.

COVID-19 severity is not a risk factor

Persistent symptoms of COVID-19 were identified in over half of the participants at a median of 29 days after onset. Meanwhile, half of those with mild cases experienced lingering symptoms.

“The most important finding is that the percentage of patients with some sequelae after approximately one month from the onset of COVID-19 was as high as 52%, and even among those with mild disease, the rate was as high as 49.5%,” study first-author Aya Sugiyama, assistant professor at Hiroshima University’s Graduate School of Biomedical and Health Sciences, said.

Their findings are consistent with previous studies reporting that 53% to 55% of non-hospitalized COVID-19 patients get lingering symptoms.

“Several reports have pointed out that COVID-19 severity is not associated with sequelae. These findings suggest that COVID-19 patients should be followed up for persistent symptoms regardless of the severity of COVID-19,” the researchers said.

Older age is a factor

The prevalence of lingering symptoms varied by age group in the study, but the researchers found that older patients are significantly more likely to become long-haulers compared to those aged 40 and below. This is consistent with previous studies showing that long-haul symptoms were more likely with increasing age.

They also discovered age-dependent differences in the prevalence of symptoms. Patients aged 60 and above were more likely than other age groups to report fatigue, palpitations, dry eyes or mouth, dyspnea, and sputum production.

The researchers noted how long-haul symptoms are common in organs with high ACE2 expression. ACE2, the major cell entry receptor for SARS-CoV-2, is extensively expressed in numerous human organs such as the mouth, liver, and lungs.

“COVID-19 affects various tissues and organs, such as those in the respiratory, cardiovascular, and neurological systems,” they stated in the paper.

Common symptoms reported by long-haulers in the study included disorders in their sense of smell (15%) and taste (14.2%), cough (14.2%), and fatigue (11%).

Recovery and community life

Their findings also found that sex was not a risk factor for long-haul COVID symptoms, a contrast to another study in the BMJ that pointed out how they are twice as common in females as in males.

Sex and the presence of long-haul symptoms, however, were found to be predictors of psychological distress. Some 45% of females and 17.9% of males scored ≥ 5 on the Kessler Psychological Distress Scale (K6), meaning the risk of psychological distress was higher in women than men.

Stigma and discrimination due to COVID-19 were reported by 43.3% of participants. The most common complaints were being treated as contagious despite being cured (61.8%), harmful rumors (29.1%), and verbal harassment (25.5%).

Meanwhile, 29.1% of study participants had possible impairments in their job performance, suggesting that post–COVID-19 conditions may influence productivity at work to only a limited extent.

The researchers noted how their findings revealed significant health impacts of long-haul COVID symptoms in local communities. They hope to conduct a large-scale and long-term study.

“We would like to elucidate how long the aftereffects last and whether the actual aftereffects differ by viral variant,” Sugiyama said.

During COVID’s omicron wave in U.S., death rates soared for older people

Authors: BENJAMIN MUELLER and Eleanor LutzThe New York Times May 31, 2022 

Despite strong levels of vaccination among older people, COVID killed them at vastly higher rates during this winter’s omicron wave than it did last year, preying on long delays since their last shots and the variant’s ability to skirt immune defenses.

This winter’s wave of deaths in older people belied the omicron variant’s relative mildness. Almost as many Americans 65 and older died in four months of the omicron surge as they did in six months of the delta wave, even though the delta variant, for any one person, tended to cause more severe illness.

While overall per capita COVID death rates have fallen, older people still account for an overwhelming share of them.

“This is not simply a pandemic of the unvaccinated,” said Andrew Stokes, an assistant professor in global health at Boston University who studies age patterns of COVID deaths. “There’s still exceptionally high risk among older adults, even those with primary vaccine series.”

COVID deaths, though always concentrated in older people, have in 2022 skewed toward older people more than they did at any point since vaccines became widely available.

That swing in the pandemic has intensified pressure on the Biden administration to protect older Americans, with health officials in recent weeks encouraging everyone 50 and older to get a second booster and introducing new models of distributing antiviral pills.

In much of the country, though, the booster campaign remains listless and disorganized, older people and their doctors said. Patients, many of whom struggle to drive or get online, have to maneuver through an often labyrinthine health care system to receive potentially lifesaving antivirals.

Nationwide COVID deaths in recent weeks have been near the lowest levels of the pandemic, below an average of 400 a day. But the mortality gap between older and younger people has grown: Middle-aged Americans, who suffered a large share of pandemic deaths last summer and fall, are now benefiting from new stores of immune protection in the population as COVID deaths once again cluster around older people.

And the new wave of omicron subvariants may create additional threats: While hospitalizations in younger age groups have remained relatively low, admission rates among people 70 and older in the Northeast have climbed to one-third of the winter omicron wave’s towering peak.

“I think we are going to see the death rates rising,” said Dr. Sharon Inouye, a geriatrician and a professor of medicine at Harvard Medical School. “It is going to become more and more risky for older adults as their immunity wanes.”

Harold Thomas Jr., 70, of Knoxville, Tennessee, is one of many older Americans whose immunity may be waning because he has not received a booster shot. The COVID States Project, an academic group, recently estimated that among people 65 and older, 13% are unvaccinated, 3% have a single Moderna or Pfizer shot, and another 14% are vaccinated but not boosted.

When vaccines first arrived, Thomas said, the state health department made getting them “convenient” by administering shots at his apartment community for older people. But he did not know of any such effort for booster doses.

On the contrary, he remembered a state official publicly casting doubt on boosters as they became available.

“The government wasn’t sure about the booster shot,” he said. “If they weren’t sure about it, and they’re the ones who put it out, why would I take it?”

Thomas said COVID recently killed a former boss of his and hospitalized an older family friend.

Deaths have fallen from the heights of the winter wave in part because of growing levels of immunity from past infections, experts said. For older people, there is also a grimmer reason: So many of the most fragile Americans were killed by COVID over the winter that the virus now has fewer targets in that age group.

But scientists warned that many older Americans remained susceptible. To protect them, geriatricians called on nursing homes to organize in-home vaccinations or mandate additional shots.

In the longer term, scientists said that policymakers needed to address the economic and medical ills that have affected especially nonwhite older Americans, lest COVID continue cutting so many of their lives short.

“I don’t think we should treat the premature death of older adults as a means of ending the pandemic,” Stokes said. “There are still plenty of susceptible older adults — living with comorbid conditions or living in multigenerational households — who are highly vulnerable.”

The pattern of COVID deaths this year has re-created the dynamics from 2020 — before vaccines were introduced, when the virus killed older Americans at markedly higher rates. Early in the pandemic, mortality rates steadily climbed with each extra year of age, Stokes and his collaborators found in a recent study.

That changed last summer and fall, during the delta surge. Older people were getting vaccinated more quickly than other groups: By November, the vaccination rate in Americans 65 and older was roughly 20 percentage points higher than that of those in their 40s. And critically, those older Americans had received vaccines relatively recently, leaving them with strong levels of residual protection.

As a result, older people suffered from COVID at lower rates than they had been before vaccines became available. Among people 85 and older, the death rate last fall was roughly 75% lower than it had been in the winter of 2020, Stokes’ recent study found.

At the same time, the virus walloped younger and less vaccinated Americans, many of whom were also returning to in-person work. Death rates for white people in their late 30s more than tripled last fall compared to the previous winter. Death rates for Black people in the same age group more than doubled.

The rebalancing of COVID deaths was so pronounced that, among Americans 80 and older, overall deaths returned to pre-pandemic levels in 2021, according to a study posted online in February. The opposite was true for middle-aged Americans: Life expectancy in that group, which had already dropped more than it had among the same age range in Europe, fell even further in 2021.

“In 2021, you see the mortality impact of the pandemic shift younger,” said Ridhi Kashyap, a lead author of that study and a demographer at the University of Oxford.

By the time the highly contagious omicron variant took over, researchers said, more older Americans had gone a long time since their last COVID vaccination, weakening their immune defenses.

As of mid-May, more than one-quarter of Americans 65 and older had not had their most recent vaccine dose within a year. And more than half of people in that age group had not been given a shot in the past six months.

The omicron variant was better than previous versions of the virus at evading those already weakening immune defenses, reducing the effectiveness of vaccines against infection and more serious illness. That was especially true for older people, whose immune systems respond less aggressively to vaccines in the first place.

For some people, even three vaccine doses appear to become less protective over time against omicron-related hospital admissions. A study published recently in The Lancet Respiratory Medicine found that trend held for people with weakened immune systems, a category that older Americans were likelier to fall into. Sara Tartof, the study’s lead author and a public health researcher at Kaiser Permanente in Southern California, said that roughly 9% of people 65 and older in the study were immunocompromised, compared with 2.5% of adults younger than 50.

During the omicron wave, COVID death rates were once again dramatically higher for older Americans than younger ones, Stokes said. Older people also made up an overwhelming share of the excess deaths — the difference between the number of people who actually died and the number who would have been expected to die if the pandemic had never happened.

Dr. Jeremy Faust, an emergency physician at Brigham and Women’s Hospital in Boston, found in a recent study that excess deaths were more heavily concentrated in people 65 and older during the omicron wave than the delta surge. Overall, the study found, there were more excess deaths in Massachusetts during the first eight weeks of omicron than during the 23-week period when delta dominated.

As older people began dying at higher rates, COVID deaths also came to include higher proportions of vaccinated people. In March, about 40% of the people who died from COVID were vaccinated, according to an analysis of figures from the Centers for Disease Control and Prevention.

Fewer older Americans have also been infected during the pandemic than younger people, leading to lower levels of natural immunity. As of February, roughly one-third of people 65 and older showed evidence of prior infections, compared with about two-thirds of adults younger than 50.

Long-ago COVID cases do not prevent future infections, but reinfected people are less likely to become seriously ill.

A drop-off in COVID precautions this winter, combined with the high transmissibility of omicron, left older people more exposed, scientists said. It is unclear how their own behavior may have changed. An earlier study, from scientists at Marquette University, suggested that while older people in Wisconsin had once been wearing masks at rates higher than those of younger people, that gap had effectively disappeared by mid-2021.

Antiviral pills are now being administered in greater numbers, but it is difficult to know who is benefiting from them. Scientists said that the wintertime spike in COVID death rates among older Americans demanded a more urgent policy response.

Inouye, of Harvard Medical School, said she had waited for a notice from her mother’s assisted living facility about the rollout of second booster shots even as reports started arriving of staff members becoming infected. But still, the facility’s director said that a second booster shot drive was impossible without state guidance.

Eventually, her family had to arrange a trip to a pharmacy on their own for a second booster.

“It just seems that now the onus is put completely on the individual,” she said. “It’s not like it’s made easy for you.”

Long COVID affects more older adults; shots don’t prevent it

Authors: LINDSEY TANNER AP Medical Writer MAY 26, 202

New U.S. research on long COVID-19 provides fresh evidence that it can happen even after breakthrough infections in vaccinated people, and that older adults face higher risks for the long-term effects.

In a study of veterans published Wednesday, about one-third who had breakthrough infections showed signs of long COVID.

A separate report from the Centers for Disease Control and Prevention found that up to a year after an initial coronavirus infection, 1 in 4 adults aged 65 and older had at least one potential long COVID health problem, compared with 1 in 5 younger adults.

Long COVID refers to any of more than two dozens symptoms that linger, recur or first appear at least one month after a coronavirus infection. These can affect all parts of the body and may include fatigue, shortness of breath, brain fog and blood clots.

Coronavirus vaccines that help prevent initial infections and serious illnesses provide some protection against long COVID but mounting research shows not as much as scientists had first hoped.

The veterans study published in Nature Medicine reviewed medical records of mostly white male veterans, aged 60, on average. Of the 13 million veterans, almost 3 million had been vaccinated last year, through October.

About 1%, or nearly 34,000, developed breakthrough infections. Lead author Dr. Ziyad Al-Aly noted that the study was done before the highly contagious omicron variant appeared at the end of the year and said the rate of breakthrough infections has likely increased.

Breakthrough infections and long COVID symptoms were more common among those who had received Johnson & Johnson’s single-dose shot compared with two doses of either Moderna or Pfizer vaccines. Whether any had received booster shots is not known; the first booster wasn’t OK’d in the U.S. until late September.

Overall, 32% had long COVID symptoms up to six months after breakthrough infections. That’s compared with 36% of unvaccinated veterans who had been infected and developed long COVID.

Vaccination reduced the chances for any long COVID symptoms by a “modest” 15%,” although it cut the risk in half for lingering respiratory or clotting problems, said Al-Aly, a researcher with Washington University and the Veterans Affairs health system in St. Louis. These symptoms included persistent shortness of breath or cough and blood clots in lungs or veins in the legs.

Infectious disease expert Dr. Kristin Englund, who runs a center for long COVID patients at the Cleveland Clinic, said the Nature Medicine study mirrors what she sees at her clinic. Long COVID patients there include people who were vaccinated and received boosters.

“We have no clear treatments for long COVID and encourage vaccination,”

However, others believe that vaccination has not been proven to be effective in preventing COVID infection nor has it been shown that the vaccines prevent long-haul illness, especially in the large majority of the elderly who have other chronic health conditions.

The CDC report, released Tuesday, used medical records for almost 2 million U.S. adults from the start of the pandemic in March 2020 to last November. They included 353,000 who had COVID-19. Patients were tracked for up to a year to determine if they developed any of 26 health conditions that have been attributed to long COVID.

Those who had COVID were much more likely than other adults without COVID to develop at least one of these conditions, and risks were greatest for those aged 65 and older. Information on vaccination, sex and race was not included.

Breathing problems and muscle aches were among the most common conditions.

Older adults’ risks were higher for certain conditions, including strokes, brain fog, kidney failure and mental health problems. The findings are worrisome because those conditions can hasten older adults’ needs for long-term care, the report authors said.

They stressed that routine assessment of all COVID patients “is critical to reduce the incidence” of long COVID.

SARS-CoV-2 mRNA Vaccination-Associated Myocarditis in Children Ages 12-17: A Stratified National Database Analysis

Authors: RALPH TURCHIANO    • 

Abstract

Establishing the rate of post-vaccination cardiac myocarditis in the 12-15 and 16-17-year-old population in the context of their COVID-19 hospitalization risk is critical for developing a vaccination recommendation framework that balances harms with benefits for this patient demographic. Design, Setting and Participants: Using the Vaccine Adverse Event Reporting System (VAERS), this retrospective epidemiological assessment reviewed reports filed between January 1, 2021, and June 18, 2021, among adolescents ages 12-17 who received mRNA vaccination against COVID-19. Symptom search criteria included the words myocarditis, pericarditis, and myopericarditis to identify children with evidence of cardiac injury. The word troponin was a required element in the laboratory findings. Inclusion criteria were aligned with the CDC working case definition for probable myocarditis. Stratified cardiac adverse event (CAE) rates were reported for age, sex and vaccination dose number. A harm-benefit analysis was conducted using existing literature on COVID-19-related hospitalization risks in this demographic. Main outcome measures: 1) Stratified rates of mRNA vaccine-related myocarditis in adolescents age 12-15 and 16-17; and 2) harm-benefit analysis of vaccine-related CAEs in relation to COVID-19 hospitalization risk. Results: A total of 257 CAEs were identified. Rates per million following dose 2 among males were 162.2 (ages 12-15) and 94.0 (ages 16-17); among females, rates were 13.0 and 13.4 per million, respectively. For boys 12-15 without medical comorbidities receiving their second mRNA vaccination dose, the rate of CAE is 3.7-6.1 times higher than their 120-day COVID-19 hospitalization risk as of August 21, 2021 (7-day hospitalizations 1.5/100k population) and 2.6-4.3-fold higher at times of high weekly hospitalization risk (2.1/100k), such as during January 2021. For boys 16-17 without medical comorbidities, the rate of CAE is currently 2.1-3.5 times higher than their 120-day COVID-19 hospitalization risk, and 1.5-2.5 times higher at times of high weekly COVID-19 hospitalization. Conclusions: Post-vaccination CAE rate was highest in young boys aged 12-15 following dose two. For boys 12-17 without medical comorbidities, the likelihood of post vaccination dose two CAE is 162.2 and 94.0/million respectively. This incidence exceeds their expected 120-day COVID-19 hospitalization rate at both moderate (August 21, 2021 rates) and high COVID-19 hospitalization incidence. Further research into the severity and long-term sequelae of post-vaccination CAE is warranted. Quantification of the benefits of the second vaccination dose and vaccination in addition to natural immunity in this demographic may be indicated to minimize harm.

Millennials Experienced the “Worst-Ever Excess Mortality in History” – An 84% Increase In Deaths After Vaccine Mandates

The most recent data from the CDC shows that U.S. millennials, aged 25-44, experienced a record-setting 84% increase in excess mortality during the final four months of 2021, according to the analysis of financial expert and Blackrock whistleblower, Edward Dowd,

Dowd, with the assistance of an insurance industry expert, compiled data from the CDC showing that, in just the second half of 2021, the total number of excess deaths for millennials was higher than the number of Americans who died in the entirety of the Vietnam War. Between August and December, there were over 61,000 deaths in this age group, compared to 58,000 over the course of 10 years in Vietnam.

In all, excess death among those who are traditionally the healthiest Americans is up by 84%.

Children with long covid

Authors: Helen Thomson

New Sci. 2021 Feb 27; 249(3323): 10–11.Published online 2021 Mar 3. doi: 10.1016/S0262-4079(21)00303-1PMCID: PMC7927578PMID: 33686318

Abstract

Almost half of children who contract covid-19 may have lasting symptoms, which should factor into decisions on reopening schools,

A SERIOUS picture is emerging about the long-term health effects of covid-19 in some children, with UK politicians calling the lack of acknowledgment of the problem a “national scandal”.

Children seem to be fairly well-protected from the most severe symptoms of covid-19. According to the European Centre for Disease Prevention and Control, the majority of children don’t develop symptoms when infected with the coronavirus, or their symptoms are very mild.

However, it is becoming increasingly apparent that a large number of children with symptomatic and asymptomatic covid-19 are experiencing long-term effects, many months after the initial infection.Go to:

Long-term symptoms

Symptoms of long covid were first thought to include fatigue, muscle and joint pain, headache, insomnia, respiratory problems and heart palpitations. Now, support groups and researchers say there may be up to 100 other symptoms, including gastrointestinal problems, nausea, dizziness, seizures, hallucinations and testicular pain.

Most long covid research is based on adults. There is less information about under-18s, in part because it takes longer to get ethical approval to study children, says Natalie Lambert at Indiana University School of Medicine.

A recent study found that 13.3 per cent of adults with symptomatic covid-19 have symptoms lasting more than 28 days (medRxiv, doi.org/ghgdsv). Long-lasting symptoms were more likely to occur with increasing age and BMI, and were more likely in women than men, although it isn’t clear why. Experiencing more than five symptoms in the first week post-infection was associated with a greater likelihood of having symptoms further down the line.

Evidence from the first study of long covid in children suggests that more than half of children aged between 6 and 16 years old who contract the virus have at least one symptom lasting more than 120 days, with 42.6 per cent impaired by these symptoms during daily activities. These interim results are based on periodic assessments of 129 children in Italy who were diagnosed with covid-19 between March and November 2020 at the Gemelli University Hospital in Rome (medRxiv, doi.org/fv9t).

The UK Office for National Statistics’s latest report estimates that 12.9 per cent of UK children aged 2 to 11, and 14.5 per cent of children aged 12 to 16, still have symptoms five weeks after their first infection. Almost 500,000 UK children have tested positive for covid-19 since March 2020.

Most medical bodies say it normally takes a few days or weeks to recover from covid-19, and that most will make a full recovery within 12 weeks.

UK advocacy group Long Covid Kids says that it currently has details of 1200 children with long covid from 890 families in England. “And that number has been rising quickly,” says founder Sammie Mcfarland. “Not one has returned to their previous health, and most are unable to do their normal activities.”

The consequences of long covid in children can be debilitating. At a UK parliamentary briefing on 26 January, Mcfarland described how her 14-year-old daughter started to become vacant, weak and unresponsive after catching covid-19 in March 2020. After three weeks in bed, she did some gentle exercise in the garden and clutched her chest, complaining of heart pain. “She went very floppy and almost couldn’t make it back into the house to bed,” says Mcfarland. “And she pretty much stayed there [in bed] for the next seven months.”

She went very floppy and almost couldn’t make it back to bed. She stayed there for seven months

Since August 2020, Mcfarland says there have been times where her daughter would feel better and they would go out of the house for a picnic, but they soon realised that every trip out triggered a long period of relapse, an issue that seems to be common in adults with long covid too.

Other cases seem to present very differently. Charlie Mountford-Hill has five children, all of whom have long covid after contracting the virus in the early stages of the pandemic. Almost a year after catching covid-19, her 4-year-old still has a sore neck, lethargy, stomach problems and headaches. Her 10-year-old has fatigue and gastric problems with pain around his heart. “Although they have bad periods and better periods, they are never well,” says Mountford-Hill.

Seeking long-covid care

A common frustration among parents is the lack of support from doctors. Mcfarland says they can dismiss the symptoms as not being related to covid-19 because they are so varied. Often, blood tests and scans also fail to supply any answers. “The majority of people known to Long Covid Kids have been unable to get support,” she says. The group is now working with NHS England to try to get access to care.

Several parents gave evidence at the parliamentary briefing on long covid in children, run by MP Layla Moran. She told New Scientist that the “lack of support, acknowledgement and treatment of long covid in children is a national scandal”. In a letter to the Prime Minister that was shown to New Scientist, several MPs refer to the situation as a crisis that needs to be taken more seriously.

The lack of information on long covid in children is especially pertinent to decisions around schools reopening, as they are due to do in parts of the UK and the US in the coming weeks.

500,000 Children in the UK who have tested positive for covid-19

“We certainly don’t have enough data on the long-term impacts of covid in children to make good policy decisions right now,” says Lambert, who is director of research for Survivor Corps, the largest covid-19 advocacy group in the world. On 18 February, the UK’s National Institute for Health Research awarded £1.4 million for a study to assess risk factors and prevalence of long covid in children.

Nurseries have been allowed to stay open in England while primary and secondary schools have remained shut since 5 January. When asked on 5 February whether the impact of long covid in children has been considered in relation to the reopening of schools, the UK Department for Education gave no reply.

12.9% Percentage of UK children aged 2 to 11 who still have covid-19 symptoms five weeks after initial infection

Sending thousands of children back to school is “insane”, says McFarland. “Sending children back to school seems to be inviting the possibility of giving a whole generation long-term chronic health issues. Why take the risk of opening schools before children have been vaccinated?”

14.5% Percentage of UK children aged 12 to 16 who still have covid-19 symptoms five weeks after initial infection

So far, no coronavirus vaccines have been approved for use in children, although CanSino Biologics in China is testing one in 6 to 12-year-olds, according to data revealed at a recent New York Academy of Science meeting. CEO Xuefeng Yu says that preliminary data will be analysed soon. US company Codagenix is also planning to test a nasal vaccine in children.

The good news is that evidence suggests children don’t easily pass covid-19 to each other in the classroom. In one study, a 9-year-old in France with flu and covid-19 was found to have exposed more than 80 other children at three different schools. However, no one became infected with covid-19 as a result, despite numerous flu infections within the schools, suggesting that although the environment was conducive to transmitting respiratory viruses, covid-19 wasn’t passed on as easily.

More recently, a study of children between 5 months and 4 years old in nurseries in France has shown low levels of infection and transmission of covid-19. The study also shows that staff weren’t at greater risk of infection than a control group of adults. The results suggest that children are more likely to get covid-19 from family members than from their peers or teachers at nursery, although more evidence is needed, say the study’s authors, because the study happened when strict measures were in place to control the virus, and before fast-spreading variants appeared.

Until now, the focus of the pandemic has been on preventing severe disease and deaths in the older generations, but Mcfarland says thoughts need to turn to the legacy the virus is leaving on children.

Study: Myocarditis risk 37 times higher for children with COVID-19 than uninfected peers

Authors: Melissa Jenco, News Content Editor August 31, 2021

The risk of myocarditis for children under 16 years is 37 times higher for those infected with COVID-19 than those who haven’t been infected with the virus, according to a new study.

Authors from the Centers for Disease Control and Prevention (CDC) said the study provides more evidence that the benefits of the vaccine outweigh a small risk of myocarditis after vaccination.

Researchers analyzed data from more than 900 hospitals and found inpatient visits for myocarditis were 42% higher in 2020 compared to 2019, according to a new Morbidity and Mortality Weekly Report.

Among 36 million patients, about 0.01% had myocarditis between March 2020 and February 2021. The median age of people with myocarditis was 54 years, and 59% were male.

About 42% of patients with myocarditis had a history of COVID-19, mostly within the same month. The team determined the risk of myocarditis to be 0.146% among those with COVID-19 and 0.009% among those not diagnosed with COVID-19.

Across all ages, the risk of myocarditis was almost 16 times higher for people with COVID-19 compared to those who aren’t infected. The myocarditis risk is 37 times higher for infected children under 16 years and seven times higher for infected people ages 16-39 compared to their uninfected peers.

Some of the myocarditis cases seen in children with COVID-19 may be cases of multisystem inflammatory syndrome, according to the study.

Authors noted the study could not prove COVID-19 causes myocarditis, but the findings of a link between the two are consistent with several other studies.

In recent months, there has been concern about a small risk of myocarditis after receiving an mRNA COVID-19 vaccine. A June study showed among males ages 12-29 years — the group with the highest rates of myocarditis after vaccination — there would be an estimated 39 to 47 cases of myocarditis for every million second doses of vaccine. Authors of the new study say their findings support health officials’ assertions that the benefits of vaccination outweigh the risks.

“These findings underscore the importance of implementing evidence-based COVID-19 prevention strategies, including vaccination, to reduce the public health impact of COVID-19 and its associated complications,” they wrote.Resources

Copyright © 2021 American Academy of Pediatrics

COVID virus linked with headaches, altered mental status in hospitalized kids

Authors: UNIVERSITY OF PITTSBURGH Peer-Reviewed Publication

PITTSBURGH, Jan. 21, 2022 – Of hospitalized children who tested or were presumed positive for SARS-CoV-2, 44% developed neurological symptoms, and these kids were more likely to require intensive care than their peers who didn’t experience such symptoms, according to a new study led by a pediatrician-scientist at UPMC and the University of Pittsburgh School of Medicine

The most common neurologic symptoms were headache and altered mental status, known as acute encephalopathy. Published in Pediatric Neurology, these preliminary findings are the first insights from the pediatric arm of GCS-NeuroCOVID, an international, multi-center consortium aiming to understand how COVID-19 affects the brain and nervous system. 

“The SARS-CoV-2 virus can affect pediatric patients in different ways: It can cause acute disease, where symptomatic illness comes on soon after infection, or children may develop an inflammatory condition called MIS-C weeks after clearing the virus,” said lead author Ericka Fink, M.D., pediatric intensivist at UPMC Children’s Hospital of Pittsburgh, and associate professor of critical care medicine and pediatrics at Pitt. “One of the consortium’s big questions was whether neurological manifestations are similar or different in pediatric patients, depending on which of these two conditions they have.” 

To answer this question, the researchers recruited 30 pediatric critical care centers around the world. Of 1,493 hospitalized children, 1,278, or 86%, were diagnosed with acute SARS-CoV-2; 215 children, or 14%, were diagnosed with MIS-C, or multisystem inflammatory syndrome in children, which typically appears several weeks after clearing the virus and is characterized by fever, inflammation and organ dysfunction. 

The most common neurologic manifestations linked with acute COVID-19 were headache, acute encephalopathy and seizures, while youths with MIS-C most often had headache, acute encephalopathy and dizziness. Rarer symptoms of both conditions included loss of smell, vision impairment, stroke and psychosis.  

“Thankfully, mortality rates in children are low for both acute SARS-CoV-2 and MIS-C,” said Fink. “But this study shows that the frequency of neurological manifestations is high—and it may actually be higher than what we found because these symptoms are not always documented in the medical record or assessable. For example, we can’t know if a baby is having a headache.” 

The analysis showed that neurological manifestations were more common in kids with MIS-C compared to those with acute SARS-CoV-2, and children with MIS-C were more likely than those with acute illness to have two or more neurologic manifestations. 

According to Fink, the team recently launched a follow up study to determine whether acute SARS-CoV-2 and MIS-C—with or without neurologic manifestations—have lasting effects on children’s health and quality of life after discharge from hospital.  

“Another long-term goal of this study is to build a database that tracks neurological manifestations over time—not just for SARS-CoV-2, but for other types of infections as well,” she added. “Some countries have excellent databases that allow them to easily track and compare children who are hospitalized, but we don’t have such a resource in the U.S.” 

This study was partly funded by the Neurocritical Care Society Investing in Clinical Neurocritical Care Research (INCLINE) grant. 

Other researchers who contributed to the study include Courtney L. Robertson, M.D., Johns Hopkins Children’s Center; Mark S. Wainwright, M.D., Ph.D., University of Washington and Seattle Children’s Hospital; Juan D. Roa, M.D., Universidad Nacional de Colombia and Fundación Universitaria de Ciencias de la Salud; Michelle E. Schober, M.D., University of Utah, and other GCS-NeuroCOVID Pediatrics investigators who are listed in the paper. 

To read this release online or share it, visit http://www.upmc.com/media/news/012122-Fink-COVID-Children.  


JOURNAL

Pediatric Neurology

DOI

10.1016/j.pediatrneurol.2021.12.010 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C

ARTICLE PUBLICATION DATE

21-Jan-2022