Long COVID: which symptoms can be attributed to SARS-CoV-2 infection?

Authors: Christopher E Brightling Rachael A Evans Published:August 06, 2022DOI:https://doi.org/10.1016/S0140-6736(22)01385-X The Lancet

Mortality rates following SARS-CoV-2 infection have decreased as a consequence of public health policies, vaccination, and acute antiviral and anti-inflammatory therapies.1 However, in the wake of the pandemic, post-acute sequelae of COVID-19, or long COVID, has emerged: a chronic illness in people who have ongoing multidimensional symptomatology and disability weeks to years after the initial infection.2 Early reports of long COVID prevalence, summarized in a systematic review examining the frequency and variety of persistent symptoms after COVID-19, found that the median proportion of people who had at least one persistent symptom 60 days or more after diagnosis or at least 30 days after recovery from COVID-19 infection was 73%. 3 However, the estimated prevalence depends on the duration, population, and symptoms used to define long COVID. More recently, community-based studies have suggested a lower prevalence of persistent symptoms; 4 whereas among people who were hospitalised following COVID-19 infection, a high proportion do not fully recover (50–70%).56

The number of COVID-19 cases continues to rise and now exceeds 500 million worldwide.1 Consequently, the number of people with long COVID is similarly increasing. Indeed, the UK Office for National Statistics (ONS) survey up to May, 2022 estimated that 2 million people in the UK had self-reported long COVID. 8 Of these people, 72% reported having long COVID for at least 12 weeks, 42% for at least 1 year, and 19% for at least 2 years. Consistent with other studies, fatigue was the most common symptom in the ONS survey, followed by breathlessness, cough, and muscle ache.45678 Risk factors for long COVID are female sex, obesity, middle age (35–65 years), living in areas of greater socioeconomic deprivation, and the presence of another activity-limiting health condition.156 Importantly, health-care use is increased in those with long COVID, with increased general practitioner consultation rates.

How many of the symptoms currently attributed to long COVID actually represent pre-existent disease or are unrelated to COVID-19 is uncertain. Symptoms that were present before SARS-CoV-2 infection are often not recorded or assessed by recall. In The Lancet, Aranka V Ballering and colleagues 10  report the findings of a longitudinal cohort study conducted in the north of the Netherlands between April, 2020, and August, 2021, where 23 somatic symptoms were assessed using 24 repeated measurements in digital COVID-19 questionnaires. The study was embedded within the large, population-based Lifelines COVID-19 cohort. The main strengths of this study were that participants were their own control, with the pattern and severity of symptoms assessed before and 3–5 months after SARS-CoV-2 infection, and were also compared with a matched control group of COVID-19-negative participants. Of the 76 422 participants, 4231 (5·5%) had COVID-19 and were compared with 8462 matched controls. Participants had a mean age of 53·7 years (SD 12·9), 46 329 (60·8%) were female, and nearly all were of White ethnicity. The proportion of participants who had at least one core symptom of substantially increased severity to at least moderate was 21·4% (381 of 1782) in COVID-19-positive participants versus 8·7% (361 of 4130) in COVID-19-negative controls. Thus, this study found that core symptoms were attributed to COVID-19 in 12·7% of participants, or approximately one in eight. This is a major advance on previous long COVID prevalence estimates, as it includes a matched control group without SARS-CoV-2 infection and accounts for symptoms that were present before infection.

The pattern of symptomatology observed by Ballering and colleagues 0  was similar to previous reports, with fatigue and breathlessness among the most common symptoms, but other symptoms such as chest pain were more common in people who had COVID-19 than in COVID-19-negative controls. Ballering and colleagues10  propose a core symptom set to be considered as part of the case definition for long COVID. Although an agreed diagnostic core symptom set would inform clinical pathways and research, the study by Ballering and colleagues 10 did not fully consider the impact on mental health, it was conducted in one region in the Netherlands, and it did not include an ethnically diverse population; thus the concept of a core symptom set will require further validation. Importantly, the study by Ballering and colleagues 10  does not provide new mechanistic insights, which are key to uncovering new therapeutic targets. In other studies, clustering of patient-reported outcomes has identified different severity groups of long COVID and identified increased systemic inflammation in people with very severe long COVID.5, 6

 How patient-centred outcomes, together with biomarkers, can further refine long COVID diagnosis and inform precision medicine approaches warrants further consideration. Encouragingly, emerging data from other studies suggest that the proportion of newly infected people developing long COVID is reduced in people who have received vaccination before SARS-CoV-2 infection,11  and might be lower in people infected with the omicron variant than those infected with earlier variants.2

 Findings from the ONS survey suggested that vaccination following infection might reduce the symptom burden of long COVID after the first dose, with sustained improvement after a second dose13  Whether acute treatments for COVID-19 affect the likelihood of developing long COVID or its severity is unknown.

Current evidence supports the view that long COVID is common and can persist for at least 2 years after SARS-CoV-2 infection, although severe debilitating disease is present in a minority. The long COVID case definition needs to be further improved, potentially to describe different types of long COVID, of which better mechanistic understanding is crucial. This will lead to personalised multimodality treatments that can be implemented to manage the increasingly high number of people with long COVID.

CEB has received consultancy and or grants paid to his institution from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, Genentech, Roche, Sanofi, Regeneron, Mologic, and 4DPharma for asthma and chronic obstructive pulmonary disease research. RAE has received consultancy fees from AstraZeneca on the topic of long COVID and from GlaxoSmithKline on digital health, and speaker’s fees from Boehringer Ingelheim on long COVID. RAE holds a National Institute for Health and Care Research (NIHR) clinician scientist award CS-2016-16-020.

References

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9

WHO report: 17 million in EU may have suffered long COVID-19

SEPTEMBER 13, 2022 Journal information:Nature Medicine

New research suggests at least 17 million people in the European Union may have experienced long COVID-19 symptoms during the first two years of the coronavirus pandemic, with women more likely than men to suffer from the condition, the World Health Organization said Tuesday.

The research, conducted for the WHO/Europe, was unclear on whether the symptoms that linger, recur or first appear at least one month after a coronavirus infection were more common in vaccinated or unvaccinated people. At least 17 million people met the WHO’s criteria of long COVID-19—with symptoms lasting at least three months in 2020 and 2021, the report said.

“Millions of people in our region, straddling Europe and Central Asia, are suffering debilitating symptoms many months after their initial COVID-19 infection,” said Hans Henri P. Kluge, WHO Regional Director for Europe, during a conference in Tel Aviv.

The modeling also suggests that women are twice as likely as men to experience long COVID-19, and the risk increases dramatically among severe infections needing hospitalization, the report said. One-in-three women and one-in-five men are likely to develop long COVID-19, according to the report.

“Knowing how many people are affected and for how long is important for health systems and government agencies to develop rehabilitative and support services,” said Christopher Murray, director of the Institute for Health Metrics and Evaluation, which conducted the research for the WHO.

The research, which represents estimates and not actual numbers of affected people, tracks with some other recent studies on the constellation of longer-term symptoms after coronavirus infections.

A U.S. study of veterans published in Nature Medicine in May provided fresh evidence that long COVID-19 can happen even after breakthrough infections in vaccinated people, and that older adults face higher risks for the long-term effects. The study showed that about one-third who had breakthrough infections exhibited 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-19 health problem, compared with 1 in 5 younger adults.

Most people who have COVID-19 fully recover. But the WHO in Europe report on Tuesday estimated that 10% to 20% develop mid- and long-term symptoms such as fatigue, breathlessness and cognitive dysfunction.

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.)

What’s to blame for the surge in excess deaths?

Authors: Ross Clark 19 August 2022, The Spectator

From the beginning, the debate over lockdowns was skewed by the fact that Covid deaths were imminent – and any other effects from lockdown would become apparent over a longer period. But are we beginning to see that now? Over the past few months the Office for National Statistics has been recording ‘excess’ non-covid deaths of around 1,000 a week in England and Wales – that is to say deaths above and beyond the level which would be expected at this time of year. Deaths over the summer months have been more in line with the number of deaths which might be expected in a normal winter.

Many of the excess deaths appear to be from heart and circulatory diseases. Recent heatwaves may have contributed negatively to this – warmer weather has long been associated with excess deaths. But the current bulge in excess deaths can be traced back to April, long before the heatwave. There have been suggestions that Covid could have weakened people’s health and that we are seeing a delayed reaction to being infected with the virus. Others point to delays in NHS treatment, with long waits in A&E.

https://datawrapper.dwcdn.net/aorwZ/1/

But the possibility remains that we are seeing the result of lockdowns – in particular, the failure of people to seek treatment or the difficulty of obtaining a consultation when we were all ordered to stay at home. The first lockdown, for example, resulted in a 33 per cent fall in diagnosis of early-stage cancers. The government was forced to change its messaging when it became clear that telling people to ‘stay at home’ and ‘protect the NHS’ was dissuading many from seeking treatment, even when they had ominous symptoms.

That lockdowns could themselves cause significant excess deaths was suspected by the government. In July 2020, the Department for Health quietly published a study which concluded that the number of Quality Adjusted Life Years (QALYS) from the indirect effects of the pandemic could eventually outstrip the number of QALYS which had been lost to Covid at that point. Covid, it estimated, would cost 530,000 QALYS. But 41,000 would be lost to reduced access to A&E, 73,000 lost to early discharge from hospital and reduced access to primary care services and 45,000 would be lost to delays in elective surgery. An additional 157,000 QALYS would eventually be lost to the effects of recession – and 294,000 to deprivation as a result of lower economic growth in the long term.

This is just modelling, of course – the limitations of which became plain during the pandemic. Moreover, not all these effects can be laid at the door of the government’s decision to order a lockdown. Had the NHS become overwhelmed by Covid cases, there would have been all manner of delays to treatment for other conditions. Lockdown or not, the economy would have taken a hit – although Sweden, which decided against the measure, suffered a lot less, in economic terms, than Britain and other European countries which did call lockdowns.

Nevertheless, the debate on the wisdom of ordering a lockdown in respect to an outbreak of infectious disease is far from over. Studies on the long-term effects are likely to rumble on for years. But the possibility that a lockdown could itself cause excess deaths was certainly known to the government in July 2020 – well before it decided to repeatedly resort to the measure.

New study suggests covid increases risks of brain disorders

Authors: Frances Stead Sellers Fri, August 19, 2022  Washington Post

A study published this week in the Lancet Psychiatry showed increased risks of some brain disorders two years after infection with the coronavirus, shedding new light on the long-term neurological and psychiatric aspects of the virus.

The analysis, conducted by researchers at the University of Oxford and drawing on health records data from more than 1 million people around the world, found that while the risks of many common psychiatric disorders returned to normal within a couple of months, people remained at increased risk for dementia, epilepsy, psychosis and cognitive deficit (or brain fog) two years after contracting covid. Adults appeared to be at particular risk of lasting brain fog, a common complaint among coronavirus survivors.

The study was a mix of good and bad news findings, said Paul Harrison, a professor of psychiatry at the University of Oxford and the senior author of the study. Among the reassuring aspects was the quick resolution of symptoms such as depression and anxiety.

“I was surprised and relieved by how quickly the psychiatric sequelae subsided,” Harrison said.

David Putrino, director of rehabilitation innovation at Mount Sinai Health System in New York, who has been studying the lasting impacts of the coronavirus since early in the pandemic, said the study revealed some very troubling outcomes.

“It allows us to see without a doubt the emergence of significant neuropsychiatric sequelae in individuals that had covid and far more frequently than those who did not,” he said.

Because it focused only on the neurological and psychiatric effects of the coronavirus, the study authors and others emphasized that it is not strictly long-covid research.

“It would be overstepping and unscientific to make the immediate assumption that everybody in the [study] cohort had long covid,” Putrino said. But the study, he said, “does inform long-covid research.”

Between 7 million and 23 million people in the United States have long covid, according to recent government estimates – a catchall term for a wide range of symptoms including fatigue, breathlessness and anxiety that persist weeks and months after the acute infection has subsided. Those numbers are expected to rise as the coronavirus settles in as an endemic disease.

The study was led by Maxime Taquet, a senior research fellow at the University of Oxford who specializes in using big data to shed light on psychiatric disorders.

The researchers matched almost 1.3 million patients with a diagnosis of covid-19 between Jan. 20, 2020, and April 13, 2022, with an equal number of patients who had other respiratory diseases during the pandemic. The data, provided by electronic health records network TriNetX, came largely from the United States but also included data from Australia, Britain, Spain, Bulgaria, India, Malaysia and Taiwan.

The study group, which included 185,000 children and 242,000 older adults, revealed that risks differed according to age groups, with people age 65 and older at greatest risk of lasting neuropsychiatric affects.

For people between the ages of 18 and 64, a particularly significant increased risk was of persistent brain fog, affecting 6.4 percent of people who had had covid compared with 5.5 percent in the control group.

Six months after infection, children were not found to be at increased risk of mood disorders, although they remained at increased risk of brain fog, insomnia, stroke and epilepsy. None of those affects were permanent for children. With epilepsy, which is extremely rare, the increased risk was larger.

The study found that 4.5 percent of older people developed dementia in the two years after infection, compared with 3.3 percent of the control group. That 1.2-point increase in a diagnosis as damaging as dementia is particularly worrisome, the researchers said.

The study’s reliance on a trove of de-identified electronic health data raised some cautions, particularly during the tumultuous time of the pandemic. Tracking long-term outcomes may be hard when patients may have sought care through many different health systems, including some outside the TriNetX network.

“I personally find it impossible to judge the validity of the data or the conclusions when the data source is shrouded in mystery and the sources of the data are kept secret by legal agreement,” said Harlan Krumholz, a Yale scientist who has developed an online platform where patients can enter their own health data.

Taquet said the researchers used several means of assessing the data, including making sure it reflected what is already known about the pandemic, such as the drop in death rates during the omicron wave.

Also, Taquet said, “the validity of data is not going to be better than validity of diagnosis. If clinicians make mistakes, we will make the same mistakes.”

The study follows earlier research from the same group, which reported last year that a third of covid patients experienced mood disorders, strokes or dementia six months after infection with the coronavirus.

While cautioning that it is impossible to make full comparisons among the effects of recent variants, including omicron and its subvariants, which are currently driving infections, and those that were prevalent a year or more ago, the researchers outlined some initial findings: Even though omicron caused less severe immediate symptoms, the longer-term neurological and psychiatric outcomes appeared similar to the delta waves, indicating that the burden on the world’s health-care systems might continue even with less-severe variants.

Hannah Davis, a co-founder of the Patient-Led Research Collaborative, which studies long covid, said that finding was meaningful. “It goes against the narrative that omicron is more mild for long covid, which is not based on science,” Davis said.

“We see this all the time,” Putrino said. “The general conversation keeps leaving out long covid. The severity of initial infection doesn’t matter when we talk about long-term sequalae.

Estimates of long Covid are startlingly high. Here’s how to understand them

Authors:  Elizabeth Cooney July 2022 STAT

Think about the adults you know who have had Covid: Does 1 out of every 5 have long Covid, as the CDC estimates?

Asking that question should in no way diminish the suffering of people who thought they were done with their infections, only to find their return to well-being still beyond reach. But knowing how many people are living with that bitter legacy of Covid-19, and who among working-age adults can’t work or care for their families, is critical to their care and to the health of our society.

It’s important to remember that long Covid is an evolving umbrella term for an array of symptoms that vary in both number and degree. Some housebound people are assailed by brain fog that completely robs them of concentration, while others find memory aids help them get through their workdays. Some former athletes can’t complete a 6-minute walk test, while others can gradually return to activity if they monitor their heart rate. Long Covid clinics that adapt techniques from rehabilitation medicine see people eventually get better. In a world transitioning away from bustling downtowns to hybrid work-from-home status, we may not see who’s missing.

Whatever long Covid’s toll turns out to be, it will be too many people. However you gather or analyze the data, experts told STAT, the proportion of people whose troublesome, sometimes disabling symptoms linger after their acute Covid-19 infections clear is sizable and worrying. It’s the cruelty of large numbers: Even if the actual prevalence of long Covid is much smaller than recent estimates, a small percentage of a large number is a large number.

And yet, the U.S. has for months been operating in a nearly normal fashion. What could explain this discrepancy between estimates and common experience? It’s eerily similar to the pandemic’s early days, when people asked one another if they knew anyone who had caught the coronavirus, followed more than two years later by the flip side: knowing few people who haven’t been infected and no one who hasn’t been exposed.

Here are some factors that make the current range of estimates easier to understand.

First, what are the numbers?

That 20% figure, from a recent CDC analysis of millions of health records, implies that tens of millions of Americans — a fifth of people infected with Covid — have at least one lingering post-infection symptom that is seriously affecting their daily life. Compared to other estimates, like an April meta-analysis that puts global long Covid at closer to 50% or a June household survey from CDC saying 1 in 3, it’s even on the low side.

Nathan Praschan, a psychiatry researcher at Massachusetts General Hospital, trusts it, calling the more rigorous CDC study’s epidemiology among the best he’s seen because for over a year it used a control group to tease out Covid effects. Still, he thinks it might have missed some people who don’t show up in medical records. Long Covid is defined by symptoms — psychiatric disorders and cognitive problems, to name two — that could make finding care more difficult, as would the same social determinants of health that mean Covid infection is more likely in some populations in the first place. “So, 1 in 5 may be an underestimate.”

What about different definitions?

CDC’s vs. WHO’s, for instance. The CDC defines long Covid, which it calls Post-Covid Conditions, as symptoms lasting four weeks after first infection. The World Health Organization starts the clock ticking after three months. Praschan said it makes sense to be inclusive, as in on the earlier side, while data are still being collected to avoid missing important information from these patients.

There may be differences in the data.

While some U.K. studies relied on records a national health system provides, others culled responses from a smartphone app asking people about their post-Covid symptoms. That limits the respondents to people who have smartphones and are also motivated to report how they are feeling.

The CDC report’s large numbers give power to the analysis, senior epidemiologist Lara Bull-Otterson told STAT. “While all studies have limitations, we believe the strengths of the data and the analysis are solid and are also supported by prior research,” she said. “Future research is always needed to support and expand on the findings of this study.”

Bruce Levy, chief of pulmonary and critical care medicine at Brigham and Women’s Hospital, doesn’t think the 20% estimate is rock solid, noting how studies have varied widely in the U.S. and in other parts of the world. “Even if it’s in single digits at the end of the day, once a formal case definition and a true prevalence study can be accomplished, it’s still a lot of people. But it’s very hard to pinpoint a solid number.”

If the size of the CDC study is impressive, the source of the data has limits, epidemiologist Priya Duggal of Johns Hopkins Bloomberg School of Public Health said. Patient records reflect only the people who sought care and whose symptoms were coded in their charts. Such data don’t include people who didn’t have access to health care, didn’t seek it, or gave up, thinking there was no help for their crazy quilt of symptoms.

“It doesn’t mean the data’s not right. It doesn’t mean that what we’re looking at isn’t important,” she told STAT. “It just means that that’s a different group of people that you might be looking at.”

Even with caveats, she finds the data pretty consistent for a range of 20% to 30% of people experiencing long Covid symptoms “It’s still a substantial number of people. To me, that’s the take-home point,” she said. “The second point is that it’s real.”

Long Covid is a constellation of diseases that manifest differently.

Symptoms linked to long Covid hit bodies from head to toe: brain fog, fatigue, shortness of breath, digestive problems, muscle weakness. The symptoms vary in severity and number, depending on the study. But most patients don’t necessarily have all of them. Some patients don’t have debilitating fatigue, but might report persistent digestive problems they didn’t have before getting Covid.

Some long Covid may be something else.

With long Covid so disparate and common, it’s possible that some doctors are misattributing symptoms to long Covid and missing the diagnosis of a different disease. Or, because lifesaving measures in intensive care units can be like a train wreck for the body, it’s hard to tease out the treatment from the disease.

Some long Covid is hidden to bystanders.

“Some of it is going to be visible like, oh, they’re weak, they’re sickly, they can’t walk, they can’t go upstairs,” Duggal said. “Then there’s also long Covid where you have kidney damage now, and the average person walking down the street doesn’t know that.”

She’s heard people say they don’t know anyone who has long Covid. “I’m like, you probably do.”

Long Covid isn’t all debilitating.

The CDC definitions capture thousands who fit the worst-case image of long Covid: formerly healthy people who can no longer function. But its prevalence estimate also includes anyone reporting at least one symptom, Bruce Walker, director of the Ragon Institute of Massachusetts General Hospital, MIT and Harvard, reminded reporters on a recent call. Estimates may also capture a worsening pre-Covid condition like asthma, an important consideration for the many people with underlying conditions before they caught Covid.

What’s next?

Bull-Otterson of the CDC urged routine screening for long Covid and better defining it so risk factors could be identified and treatments devised. The impact of vaccination and the wild card of variants also need to be understood.

Long Covid has the potential to widen existing gaps in health, Linda Sprague Martinez of the Boston University School of Social Work said on a video call with reporters, pointing to a map of counties with high case numbers but few long Covid clinics. “We don’t want to wait,” she said. “Getting ahead of it will be really important for us,” she said.

OK, what can we say now?

Estimates of long Covid will certainly evolve, and perhaps be refined into the systems they affect: cardiopulmonary, digestive, musculoskeletal, or neurological, including autonomic powers that control breathing, heart rate, and other unconscious functions. If, as experts say, there is an inevitability to catching Covid now, or catching it again, long Covid will likely follow in some proportion of cases, disabling some further fraction of those people. Recent studies suggest that Covid infections precede the risk of certain other chronic diseases like type 2 diabetes, but the mechanism isn’t clear. Even if the world wasn’t ready for one pandemic, it has to deal with its aftereffects somehow.

“We see people still two years out having long-term symptoms, so if that’s true and people can continue to get infected, this is going to be with us for quite a while,” Duggal said.

Americans Reflect on Nation’s COVID-19 Response

Priorities Are Misguided

Authors: BY CARY FUNKALEC TYSONGIANCARLO PASQUINI AND ALISON SPENCER July 7, 2022 Pew Research

As levels of public concern over the coronavirus outbreak recede, Americans offer a lackluster evaluation of how the country has balanced priorities during the outbreak. A majority of U.S. adults say the country has given too little priority to meeting the educational needs of K-12 students since the outbreak first took hold in February 2020. Assessments of the nation’s response across other domains are little better: Fewer than half of Americans say the country has done about the right amount to support quality of life and economic activity or to protect public health.

When asked to take stock of what measures have worked to limit the spread of the coronavirus, the public is conflicted. Vaccines and masks rank at the top of the list of effective steps; but even for these public health tools, sizable shares of Americans describe them as no more than somewhat effective at limiting the spread of the coronavirus.

A Pew Research Center survey of 10,282 U.S. adults conducted from May 2 to 8, 2022, finds 62% of Americans say the country has given too little priority to meeting the educational needs of K-12 students during its response to the coronavirus outbreak; far fewer (31%) say this has received about the right amount of priority since the outbreak first began in February of 2020 (just 6% say it’s received too much priority).

On balance, larger shares of Americans also say too little priority – rather than the right amount – has been given to supporting the public’s overall quality of life, supporting businesses and economic activity, and respecting individuals’ choices.

When it comes to the central goal of protecting public health, Americans have decidedly mixed views: 43% say the country has given about the right amount of priority to protecting public health, while 34% say this has received too little priority and 21% say it has received too much.

The overall findings reflect two competing critiques of the nation’s response. One, widely expressed among Republicans, is that the country has not focused enough on business concerns and respecting individual choices. The other, more widely held by Democrats, centers concern around efforts to protect public health and limit health risks for vulnerable populations.

In short, neither Republicans nor Democrats think the country has hit the mark in its response to the outbreak – one that has spanned the presidential administrations of both Donald Trump and Joe Biden.

Among Democrats and Democratic-leaning independents, larger shares say protecting public health has received too little priority than say it has received too much (46% vs. 7%), while 46% say it has gotten about the right amount of priority. Republicans and Republican leaners offer a very different assessment: More say public health has received too much priority (40%) than say it’s been given too little (20%), while 38% say it’s gotten about the right amount of priority.

Majorities of Republicans say the country has done too little during the outbreak when it comes to respecting individuals’ choices (69%) and supporting businesses and economic activity (62%). Relatively small shares of Democrats express these views. In fact, half of Democrats say there has been about the right amount of attention given to supporting businesses and economic activity. And Democrats are roughly as likely to say too much priority has been given to respecting individuals’ choices as to say too little (33% and 28%, respectively). See the Appendix for more details on this question.

Amid these contrasting views of the nation’s response to the coronavirus outbreak stands a notable point of general partisan agreement: Majorities of both Republicans (69%) and Democrats (57%) say the country has given too little priority to meeting the educational needs of K-12 students. A January survey by the Center found a majority of parents of K-12 students expressed concern about academic progress when it came to decisions about whether to keep schools open for in-person instruction.

Over the past two years, public health and elected officials have invested extensively in communicating ways to limit the spread of the coronavirus. For Americans, vaccines rank at the top of the list of what they believe has worked, followed by mask-wearing and limiting interactions with other people. Still, not all Americans see these measures as particularly effective.

For instance, a narrow majority (55%) says vaccination against COVID-19 has been extremely or very effective at limiting the spread of the coronavirus; 22% say this has been somewhat effective and 23% say it has been not too or not at all effective.

About half say wearing masks around people indoors (48%) and limiting activities and interactions with other people (47%) have been extremely or very effective at limiting the spread of the coronavirus. The remainder of Americans describe these two steps as no more than somewhat effective.

The partisan gaps over the effectiveness of these interventions are about as wide as any seen in the survey. For instance, 75% of Democrats say COVID-19 vaccines have been extremely or very effective at limiting the spread of the coronavirus; 16% say they have been somewhat effective and just 9% describe them as not too or not at all effective.

Republicans offer a much more skeptical view: A slightly larger share of Republicans say vaccines have been not too or not at all effective at limiting the spread of the coronavirus than say they have been extremely or very effective (39% vs. 32%); 29% fall between these two views and say vaccines have been somewhat effective.

Asked to assess where the country stands at this stage of the outbreak, about three-quarters of Americans (76%) say the worst of the country’s problems from the coronavirus are behind us. And declining shares express deep personal concern about getting the coronavirus themselves.

But while the intensity of public concern about the coronavirus outbreak has waned, cases in the U.S. remain stubbornly high and 86% of Americans say the outbreak remains at least a minor threat to the health of the U.S. population.

To date, over a million Americans have died from COVID-19. Firsthand connections to people who have experienced serious cases of COVID-19 are common among the public: 81% of U.S. adults – including 88% of Black and 86% of Hispanic adults – say they know someone personally who has been hospitalized or died from the coronavirus. See the Appendix for more details.

Ratings of Biden’s, public officials’ response to the coronavirus outbreak

Four months ahead of the November midterm elections, President Joe Biden’s standing on the issue of the coronavirus outbreak has diminished. A majority of adults (56%) say he is doing an only fair or poor job responding to the outbreak, compared with 43% who say he is doing an excellent or good job.

In October of 2020, Biden held a clear advantage over Donald Trump as the candidate voters saw as better able to handle the public health impact of the outbreak – among the issues voters identified as most important to the election. And at the start of Biden’s term, 65% of Americans said they were confident in his ability to deal with the outbreak.

Biden is not the only official, or set of officials, to see their ratings fall over the course of the outbreak. Ratings for state and local elected officials as well as for public health officials – such as those at the Centers for Disease Control and Prevention – are all lower today than at early stages of the outbreak, though they are about the same as they were in January of this year.

Ratings for the performance of local hospitals and medical centers stand well above those of other groups. Eight-in-ten Americans say hospitals and medical centers in their area are doing an excellent or good job responding to the coronavirus outbreak – far higher than ratings of all other groups and individuals included in the survey. The gap between ratings for local hospitals and medical centers and those for other groups, including public health and state and local officials, is much wider today than at early stages of the outbreak.

Ratings of public health officials are an example of intensifying partisan differences that have formed over the course of the outbreak. Democrats and those who lean to the Democratic Party are far more likely than Republicans and GOP leaners (72% vs. 29%) to say public health officials, such as those at the CDC, have done an excellent or good job responding to the coronavirus outbreak. In the early stages of the outbreak, majorities of both Republicans and Democrats gave public health officials positive ratings.

While the overall decline in ratings for public health officials has been driven by sharply lower assessments among Republicans, the declines in ratings for state and local elected officials have occurred among both Republicans and Democrats.

National preparedness for a future global health emergency

Asked to consider preparedness for a future global health emergency, 59% of Americans say they have either a great deal (15%) or some confidence (44%) in the U.S. health care system to handle a future global health emergency. Four-in-ten say they have not too much or no confidence at all in the U.S. health care system to handle a future global health emergency.

Overall views are similar to those measured in February of 2021, when 55% of Americans said they had at least some confidence in the health care system to handle a future global health emergency.

However, views among partisans have changed considerably over the last year. Democrats are now significantly more likely than Republicans to say they have a great deal of or some confidence in the health care system to handle a future emergency (67% vs. 51%). In February 2021, during the final days of the Trump administration, Republicans (57%) were about as likely as Democrats (54%) to express this level of confidence in the preparedness of the U.S. health care system.

Attitudes also differ on this question by vaccination status. A majority of adults (67%) who have received at least one dose of a COVID-19 vaccine say they have a great deal of or some confidence in the health care system to handle a future emergency, compared with just 34% of those who have not received a vaccine. Republicans and Democrats who have received a vaccine are each more likely to express confidence in the health care system than unvaccinated members of their respective parties.

Overall, 55% of Americans say vaccination against COVID-19 has been extremely (33%) or very (22%) effective at limiting the spread of the coronavirus; 22% say vaccines have been somewhat effective and 23% say they have been not too or not at all effective.

About half of Americans (48%) say wearing masks around other people indoors has been extremely or very effective at limiting the spread of the coronavirus. A similar share (47%) say limiting activities and interactions with other people has been extremely or very effective. Still, for both measures, roughly as many Americans describe these actions as no more than somewhat effective at limiting the spread of the coronavirus.

The wide availability of rapid COVID-19 tests is seen as very or extremely effective at limiting the spread of the coronavirus by 43% of the public. Relatively fewer (35%) say staying six feet apart from other people indoors has been extremely or very effective at limiting the spread of the coronavirus.

Democrats are much more likely than Republicans to view all five measures as extremely or very effective at limiting the spread of the coronavirus. For instance, 71% of Democrats say wearing masks around other people indoors is extremely or very effective at limiting the spread of the coronavirus; a considerably smaller share of Republicans (21%) say the same.

Across the five public health tools asked about in the survey, wide differences in views are also seen between adults that have received at least one dose of a COVID-19 vaccine and those that have not been vaccinated. Among respondents that have received at least one dose of a vaccine, a majority views several of these measures – vaccines, wearing masks and limiting social interactions – as extremely or very effective at limiting the spread of the coronavirus. Among the much smaller share of Americans who have not been vaccinated, no more than two-in-ten say any of these five measures are extremely or very effective.

A majority of Americans think treatments and drugs for those with the coronavirus have gotten a lot (46%) or a little (33%) better since the early stages of the outbreak. The share who say they have gotten a lot better is up 9 points from 37% in November of 2020, when this question was last asked.

Democrats and Democratic leaners are now more likely than Republicans and Republican leaners to say the effectiveness of treatments for the coronavirus has gotten a lot better (57% vs. 35%) since the early stages of the outbreak.

Democrats’ views about the improvement of medical treatments for COVID-19 have become more positive since November 2020, during the last months of the Trump administration. By contrast, Republicans are less likely today to say medical treatments have improved over the course of the outbreak than they were in November 2020.

Overall, 73% of U.S. adults say they are fully vaccinated for coronavirus as of May 2022. This share is the same as it was in a January 2022 Pew Research Center survey. According to the Centers for Disease Control and Prevention (CDC), “fully vaccinated” means having received two doses of Pfizer or Moderna vaccines or one dose of the Johnson & Johnson.

A relatively small share of U.S. adults say they have received one dose of a vaccine but need one more (5%); 21% say they have not received a vaccine for COVID-19. Both shares are virtually unchanged from January 2022.

Republicans and Republican-leaning independents (60%) continue to be less likely than Democrats and Democratic leaners (85%) to say they are fully vaccinated.

Older adults also continue to be more likely than younger adults to say they are fully vaccinated, a pattern that holds true within each party.

As in the past, those who live in urban or suburban communities (76% each) are more likely than those living in rural areas (64%) to say they are fully vaccinated.

When it comes to booster shots, about half (49%) of the public say they are fully vaccinated and have received a booster shot within the past six months. The share is about the same as it was in January 2022.

Differences by partisanship persist in both the shares who say they are fully vaccinated and in the shares who say they’ve received a booster shot among fully vaccinated adults. A narrow majority of fully vaccinated Republicans (56%) have received a booster shot. This group makes up 34% of all Republicans. Meanwhile, a larger majority (75%) of fully vaccinated Democrats – or 64% of all Democrats – say they have received a booster shot.

Among both partisan groups, younger adults who are fully vaccinated remain less likely than older adults who are fully vaccinated to say they have received a COVID-19 booster shot.

With vaccination rates among U.S. adults leveling off in recent months, differences across groups in the country have crystalized.

Looking across a wide range of characteristics associated with the decision to get a vaccine, some of those most likely to be fully vaccinated in the U.S. include those with a postgraduate degree, those in higher-income households with health insurance, and Americans ages 65 and older.

At the other end of the spectrum, those relatively less likely to be fully vaccinated include White evangelical Protestants, adults younger than 50 living in rural areas, and those without health insurance. See the Appendix for more details about vaccination rates across groups.

When it comes to personal experiences with the coronavirus, 46% of U.S. adults say they have tested positive for COVID-19 or been pretty sure they have had it.

The share of Americans who say they have had COVID-19 has risen since August 2021, when three-in-ten (30%) said this.

Across age groups, younger adults are more likely than older adults to say they have tested positive for COVID-19 or been pretty sure they had it. A majority (59%) of adults ages 18 to 29 say this, compared with 26% of adults 65 and older.

Those who are fully vaccinated (42%) are less likely to say they have had COVID-19 than those who are not vaccinated (61%). (The survey did not ask respondents whether they got COVID-19 before or after being vaccinated.)

Among those who are fully vaccinated, younger adults are more likely than older adults to say they have had COVID-19.

When vaccination status and exposure to COVID-19 are taken together, 90% of Americans report some level of immune response to COVID-19 (78% have received at least one dose of a vaccine and an additional 12% are not vaccinated but say they’ve had the coronavirus). Public health experts are continuing to evaluate how long immunity from vaccination or previous infection last as coronavirus variants evolve.

The CDC recommends the use of at-home coronavirus tests as one way for Americans to help reduce the spread of COVID-19.

About four-in-ten U.S. adults (39%) say they have taken an at-home COVID-19 test in the past six months.

Across age groups, younger adults are more likely to say that they have taken an at-home coronavirus test in the past six months. Around half (52%) of adults ages 18 to 29 say this, compared with 27% of those 65 and older.

Upper-income adults (48%) are more likely than middle-income (39%) or lower-income (36%) adults to say that they have taken an at-home COVID-19 test in the past six months.

When the 39% of Americans who have taken an at-home COVID-19 test in the past six months were asked about their reasons for doing so, a majority of this group (63%) say that a reason was that they were experiencing coronavirus symptoms.

Around four-in-ten or more say that a reason they had taken an at-home COVID-19 test was that they had contact with someone who tested positive (47%) or wanted to take one before attending a gathering with other people (41%).

About a quarter (24%) say that a reason they have taken an at-home COVID-19 test was that they were required to do so before an event.

For each of the possible reasons listed for taking a COVID-19 test, younger adults are generally more likely than older adults to say that each had been a factor. For example, 57% of adults ages 18 to 29 say that having contact with someone who tested positive for COVID-19 was a reason they had done an at-home test, compared with 37% of adults 65 and older.

About a third of Americans (34%) say they are at least somewhat concerned that they will get COVID-19 and require hospitalization, a much smaller share than said this at earlier stages of the outbreak.

Half of Americans say they are at least somewhat concerned that they might unknowingly spread COVID-19 to others. This share has declined steadily since November 2020, when about two-thirds (64%) of U.S. adults said this.

Consistent with these declines, Americans are also less likely to see the coronavirus outbreak as a major threat to their personal health than at earlier stages of the outbreak. About a quarter (23%) now say this, down from 30% in January 2022. See the Appendix for more details.

Understanding COVID-19 through genome-wide association studies

Authors: Tom H. Karlsen  Nature Genetics volume 54, pages368–369 (2022)Cite this article

8742 Accesses 1 Citations 87 Altmetric

Defining the most appropriate phenotypes in genome-wide association studies of COVID-19 is challenging, and two new publications demonstrate how case-control definitions critically determine outcomes and downstream clinical utility of findings.

Exploring self-reported data from more than 700,000 participants in a direct-to-consumer ancestry genetics company, in this issue of Nature Genetics, Roberts et al. report how several commonly used phenotype definitions in COVID-19 genetics studies converge to represent either susceptibility to infection by the SARS-CoV-2 virus or risk of severe COVID-19 disease1. For pragmatic reasons, early genome-wide association studies (GWAS) in COVID-19 focused on hospitalized cases compared with unscreened and often previously genotyped controls2,3. While allowing for rapid assessments during the first and very challenging wave of the pandemic, such study designs are biased towards the biology of complications in COVID-19. The emphasis on patients with mild or no symptoms, including identification of household COVID-19 exposure as a high-risk measure, allowed the authors to conduct a deep investigation of susceptibility to SARS-CoV-2 infection through comparisons such as exposed individuals who tested positive for COVID-19 versus exposed individuals who tested negative. Not only did these assessments corroborate the controversial ABO locus as a bona fide susceptibility gene for SARS-CoV-2 infection2,4, they also suggested the presence of a hitherto unexplored pool of protective variants.

In a dedicated query of rare variants (minor allele frequency (MAF) < 0.005), also reported in this issue of Nature Genetics, Horowitz et al. identified an association signal between a non-coding X chromosome variant (rs190509934) upstream of angiotensin-converting enzyme 2 (ACE2) and protection against SARS-CoV-2 infection5. The authors go on to substantiate their finding using RNA sequencing – data from liver tissue, showing that the protective allele leads to an almost 40% reduction in ACE2 expression levels in carriers. The association inherently holds considerable plausibility, with the membrane-bound ACE2 serving as the binding site for the SARS-CoV-2 spike glycoprotein, initiating virus cell entry6. Furthermore, Horowitz et al.5 and Roberts et al.1 utilize rich phenotype data to dissect the chromosome 3p21.31 association into a susceptibility signal and a severity signal, which localize to SLC6A20 and LZTFL1, respectively, as also observed by others7SLC6A20 encodes the sodium–imino-acid (proline) transporter 1 (SIT1), which functionally interacts with ACE2 (ref. 8), and the risk allele has been shown to associate with increased expression of SLC6A20 (ref. 2). Along with data suggesting that the receptor-binding domain of the SARS-CoV-2 spike protein preferentially interacts with blood group A9, which is encoded by the risk variant at the ABO locus, genetics of the susceptibility to SARS-CoV-2 infection appear to converge on the cell entry apparatus for the virus.

Critical illness in COVID-19 develops in fewer than 10% of individuals infected with SARS-CoV-2 (ref. 10). Given the window from the first symptoms of COVID-19 to onset of severe disease with respiratory failure (typically about one week)10, prediction of a severe disease course following SARS-CoV-2 infection is of considerable clinical interest as well as from a therapeutic point of view. Reliable risk stratification may guide therapeutic interventions during this lead-in period, characterized by enhanced viral replication. These interventions potentially include antiviral therapies, convalescent plasma, neutralizing monoclonal antibodies or — possibly more important for hospitalized patients — immunomodulating drugs.

Horowitz et al. found that a high genetic risk score (top 10%) based on six established severity variants was associated with a 1.65-fold and 1.75-fold higher risk of severe disease, in individuals with or without the presence of clinical risk factors such as age and diabetes, respectively5. Others have found an odds ratio of 2.0 for the impact of the rs10490770 risk allele at the 3p21.31 locus on the combined end-point of death or severe respiratory failure in an overall COVID-19 patient population11, with almost double the effect size in individuals 60 years or younger (odds ratio of 3.5). These magnitudes are comparable with those associated with clinical risk factors. Findings of lower age in individuals homozygous for the chromosome 3p21.31 risk variant support enhanced utility of genetic risk stratification in the young patient population2.

The execution of GWAS in COVID-19 has been remarkably nimble, due in part to robust collaborative networks set up during past GWAS12, as well as the utilization of previously genotyped study populations such as the UK Biobank, AncestryDNA and 23andme1,3,4,5. The rapid phenotyping undertaken by several biobanks and direct-to-consumer genetics companies during the COVID-19 pandemic is unprecedented, and the resulting publications deserve acknowledgement as a form of ‘population-level testing’ for genetic clues in emerging diseases. The orchestration of projects by the COVID-19 Host Genetics Initiative has also been an important catalyzer of activities13. Figure 1 summarizes published and peer-reviewed GWAS articles on COVID-19. However, even at time of writing, the meta-analysis of the sixth data freeze of the COVID-19 Host Genetics Initiative has been released online, reporting on a total of 23 loci involving in COVID-19 susceptibility (7 loci) and severity (15 loci); adding 10 new loci to the consortium’s own publication only 3 months ago7. The 22-month period that has passed since the publication of the first COVID-19 GWAS2 appears even more impressive in comparison with the 7 years of Crohn’s disease genetics — spanning from the 2001 nucleotide-binding oligomerization domain 2 (NOD2) susceptibility gene discovery to a 2008 meta-analysis14,15 — that it took to achieve the same amount of insight. Further exemplified by the 20-year history of genetics of Crohn’s disease, translational studies of GWAS findings take time, but may reveal new and unexpected aspects of pathophysiology. It is in this context that the rapid unravelling of COVID-19 genetics becomes important. Some of the loci hold immediate biological plausibility (for example, ACE2 and some of the chemokines), whereas the underlying mechanisms of others remain obscure. Following this recent sprint of COVID-19 GWAS to which Horowitz et al.5 and Roberts et al.1 significantly contribute, the subsequent translational ultramarathon of biological studies can begin — and with this a deeper understanding of the pathophysiology of SARS-CoV-2 infection and its complications will emerge. Vaccination has proven the ultimate protection against SARS-CoV-2 infection. The hope is that the biological insights provided by COVID-19 GWAS will facilitate identification and development of novel treatment options of not only hospitalized and critically ill COVID-19 patients, but also treatment modalities that can prevent hospitalization.

figure 1
Fig. 1: Genetic loci from COVID-19 GWAS in peer-reviewed publications to date.

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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.

About 30 percent of COVID patients develop ‘Long COVID,’ research finds

Authors: April 19, 2022Source:University of California – Los Angeles Health Sciences

New UCLA research finds that 30% of people treated for COVID-19 developed Post Acute Sequelae of COVID-19 (PASC), most commonly known as “Long COVID.” People with a history of hospitalization, diabetes, and higher body mass index were most likely to develop the condition, while those covered by Medicaid, as opposed to commercial health insurance, or had undergone an organ transplant were less likely to develop it. Surprisingly, ethnicity, older age, and socioeconomic status were not associated with the syndrome even though those characteristics have been linked with severe illness and greater risk of death from COVID-19.