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      Post–COVID Conditions Among Adult COVID-19 Survivors Aged 18–64 and ≥65 Years — United States, March 2020–November 2021

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          Abstract

          A growing number of persons previously infected with SARS-CoV-2, the virus that causes COVID-19, have reported persistent symptoms, or the onset of long-term symptoms, ≥4 weeks after acute COVID-19; these symptoms are commonly referred to as post-COVID conditions, or long COVID ( 1 ). Electronic health record (EHR) data during March 2020–November 2021, for persons in the United States aged ≥18 years were used to assess the incidence of 26 conditions often attributable to post-COVID (hereafter also referred to as incident conditions) among patients who had received a previous COVID-19 diagnosis (case-patients) compared with the incidence among matched patients without evidence of COVID-19 in the EHR (control patients). The analysis was stratified by two age groups (persons aged 18–64 and ≥65 years). Patients were followed for 30–365 days after the index encounter until one or more incident conditions were observed or through October 31, 2021 (whichever occurred first). Among all patients aged ≥18 years, 38% of case-patients experienced an incident condition compared with 16% of controls; conditions affected multiple systems, and included cardiovascular, pulmonary, hematologic, renal, endocrine, gastrointestinal, musculoskeletal, neurologic, and psychiatric signs and symptoms. By age group, the highest risk ratios (RRs) were for acute pulmonary embolism (RR = 2.1 and 2.2 among persons aged 18–64 and ≥65 years, respectively) and respiratory signs and symptoms (RR = 2.1 in both age groups). Among those aged 18–64 years, 35.4% of case-patients experienced an incident condition compared with 14.6% of controls. Among those aged ≥65 years, 45.4% of case-patients experienced an incident condition compared with 18.5% of controls. These findings translate to one in five COVID-19 survivors aged 18–64 years, and one in four survivors aged ≥65 years experiencing an incident condition that might be attributable to previous COVID-19. Implementation of COVID-19 prevention strategies, as well as routine assessment for post-COVID conditions among persons who survive COVID-19, is critical to reducing the incidence and impact of post-COVID, particularly among adults aged ≥65 years ( 2 ). A retrospective matched cohort design was used to analyze EHRs during March 2020–November 2021, from Cerner Real-World Data,* a national, deidentified data set of approximately 63.4 million unique adult records from 110 data contributors in the 50 states. Case-patients (353,164) were adults aged ≥18 years who received either a diagnosis of COVID-19 or a positive SARS-CoV-2 test result † (case-patient index encounter) in an inpatient, emergency department, or outpatient settings within a subset of health care facilities that use Cerner EHRs. Control patients (1,640,776) had a visit in the same month as the matched case-patient (control index encounter) and did not receive a COVID-19 diagnosis or a positive SARS-CoV-2 test result during the observation period. Controls were matched 5:1 with case-patients. All patients included in the analysis were required to have at least one encounter in their EHR during the year preceding and the year after the index encounter. The occurrence of 26 clinical conditions previously attributed to post-COVID illness was assessed by review of the scientific literature § ( 3 – 5 ) (Supplementary Table 1, https://stacks.cdc.gov/view/cdc/117411). Patients were followed for 30–365 days after the index encounter until the first occurrence of an incident condition or until October 31, 2021, whichever occurred first. Case-patients or control patients with a previous history of one of the included conditions in the year before the index encounter were excluded (478,072 patients). The analysis was stratified by age into two groups: adults aged 18–64 and adults aged ≥65 years. Incidence rates per 100 person-months, and RRs with 95% CIs, were calculated. The number of COVID-19 case-patients having experienced an incident condition was also estimated by age group. ¶ Nonoverlapping CIs between age groups were considered statistically significant. Analyses were performed using RStudio Workbench (version 3.0; RStudio). This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.** Among all patients aged ≥18 years, 38.2% of case-patients and 16.0% of controls experienced at least one incident condition (Table). Among persons aged 18–64 years, 35.4% of case-patients and 14.6% of controls experienced at least one incident condition. Among persons aged ≥65 years, 45.4% of case-patients and 18.5% of controls experienced at least one incident condition. The absolute risk difference between the percentage of case-patients and controls who developed an incident condition was 20.8 percentage points for those aged 18–64 years and 26.9 percentage points for those aged ≥65 years. This finding translates to one in five COVID-19 survivors aged 18–64 years and one in four survivors aged ≥65 years experiencing an incident condition that might be attributable to previous COVID-19. TABLE Percentage of adult COVID-19 case-patients and control patients with ≥1 post-COVID–attributable incident conditions and estimated number of COVID-19 survivors who will experience a post-COVID condition — United States, March 2020–November 2021 Age group, yrs No. of patients (column %) No. of patients with ≥1 incident condition
(column %*) Absolute risk difference† No. of COVID-19 survivors with a post-COVID condition§ Case-patients Control patients Case-patients Control patients 18–64 254,345 (72.0) 1,051,588 (64.1) 90,111 (35.4) 154,011 (14.6) 20.8 1/5 ≥65 98,819 (28.0) 589,188 (35.9) 44,840 (45.4) 108,850 (18.5) 26.9 1/4 Total 353,164 (100) 1,640,776 (100) 134,951 (38.2) 262,861 (16.0) 22.2 1/4–5 * Percentage of COVID-19 case-patients or control patients with ≥1 incident condition divided by the total study COVID-19 cohort or control cohort row’s age group total. † Percentage point difference between COVID-19 case-patients and control patients (e.g., the value 20.8 is calculated as 35.4 minus 14.6). § Number of COVID-19 survivors who experienced a post-COVID condition estimated as the inverse of the absolute risk difference. The most common incident conditions in both age groups were respiratory symptoms and musculoskeletal pain (Supplementary Table 2, https://stacks.cdc.gov/view/cdc/117411). Among both age groups, the highest RRs were for incident conditions involving the pulmonary system, including acute pulmonary embolism (RR = 2.2 [patients aged ≥65 years] and 2.1 [patients aged 18–64 years]) and respiratory symptoms (RR = 2.1, both age groups) (Figure). Among patients aged ≥65 years, the risks were higher among case-patients than among controls for all 26 incident conditions, with RRs ranging from 1.2 (substance-related disorder) to 2.2 (acute pulmonary embolism). Among patients aged 18–64 years, the risks were higher among case-patients than among controls for 22 incident conditions, with RRs ranging from 1.1 (anxiety) to 2.1 (acute pulmonary embolism); no significant difference was observed for cerebrovascular disease, or mental health conditions, such as mood disorders, other mental conditions, and substance-related disorders. FIGURE Risk ratios* for developing post-COVID conditions among adults aged 18–64 years and ≥65 years — United States, March 2020– November 2021 Abbreviation: GI = gastrointestinal. * With CIs indicated by error bars; some error bars are not visible because of small CIs. The figure is a forest plot showing the risk ratios for developing post-COVID-19 conditions among adults aged 18–64 years and ≥65 years, by condition in the United States during March 2020– November 2021. Differences by age group were noted. The RR for cardiac dysrhythmia was significantly higher among patients aged 18–64 years (RR = 1.7) compared with those aged ≥65 years (1.5). Similarly, the RR for musculoskeletal pain was higher among patients aged 18–64 years (1.6) than among those aged ≥65 years (1.4). Among case-patients, the RRs for 10 incident conditions was significantly higher among those aged ≥65 years than among those aged 18–64 years; these conditions were renal failure, thromboembolic events, cerebrovascular disease, type 2 diabetes, muscle disorders, neurologic conditions, and mental health conditions (including mood disorders, anxiety, other mental conditions, and substance-related disorders). Discussion The findings from this analysis of a large EHR-based database of U.S. adults indicated that COVID-19 survivors were significantly more likely than were control patients to have incident conditions that might be attributable to previous COVID-19. One in five COVID-19 survivors aged 18–64 years and one in four survivors aged ≥65 years experienced at least one incident condition that might be attributable to previous COVID-19. Independent of age group, the highest RRs were for acute pulmonary embolism and respiratory symptoms. These findings are consistent with those from several large studies that indicated that post-COVID incident conditions occur in 20%–30% of patients ( 6 , 7 ), and that a proportion of patients require expanded follow-up care after the initial infection. COVID-19 severity and illness duration can affect patients’ health care needs and economic well-being ( 8 ). The occurrence of incident conditions following infection might also affect a patient’s ability to contribute to the workforce and might have economic consequences for survivors and their dependents, particularly among adults aged 18–64 years ( 5 ). In addition, care requirements might place a strain on health services after acute illness in communities that experience heavy COVID-19 case surges. COVID-19 survivors aged ≥65 years in this study were at increased risk for neurologic conditions, as well as for four of five mental health conditions (mood disorders, other mental conditions, anxiety, and substance-related disorders). Neurocognitive symptoms have been reported to persist for up to 1 year after acute infection and might persist longer ( 9 ). Overall, 45.4% of survivors aged ≥65 years in this study had incident conditions. Among adults aged ≥65 years, who are already at higher risk for stroke and neurocognitive impairment, post-COVID conditions affecting the nervous system are of particular concern because these conditions can lead to early entry into supportive services or investment of additional resources into care ( 10 ). The findings in this study are subject to at least five limitations. First, patient data were limited to those seen at facilities serviced by Cerner EHR network during January 2020–November 2021; therefore, the findings might not be representative of the entire U.S. adult population or of COVID-19 case patients infected with recent variants. Second, the incidence of new conditions after an acute COVID-19 infection might be biased toward a population that is seeking care, either as a follow-up to a previous complaint (including COVID-19) or for another medical complaint, which might result in a “sicker” control group leading to underestimation of observed risk. Third, COVID-19 vaccination status was not considered in this analysis, nor were potentially confounding factors (e.g., SARS-CoV-2 variant, sex, race, ethnicity, health care entity, or geographic region), because data were not available, were inconsistent, or included a high proportion of missing or unknown values; for example, data were not matched by data contributors, so controls were not necessarily from the same health care entity or region of the country. Differences between the groups might influence the risks associated with survival from COVID-19 and incident conditions, which require further study. Fourth, International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM) codes were used to identify COVID-19 case-patients, and misclassification of controls is possible. However, the inclusion of laboratory data to identify case-patients and exclude controls helped to limit the potential for such misclassification. Finally, the study only assessed conditions thought to be attributable to COVID-19 or post-COVID illness, which might have biased RRs away from the null. For example, clinicians might have been more likely to document possible post-COVID conditions among case-patients. In addition, because several conditions examined are also risk factors for moderate to severe COVID-19, it is possible that case-patients were more likely to have had an existing condition that was not documented in their EHR during the year preceding their COVID-19 diagnosis, resulting in overestimated risk for this group. As the cumulative number of persons ever having been infected with SARS-CoV-2 increases, the number of survivors suffering post-COVID conditions is also likely to increase. Therefore, implementation of COVID-19 prevention strategies, as well as routine assessment for post-COVID conditions among persons who survive COVID-19, is critical to reducing the incidence and impact of post-COVID conditions, particularly among adults aged ≥65 years ( 2 ). These findings can increase awareness for post-COVID conditions and improve post-acute care and management of patients after illness. Further investigation is warranted to understand the pathophysiologic mechanisms associated with increased risk for post-COVID conditions, including by age and type of condition. Summary What is already known about this topic? As more persons are exposed to and infected by SARS-CoV-2, reports of patients who experience persistent symptoms or organ dysfunction after acute COVID-19 and develop post-COVID conditions have increased. What is added by this report? COVID-19 survivors have twice the risk for developing pulmonary embolism or respiratory conditions; one in five COVID-19 survivors aged 18–64 years and one in four survivors aged ≥65 years experienced at least one incident condition that might be attributable to previous COVID-19. What are the implications for public health practice? Implementation of COVID-19 prevention strategies, as well as routine assessment for post-COVID conditions among persons who survive COVID-19, is critical to reducing the incidence and impact of post-COVID conditions, particularly among adults aged ≥65 years.

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          Why does COVID-19 disproportionately affect older people?

          The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient’s age. Adults over 65 years of age represent 80% of hospitalizations and have a 23-fold greater risk of death than those under 65. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea, and from there the disease can progress to acute respiratory distress syndrome, lung consolidation, cytokine release syndrome, endotheliitis, coagulopathy, multiple organ failure and death. Comorbidities such as cardiovascular disease, diabetes and obesity increase the chances of fatal disease, but they alone do not explain why age is an independent risk factor. Here, we present the molecular differences between young, middle-aged and older people that may explain why COVID-19 is a mild illness in some but life-threatening in others. We also discuss several biological age clocks that could be used in conjunction with genetic tests to identify both the mechanisms of the disease and individuals most at risk. Finally, based on these mechanisms, we discuss treatments that could increase the survival of older people, not simply by inhibiting the virus, but by restoring patients’ ability to clear the infection and effectively regulate immune responses.
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            Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study

            Background COVID-19 vaccines show excellent efficacy in clinical trials and effectiveness in real-world data, but some people still become infected with SARS-CoV-2 after vaccination. This study aimed to identify risk factors for post-vaccination SARS-CoV-2 infection and describe the characteristics of post-vaccination illness. Methods This prospective, community-based, nested, case-control study used self-reported data (eg, on demographics, geographical location, health risk factors, and COVID-19 test results, symptoms, and vaccinations) from UK-based, adult (≥18 years) users of the COVID Symptom Study mobile phone app. For the risk factor analysis, cases had received a first or second dose of a COVID-19 vaccine between Dec 8, 2020, and July 4, 2021; had either a positive COVID-19 test at least 14 days after their first vaccination (but before their second; cases 1) or a positive test at least 7 days after their second vaccination (cases 2); and had no positive test before vaccination. Two control groups were selected (who also had not tested positive for SARS-CoV-2 before vaccination): users reporting a negative test at least 14 days after their first vaccination but before their second (controls 1) and users reporting a negative test at least 7 days after their second vaccination (controls 2). Controls 1 and controls 2 were matched (1:1) with cases 1 and cases 2, respectively, by the date of the post-vaccination test, health-care worker status, and sex. In the disease profile analysis, we sub-selected participants from cases 1 and cases 2 who had used the app for at least 14 consecutive days after testing positive for SARS-CoV-2 (cases 3 and cases 4, respectively). Controls 3 and controls 4 were unvaccinated participants reporting a positive SARS-CoV-2 test who had used the app for at least 14 consecutive days after the test, and were matched (1:1) with cases 3 and 4, respectively, by the date of the positive test, health-care worker status, sex, body-mass index (BMI), and age. We used univariate logistic regression models (adjusted for age, BMI, and sex) to analyse the associations between risk factors and post-vaccination infection, and the associations of individual symptoms, overall disease duration, and disease severity with vaccination status. Findings Between Dec 8, 2020, and July 4, 2021, 1 240 009 COVID Symptom Study app users reported a first vaccine dose, of whom 6030 (0·5%) subsequently tested positive for SARS-CoV-2 (cases 1), and 971 504 reported a second dose, of whom 2370 (0·2%) subsequently tested positive for SARS-CoV-2 (cases 2). In the risk factor analysis, frailty was associated with post-vaccination infection in older adults (≥60 years) after their first vaccine dose (odds ratio [OR] 1·93, 95% CI 1·50–2·48; p<0·0001), and individuals living in highly deprived areas had increased odds of post-vaccination infection following their first vaccine dose (OR 1·11, 95% CI 1·01–1·23; p=0·039). Individuals without obesity (BMI <30 kg/m 2 ) had lower odds of infection following their first vaccine dose (OR 0·84, 95% CI 0·75–0·94; p=0·0030). For the disease profile analysis, 3825 users from cases 1 were included in cases 3 and 906 users from cases 2 were included in cases 4. Vaccination (compared with no vaccination) was associated with reduced odds of hospitalisation or having more than five symptoms in the first week of illness following the first or second dose, and long-duration (≥28 days) symptoms following the second dose. Almost all symptoms were reported less frequently in infected vaccinated individuals than in infected unvaccinated individuals, and vaccinated participants were more likely to be completely asymptomatic, especially if they were 60 years or older. Interpretation To minimise SARS-CoV-2 infection, at-risk populations must be targeted in efforts to boost vaccine effectiveness and infection control measures. Our findings might support caution around relaxing physical distancing and other personal protective measures in the post-vaccination era, particularly around frail older adults and individuals living in more deprived areas, even if these individuals are vaccinated, and might have implications for strategies such as booster vaccinations. Funding ZOE, the UK Government Department of Health and Social Care, the Wellcome Trust, the UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging and Artificial Intelligence Centre for Value Based Healthcare, the UK National Institute for Health Research, the UK Medical Research Council, the British Heart Foundation, and the Alzheimer's Society.
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              Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study

              Abstract Objective To quantify rates of organ specific dysfunction in individuals with covid-19 after discharge from hospital compared with a matched control group from the general population. Design Retrospective cohort study. Setting NHS hospitals in England. Participants 47 780 individuals (mean age 65, 55% men) in hospital with covid-19 and discharged alive by 31 August 2020, exactly matched to controls from a pool of about 50 million people in England for personal and clinical characteristics from 10 years of electronic health records. Main outcome measures Rates of hospital readmission (or any admission for controls), all cause mortality, and diagnoses of respiratory, cardiovascular, metabolic, kidney, and liver diseases until 30 September 2020. Variations in rate ratios by age, sex, and ethnicity. Results Over a mean follow-up of 140 days, nearly a third of individuals who were discharged from hospital after acute covid-19 were readmitted (14 060 of 47 780) and more than 1 in 10 (5875) died after discharge, with these events occurring at rates four and eight times greater, respectively, than in the matched control group. Rates of respiratory disease (P<0.001), diabetes (P<0.001), and cardiovascular disease (P<0.001) were also significantly raised in patients with covid-19, with 770 (95% confidence interval 758 to 783), 127 (122 to 132), and 126 (121 to 131) diagnoses per 1000 person years, respectively. Rate ratios were greater for individuals aged less than 70 than for those aged 70 or older, and in ethnic minority groups compared with the white population, with the largest differences seen for respiratory disease (10.5 (95% confidence interval 9.7 to 11.4) for age less than 70 years v 4.6 (4.3 to 4.8) for age ≥70, and 11.4 (9.8 to 13.3) for non-white v 5.2 (5.0 to 5.5) for white individuals). Conclusions Individuals discharged from hospital after covid-19 had increased rates of multiorgan dysfunction compared with the expected risk in the general population. The increase in risk was not confined to the elderly and was not uniform across ethnicities. The diagnosis, treatment, and prevention of post-covid syndrome requires integrated rather than organ or disease specific approaches, and urgent research is needed to establish the risk factors.
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                Author and article information

                Journal
                MMWR Morb Mortal Wkly Rep
                MMWR Morb Mortal Wkly Rep
                WR
                Morbidity and Mortality Weekly Report
                Centers for Disease Control and Prevention
                0149-2195
                1545-861X
                27 May 2022
                27 May 2022
                : 71
                : 21
                : 713-717
                Affiliations
                CDC COVID-19 Emergency Response Team; GAP Solutions, Inc., Herndon, Virginia.
                Author notes
                Corresponding author: Lara Bull-Otterson, lbull@ 123456cdc.gov
                Article
                mm7121e1
                10.15585/mmwr.mm7121e1
                9153460
                fd93a963-d820-4954-9582-9f99de76ffb3

                All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated.

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