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      Clinical Characteristics of Multisystem Inflammatory Syndrome in Adults : A Systematic Review

      research-article
      , MD, MPH 1 , , , MD, PhD 1 , 2 , , PhD 1 , , MD, MPH 1 , , DO 1 , , MD 1
      JAMA Network Open
      American Medical Association

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          Key Points

          Question

          What are the clinical characteristics of multisystem inflammatory syndrome in adults (MIS-A)?

          Findings

          This systematic review of patients with MIS-A reported in the literature and to the US Centers for Disease Control and Prevention identified 221 patients worldwide. The syndrome presented approximately 4 weeks after acute COVID-19 with hyperinflammation and extrapulmonary multiorgan involvement that may be difficult to discern from acute biphasic COVID-19 and postacute sequelae of SARS-CoV-2 infection.

          Meaning

          These findings suggest that MIS-A occurs in the postacute COVID-19 period with a heterogeneous clinical presentation likely owing to a dysregulated immune response.

          Abstract

          This systematic review provides a comprehensive overview of the clinical characteristics of multisystem inflammatory syndrome in adults.

          Abstract

          Importance

          Multisystem inflammatory syndrome in adults (MIS-A) has not been well described. Improved diagnosis and treatment of MIS-A might mitigate COVID-19 morbidity and mortality.

          Objective

          To summarize the descriptive epidemiology and clinical characteristics of MIS-A.

          Evidence Review

          This systematic review identified patients with MIS-A using 3 strategies: (1) literature review from May 1, 2020, to May 25, 2021, by searching MEDLINE, Embase, Global Health, CAB Abstracts, PsycINFO, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Academic Search Complete, Scopus, World Health Organization Global COVID-19 Literature Database, and Google Scholar; (2) voluntary reports of MIS-A to the Centers for Disease Control and Prevention (CDC); and (3) reports among persons aged 18 to 20 years in the CDC surveillance system for MIS in children.

          Findings

          Of 221 patients with MIS-A, the median age was 21 (interquartile range [IQR], 19-34) years, and 154 of 219 (70%) with data available were men. Sixty of 169 patients (36%) were non-Hispanic Black individuals, and 122 of 209 (58%) had no underlying comorbidity. One hundred two of 149 patients (68%) noted a previous symptomatic COVID-19–like illness (median, 28 [IQR, 20-36] days previously). Most patients with MIS-A presented with fever (197 of 205 [96%]), hypotension (133 of 220 [60%]), cardiac dysfunction (114 of 210 [54%]), shortness of breath (102 of 198 [52%]), and/or diarrhea (102 of 197 [52%]). The median number of organ systems involved was 5 (IQR, 4-6). Median hospital stay was 8 (IQR, 5-12) days; 115 of 201 patients (57%) were admitted to the intensive care unit; 101 of 213 (47%) required respiratory support, and 15 of 220 (7%) died. Most patients (176 of 195 [90%]) had elevated markers of coagulopathy and/or inflammation and a positive SARS-CoV-2 serologic finding (139 of 194 [72%]). Ten patients with MIS-A presented with Kawasaki disease.

          Conclusions and Relevance

          These findings suggest that MIS-A is a serious hyperinflammatory condition that presents approximately 4 weeks after onset of acute COVID-19 with extrapulmonary multiorgan dysfunction.

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          Most cited references95

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          Extrapulmonary manifestations of COVID-19

          Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.
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            Coronavirus Disease 2019 Case Surveillance — United States, January 22–May 30, 2020

            The coronavirus disease 2019 (COVID-19) pandemic resulted in 5,817,385 reported cases and 362,705 deaths worldwide through May, 30, 2020, † including 1,761,503 aggregated reported cases and 103,700 deaths in the United States. § Previous analyses during February–early April 2020 indicated that age ≥65 years and underlying health conditions were associated with a higher risk for severe outcomes, which were less common among children aged 10% of persons in this age group. TABLE 2 Reported underlying health conditions* and symptoms † among persons with laboratory-confirmed COVID-19, by sex and age group — United States, January 22–May 30, 2020 Characteristic No. (%) Total Sex Age group (yrs) Male Female ≤9 10–19 20–29 30–39 40–49 50–59 60–69 70–79 ≥80 Total population 1,320,488 646,358 674,130 20,458 49,245 182,469 214,849 219,139 235,774 179,007 105,252 114,295 Underlying health condition§ Known underlying medical condition status* 287,320 (21.8) 138,887 (21.5) 148,433 (22.0) 2,896 (14.2) 7,123 (14.5) 27,436 (15.0) 33,483 (15.6) 40,572 (18.5) 54,717 (23.2) 50,125 (28.0) 34,400 (32.7) 36,568 (32.0) Any cardiovascular disease¶ 92,546 (32.2) 47,567 (34.2) 44,979 (30.3) 78 (2.7) 164 (2.3) 1,177 (4.3) 3,588 (10.7) 8,198 (20.2) 16,954 (31.0) 21,466 (42.8) 18,763 (54.5) 22,158 (60.6) Any chronic lung disease 50,148 (17.5) 20,930 (15.1) 29,218 (19.7) 363 (12.5) 1,285 (18) 4,537 (16.5) 5,110 (15.3) 6,127 (15.1) 8,722 (15.9) 9,200 (18.4) 7,436 (21.6) 7,368 (20.1) Renal disease 21,908 (7.6) 12,144 (8.7) 9,764 (6.6) 21 (0.7) 34 (0.5) 204 (0.7) 587 (1.8) 1,273 (3.1) 2,789 (5.1) 4,764 (9.5) 5,401 (15.7) 6,835 (18.7) Diabetes 86,737 (30.2) 45,089 (32.5) 41,648 (28.1) 12 (0.4) 225 (3.2) 1,409 (5.1) 4,106 (12.3) 9,636 (23.8) 19,589 (35.8) 22,314 (44.5) 16,594 (48.2) 12,852 (35.1) Liver disease 3,953 (1.4) 2,439 (1.8) 1,514 (1.0) 5 (0.2) 19 (0.3) 132 (0.5) 390 (1.2) 573 (1.4) 878 (1.6) 1,074 (2.1) 583 (1.7) 299 (0.8) Immunocompromised 15,265 (5.3) 7,345 (5.3) 7,920 (5.3) 61 (2.1) 146 (2.0) 646 (2.4) 1,253 (3.7) 2,005 (4.9) 3,190 (5.8) 3,421 (6.8) 2,486 (7.2) 2,057 (5.6) Neurologic/Neurodevelopmental disability 13,665 (4.8) 6,193 (4.5) 7,472 (5.0) 41 (1.4) 113 (1.6) 395 (1.4) 533 (1.6) 734 (1.8) 1,338 (2.4) 2,006 (4.0) 2,759 (8.0) 5,746 (15.7) Symptom§ Known symptom status† 373,883 (28.3) 178,223 (27.6) 195,660 (29.0) 5,188 (25.4) 12,689 (25.8) 51,464 (28.2) 59,951 (27.9) 62,643 (28.6) 70,040 (29.7) 52,178 (29.1) 28,583 (27.2) 31,147 (27.3) Fever, cough, or shortness of breath 260,706 (69.7) 125,768 (70.6) 134,938 (69.0) 3,278 (63.2) 7,584 (59.8) 35,072 (68.1) 42,016 (70.1) 45,361 (72.4) 51,283 (73.2) 37,701 (72.3) 19,583 (68.5) 18,828 (60.4) Fever †† 161,071 (43.1) 80,578 (45.2) 80,493 (41.1) 2,404 (46.3) 4,443 (35.0) 20,381 (39.6) 25,887 (43.2) 28,407 (45.3) 32,375 (46.2) 23,591 (45.2) 12,190 (42.6) 11,393 (36.6) Cough 187,953 (50.3) 89,178 (50.0) 98,775 (50.5) 1,912 (36.9) 5,257 (41.4) 26,284 (51.1) 31,313 (52.2) 34,031 (54.3) 38,305 (54.7) 27,150 (52.0) 12,837 (44.9) 10,864 (34.9) Shortness of breath 106,387 (28.5) 49,834 (28.0) 56,553 (28.9) 339 (6.5) 2,070 (16.3) 13,649 (26.5) 16,851 (28.1) 18,978 (30.3) 21,327 (30.4) 16,018 (30.7) 8,971 (31.4) 8,184 (26.3) Myalgia 135,026 (36.1) 61,922 (34.7) 73,104 (37.4) 537 (10.4) 3,737 (29.5) 21,153 (41.1) 26,464 (44.1) 28,064 (44.8) 28,594 (40.8) 17,360 (33.3) 6,015 (21.0) 3,102 (10.0) Runny nose 22,710 (6.1) 9,900 (5.6) 12,810 (6.5) 354 (6.8) 1,025 (8.1) 4,591 (8.9) 4,406 (7.3) 4,141 (6.6) 4,100 (5.9) 2,671 (5.1) 923 (3.2) 499 (1.6) Sore throat 74,840 (20.0) 31,244 (17.5) 43,596 (22.3) 664 (12.8) 3,628 (28.6) 14,493 (28.2) 14,855 (24.8) 14,490 (23.1) 13,930 (19.9) 8,192 (15.7) 2,867 (10.0) 1,721 (5.5) Headache 128,560 (34.4) 54,721 (30.7) 73,839 (37.7) 785 (15.1) 5,315 (41.9) 23,723 (46.1) 26,142 (43.6) 26,245 (41.9) 26,057 (37.2) 14,735 (28.2) 4,163 (14.6) 1,395 (4.5) Nausea/Vomiting 42,813 (11.5) 16,549 (9.3) 26,264 (13.4) 506 (9.8) 1,314 (10.4) 6,648 (12.9) 7,661 (12.8) 8,091 (12.9) 8,737 (12.5) 5,953 (11.4) 2,380 (8.3) 1,523 (4.9) Abdominal pain 28,443 (7.6) 11,553 (6.5) 16,890 (8.6) 349 (6.7) 978 (7.7) 4,211 (8.2) 5,150 (8.6) 5,531 (8.8) 6,134 (8.8) 3,809 (7.3) 1,449 (5.1) 832 (2.7) Diarrhea 72,039 (19.3) 32,093 (18.0) 39,946 (20.4) 704 (13.6) 1,712 (13.5) 9,867 (19.2) 12,769 (21.3) 13,958 (22.3) 15,536 (22.2) 10,349 (19.8) 4,402 (15.4) 2,742 (8.8) Loss of smell or taste 31,191 (8.3) 12,717 (7.1) 18,474 (9.4) 67 (1.3) 1,257 (9.9) 6,828 (13.3) 6,907 (11.5) 6,361 (10.2) 5,828 (8.3) 2,930 (5.6) 775 (2.7) 238 (0.8) Abbreviation: COVID-19 = coronavirus disease 2019. * Status of underlying health conditions known for 287,320 persons. Status was classified as “known” if any of the following conditions were reported as present or absent: diabetes mellitus, cardiovascular disease (including hypertension), severe obesity (body mass index ≥40 kg/m2), chronic renal disease, chronic liver disease, chronic lung disease, immunocompromising condition, autoimmune condition, neurologic condition (including neurodevelopmental, intellectual, physical, visual, or hearing impairment), psychologic/psychiatric condition, and other underlying medical condition not otherwise specified. † Symptom status was known for 373,883 persons. Status was classified as “known” if any of the following symptoms were reported as present or absent: fever (measured >100.4°F [38°C] or subjective), cough, shortness of breath, wheezing, difficulty breathing, chills, rigors, myalgia, rhinorrhea, sore throat, chest pain, nausea or vomiting, abdominal pain, headache, fatigue, diarrhea (≥3 loose stools in a 24-hour period), or other symptom not otherwise specified on the form. § Responses include data from standardized fields supplemented with data from free-text fields. Information for persons with loss of smell or taste was exclusively extracted from a free-text field; therefore, persons exhibiting this symptom were likely underreported. ¶ Includes persons with reported hypertension. ** Includes all persons with at least one of these symptoms reported. †† Persons were considered to have a fever if information on either measured or subjective fever variables if “yes” was reported for either variable. Among 287,320 (22%) cases with data on individual underlying health conditions, those most frequently reported were cardiovascular disease (32%), diabetes (30%), and chronic lung disease (18%) (Table 2); the reported proportions were similar among males and females. The frequency of conditions reported varied by age group: cardiovascular disease was uncommon among those aged ≤39 years but was reported in approximately half of the cases among persons aged ≥70 years. Among 63,896 females aged 15–44 years with known pregnancy status, 6,708 (11%) were reported to be pregnant. Among the 1,320,488 cases, outcomes for hospitalization, ICU admission, and death were available for 46%, 14%, and 36%, respectively. Overall, 184,673 (14%) patients were hospitalized, including 29,837 (2%) admitted to the ICU; 71,116 (5%) patients died (Table 3). Severe outcomes were more commonly reported for patients with reported underlying conditions. Hospitalizations were six times higher among patients with a reported underlying condition than those without reported underlying conditions (45.4% versus 7.6%). Deaths were 12 times higher among patients with reported underlying conditions compared with those without reported underlying conditions (19.5% versus 1.6%). The percentages of males who were hospitalized (16%), admitted to the ICU (3%), and who died (6%) were higher than were those for females (12%, 2%, and 5%, respectively). The percentage of ICU admissions was highest among persons with reported underlying conditions aged 60–69 years (11%) and 70–79 years (12%). Death was most commonly reported among persons aged ≥80 years regardless of the presence of underlying conditions (with underlying conditions 50%; without 30%). TABLE 3 Reported hospitalizations,* , † intensive care unit (ICU) admissions, § and deaths ¶ among laboratory-confirmed COVID-19 patients with and without reported underlying health conditions, ** by sex and age — United States, January 22–May 30, 2020 Characteristic (no.) Outcome, no./total no. (%)†† Reported hospitalizations*,† (including ICU) Reported ICU admission§ Reported deaths¶ Among all patients Among patients with reported underlying health conditions Among patients with no reported underlying health conditions Among all patients Among patients with reported underlying health conditions Among patients with no reported underlying health conditions Among all patients Among patients with reported underlying health conditions Among patients with no reported underlying health conditions Sex Male (646,358) 101,133/646,358 (15.6) 49,503/96,839 (51.1) 3,596/42,048 (8.6) 18,394/646,358 (2.8) 10,302/96,839 (10.6) 864/42,048 (2.1) 38,773/646,358 (6.0) 21,667/96,839 (22.4) 724/42,048 (1.7) Female (674,130) 83,540/674,130 (12.4) 40,698/102,040 (39.9) 3,087/46,393 (6.7) 11,443/674,130 (1.7) 6,672/102,040 (6.5) 479/46,393 (1.0) 32,343/674,130 (4.8) 17,145/102,040 (16.8) 707/46,393 (1.5) Age group (yrs) ≤9 (20,458) 848/20,458 (4.1) 138/619 (22.3) 84/2,277 (3.7) 141/20,458 (0.7) 31/619 (5.0) 16/2,277 (0.7) 13/20,458 (0.1) 4/619 (0.6) 2/2,277 (0.1) 10–19 (49,245) 1,234/49,245 (2.5) 309/2,076 (14.9) 115/5,047 (2.3) 216/49,245 (0.4) 72/2,076 (3.5) 17/5,047 (0.3) 33/49,245 (0.1) 16/2,076 (0.8) 4/5,047 (0.1) 20–29 (182,469) 6,704/182,469 (3.7) 1,559/8,906 (17.5) 498/18,530 (2.7) 864/182,469 (0.5) 300/8,906 (3.4) 56/18,530 (0.3) 273/182,469 (0.1) 122/8,906 (1.4) 24/18,530 (0.1) 30–39 (214,849) 12,570/214,849 (5.9) 3,596/14,854 (24.2) 828/18,629 (4.4) 1,879/214,849 (0.9) 787/14,854 (5.3) 135/18,629 (0.7) 852/214,849 (0.4) 411/14,854 (2.8) 21/18,629 (0.1) 40–49 (219,139) 19,318/219,139 (8.8) 7,151/24,161 (29.6) 1,057/16,411 (6.4) 3,316/219,139 (1.5) 1,540/24,161 (6.4) 208/16,411 (1.3) 2,083/219,139 (1.0) 1,077/24,161 (4.5) 58/16,411 (0.4) 50–59 (235,774) 31,588/235,774 (13.4) 14,639/40,297 (36.3) 1,380/14,420 (9.6) 5,986/235,774 (2.5) 3,335/40,297 (8.3) 296/14,420 (2.1) 5,639/235,774 (2.4) 3,158/40,297 (7.8) 131/14,420 (0.9) 60–69 (179,007) 39,422/179,007 (22.0) 21,064/42,206 (49.9) 1,216/7,919 (15.4) 7,403/179,007 (4.1) 4,588/42,206 (10.9) 291/7,919 (3.7) 11,947/179,007 (6.7) 7,050/42,206 (16.7) 187/7,919 (2.4) 70–79 (105,252) 35,844/105,252 (34.1) 20,451/31,601 (64.7) 780/2,799 (27.9) 5,939/105,252 (5.6) 3,771/31,601 (11.9) 199/2,799 (7.1) 17,510/105,252 (16.6) 10,008/31,601 (31.7) 286/2,799 (10.2) ≥80 (114,295) 37,145/114,295 (32.5) 21,294/34,159 (62.3) 725/2,409 (30.1) 4,093/114,295 (3.6) 2,550/34,159 (7.5) 125/2,409 (5.2) 32,766/114,295 (28.7) 16,966/34,159 (49.7) 718/2,409 (29.8) Total (1,320,488) 184,673/1,320,488 (14.0) 90,201/198,879 (45.4) 6,683/88,441 (7.6) 29,837/1,320,488 (2.3) 16,974/198,879 (8.5) 1,343/88,441 (1.5) 71,116/1,320,488 (5.4) 38,812/198,879 (19.5) 1,431/88,441 (1.6) Abbreviation: COVID-19 = coronavirus disease 2019. * Hospitalization status was known for 600,860 (46%). Among 184,673 hospitalized patients, the presence of underlying health conditions was known for 96,884 (53%). † Includes reported ICU admissions. § ICU admission status was known for 186,563 (14%) patients among the total case population, representing 34% of hospitalized patients. Among 29,837 patients admitted to the ICU, the status of underlying health conditions was known for 18,317 (61%). ¶ Death outcomes were known for 480,565 (36%) patients. Among 71,116 reported deaths through case surveillance, the status of underlying health conditions was known for 40,243 (57%) patients. ** Status of underlying health conditions was known for 287,320 (22%) patients. Status was classified as “known” if any of the following conditions were noted as present or absent: diabetes mellitus, cardiovascular disease including hypertension, severe obesity body mass index ≥40 kg/m2, chronic renal disease, chronic liver disease, chronic lung disease, any immunocompromising condition, any autoimmune condition, any neurologic condition including neurodevelopmental, intellectual, physical, visual, or hearing impairment, any psychologic/psychiatric condition, and any other underlying medical condition not otherwise specified. †† Outcomes were calculated as the proportion of persons reported to be hospitalized, admitted to an ICU, or who died among total in the demographic group. Outcome underreporting could result from outcomes that occurred but were not reported through national case surveillance or through clinical progression to severe outcomes that occurred after time of report. Discussion As of May 30, a total of 1,761,503 aggregate U.S. cases of COVID-19 and 103,700 associated deaths were reported to CDC. Although average daily reported cases and deaths are declining, 7-day moving averages of daily incidence of COVID-19 cases indicate ongoing community transmission. ¶¶¶¶ The COVID-19 case data summarized here are essential statistics for the pandemic response and rely on information systems developed at the local, state, and federal level over decades for communicable disease surveillance that were rapidly adapted to meet an enormous, new public health threat. CDC aggregate counts are consistent with those presented through the Johns Hopkins University (JHU) Coronavirus Resource Center, which reported a cumulative total of 1,770,165 U.S. cases and 103,776 U.S. deaths on May 30, 2020.***** Differences in aggregate counts between CDC and JHU might be attributable to differences in reporting practices to CDC and jurisdictional websites accessed by JHU. Reported cumulative incidence in the case surveillance population among persons aged ≥20 years is notably higher than that among younger persons. The lower incidence in persons aged ≤19 years could be attributable to undiagnosed milder or asymptomatic illnesses among this age group that were not reported. Incidence in persons aged ≥80 years was nearly double that in persons aged 70–79 years. Among cases with known race and ethnicity, 33% of persons were Hispanic, 22% were black, and 1.3% were AI/AN. These findings suggest that persons in these groups, who account for 18%, 13%, and 0.7% of the U.S. population, respectively, are disproportionately affected by the COVID-19 pandemic. The proportion of missing race and ethnicity data limits the conclusions that can be drawn from descriptive analyses; however, these findings are consistent with an analysis of COVID-19–Associated Hospitalization Surveillance Network (COVID-NET) ††††† data that found higher proportions of black and Hispanic persons among hospitalized COVID-19 patients than were in the overall population ( 4 ). The completeness of race and ethnicity variables in case surveillance has increased from 20% to >40% from April 2 to June 2. Although reporting of race and ethnicity continues to improve, more complete data might be available in aggregate on jurisdictional websites or through sources like the COVID Tracking Project’s COVID Racial Data Tracker. §§§§§ The data in this report show that the prevalence of reported symptoms varied by age group but was similar among males and females. Fewer than 5% of persons were reported to be asymptomatic when symptom data were submitted. Persons without symptoms might be less likely to be tested for COVID-19 because initial guidance recommended testing of only symptomatic persons and was hospital-based. Guidance on testing has evolved throughout the response. ¶¶¶¶¶ Whereas incidence among males and females was similar overall, severe outcomes were more commonly reported among males. Prevalence of reported severe outcomes increased with age; the percentages of hospitalizations, ICU admissions, and deaths were highest among persons aged ≥70 years, regardless of underlying conditions, and lowest among those aged ≤19 years. Hospitalizations were six times higher and deaths 12 times higher among those with reported underlying conditions compared with those with none reported. These findings are consistent with previous reports that found that severe outcomes increased with age and underlying condition, and males were hospitalized at a higher rate than were females ( 2 , 4 , 5 ). The findings in this report are subject to at least three limitations. First, case surveillance data represent a subset of the total cases of COVID-19 in the United States; not every case in the community is captured through testing and information collected might be limited if persons are unavailable or unwilling to participate in case investigations or if medical records are unavailable for data extraction. Reported cumulative incidence, although comparable across age and sex groups within the case surveillance population, are underestimates of the U.S. cumulative incidence of COVID-19. Second, reported frequencies of individual symptoms and underlying health conditions presented from case surveillance likely underestimate the true prevalence because of missing data. Finally, asymptomatic cases are not captured well in case surveillance. Asymptomatic persons are unlikely to seek testing unless they are identified through active screening (e.g., contact tracing), and, because of limitations in testing capacity and in accordance with guidance, investigation of symptomatic persons is prioritized. Increased identification and reporting of asymptomatic cases could affect patterns described in this report. Similar to earlier reports on COVID-19 case surveillance, severe outcomes were more commonly reported among persons who were older and those with underlying health conditions ( 1 ). Findings in this report align with demographic and severe outcome trends identified through COVID-NET ( 4 ). Findings from case surveillance are evaluated along with enhanced surveillance data and serologic survey results to provide a comprehensive picture of COVID-19 trends, and differences in proportion of cases by racial and ethnic groups should continue to be examined in enhanced surveillance to better understand populations at highest risk. Since the U.S. COVID-19 response began in January, CDC has built on existing surveillance capacity to monitor the impact of illness nationally. Collection of detailed case data is a resource-intensive public health activity, regardless of disease incidence. The high incidence of COVID-19 has highlighted limitations of traditional public health case surveillance approaches to provide real-time intelligence and supports the need for continued innovation and modernization. Despite limitations, national case surveillance of COVID-19 serves a critical role in the U.S. COVID-19 response: these data demonstrate that the COVID-19 pandemic is an ongoing public health crisis in the United States that continues to affect all populations and result in severe outcomes including death. National case surveillance findings provide important information for targeted enhanced surveillance efforts and development of interventions critical to the U.S. COVID-19 response. Summary What is already known about this topic? Surveillance data reported to CDC through April 2020 indicated that COVID-19 leads to severe outcomes in older adults and those with underlying health conditions. What is added by this report? As of May 30, 2020, among COVID-19 cases, the most common underlying health conditions were cardiovascular disease (32%), diabetes (30%), and chronic lung disease (18%). Hospitalizations were six times higher and deaths 12 times higher among those with reported underlying conditions compared with those with none reported. What are the implications for public health practice? Surveillance at all levels of government, and its continued modernization, is critical for monitoring COVID-19 trends and identifying groups at risk for infection and severe outcomes. These findings highlight the continued need for community mitigation strategies, especially for vulnerable populations, to slow COVID-19 transmission.
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              Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection — United Kingdom and United States, March–August 2020

              During the course of the coronavirus disease 2019 (COVID-19) pandemic, reports of a new multisystem inflammatory syndrome in children (MIS-C) have been increasing in Europe and the United States ( 1 – 3 ). Clinical features in children have varied but predominantly include shock, cardiac dysfunction, abdominal pain, and elevated inflammatory markers, including C-reactive protein (CRP), ferritin, D-dimer, and interleukin-6 ( 1 ). Since June 2020, several case reports have described a similar syndrome in adults; this review describes in detail nine patients reported to CDC, seven from published case reports, and summarizes the findings in 11 patients described in three case series in peer-reviewed journals ( 4 – 6 ). These 27 patients had cardiovascular, gastrointestinal, dermatologic, and neurologic symptoms without severe respiratory illness and concurrently received positive test results for SARS-CoV-2, the virus that causes COVID-19, by polymerase chain reaction (PCR) or antibody assays indicating recent infection. Reports of these patients highlight the recognition of an illness referred to here as multisystem inflammatory syndrome in adults (MIS-A), the heterogeneity of clinical signs and symptoms, and the role for antibody testing in identifying similar cases among adults. Clinicians and health departments should consider MIS-A in adults with compatible signs and symptoms. These patients might not have positive SARS-CoV-2 PCR or antigen test results, and antibody testing might be needed to confirm previous SARS-CoV-2 infection. Because of the temporal association between MIS-A and SARS-CoV-2 infections, interventions that prevent COVID-19 might prevent MIS-A. Further research is needed to understand the pathogenesis and long-term effects of this newly described condition. Potential MIS-A patients were identified from several sources: reports from clinicians and health departments, published case reports, and published case series. Clinicians and health departments in the United States voluntarily reported adult patients with suspected MIS-A to CDC using the case report form* developed for MIS-C after a Health Advisory was published on May 14, 2020, calling for reporting of MIS-C cases. The case report form included information on patient demographics, underlying medical conditions, clinical findings, complications, laboratory test results including those from SARS-CoV-2 testing, imaging findings, treatments, and outcomes. Two clinician reviewers selected patients who fulfilled the working MIS-A case definition used in this report, which included the following five criteria: 1) a severe illness requiring hospitalization in a person aged ≥21 years; 2) a positive test result for current or previous SARS-CoV-2 infection (nucleic acid, antigen, or antibody) during admission or in the previous 12 weeks; 3) severe dysfunction of one or more extrapulmonary organ systems (e.g., hypotension or shock, cardiac dysfunction, arterial or venous thrombosis or thromboembolism, or acute liver injury); 4) laboratory evidence of severe inflammation (e.g., elevated CRP, ferritin, D-dimer, or interleukin-6); and 5) absence of severe respiratory illness (to exclude patients in which inflammation and organ dysfunction might be attributable simply to tissue hypoxia). Patients with mild respiratory symptoms who met these criteria were included. Patients were excluded if alternative diagnoses such as bacterial sepsis were identified. To identify potential published cases, a literature search was performed on August 20, 2020, and 355 publications were identified. † Abstracts were screened by one reviewer to determine whether cases met the working MIS-A case definition; when no abstract was available, the full paper was examined. The references were reviewed to identify additional relevant articles. Data were obtained from published reports; authors were contacted to confirm published data and, when necessary, to provide data not included in the original articles. Case Reports Demographic characteristics and underlying conditions. Cases in nine patients reported to CDC (Table 1) and seven published case reports (Table 2), originating from seven U.S. jurisdictions and the United Kingdom, met the working case definition. The 16 patients ranged in age from 21 to 50 years and included seven men and nine women. Five were reported as Hispanic, nine as African American, one as Asian, and one as a United Kingdom–born man of African ethnicity. Nine patients had no reported underlying medical conditions; six were obese, one had poorly controlled diabetes mellitus type 2 (hemoglobin A1C >9.0%), two had hypertension, and one had obstructive sleep apnea. Eight patients had documented respiratory illness before developing symptoms of MIS-A, and eight did not. TABLE 1 Demographics, clinical features, treatments, and outcomes of nine adults reported to CDC with multisystem inflammatory syndrome (MIS) associated with SARS-CoV-2 infection — United States, March–August 2020 Age (yrs), sex, race/ethnicity, location Underlying medical conditions Clinical signs and symptoms Previous respiratory illness/SARS-CoV-2 testing SARS-CoV-2 testing at time of MIS-A admission Laboratory studies (peak)* Imaging/Other diagnostic studies Treatments Outcome and length of stay Patient 1: 27, female, African American, Maine None Rigors, profuse diarrhea, diffuse rash x 5 days. Admitted with mixed shock (hypovolemic, vasoplegic, cardiogenic) and acute renal failure. No/Testing unknown PCR (-), Ab (+) CRP 344 mg/L; D-dimer 2818 ng/mL; ferritin 1082 ng/mL; troponin I 0.43 ng/mL; ALT 37 IU/L; ALC nadir 420 cells/μL TTE: mild to moderate global hypokinesis, left ventricular ejection fraction 45%, mildly dilated right ventricle, mild tricuspid regurgitation, pericardial effusion. 
CT chest: bilateral patchy ground-glass opacities, pleural effusion. 
CT abdomen/pelvis: abdominal free fluid. Norepinephrine, vasopressin, midodrine, heparin, corticosteroids Discharged after 13 days Patient 2: 50, male, African American, Florida None Poor oral intake, chest pressure, palpitations, diaphoresis x 3 days. Hemodynamically unstable on admission. No/Testing unknown PCR (+), Ab (+) CRP 84 mg/L; D-dimer 2310 ng/mL; ferritin 1919 ng/mL; troponin I 0.48 ng/mL; ALT 440 IU/L; ALC nadir 2500 cells/μL EKG: atrial fibrillation/flutter with rapid ventricular response, ST segment changes. 
TTE: ejection fraction 25%–30% with global hypokinesis. 
CXR: small pleural effusions. Remdesivir, corticosteroids Discharged after 17 days Patient 3: 46, male, African American, Florida Obesity, chronic right lower extremity pain Malaise, bilateral tinnitus, chest pain, and vomiting x 4 days. Hypotensive and mildly hypoxemic on admission. Yes/Testing unknown PCR (-), Ab (+) CRP 217 mg/L; D-dimer 3790 ng/mL; ferritin >100,000 ng/mL; troponin I 2.5 ng/mL; IL-6 1412 pg/mL; ALT >10,000 IU/L; ALC nadir 400 cells/μL EKG: ST-T segment changes. 
CT chest: dependent ground glass opacities. 
CT abdomen: hepatic steatosis. Vasopressors, tocilizumab x 1, heparin Deceased Patient 4: 21, male, African American, Louisiana Obesity Fever, cough, nausea, vomiting, lymphadenopathy x 6 days. No/Testing unknown PCR (-), Ab (+) CRP 318 mg/L; D-dimer 1760 ng/mL; ferritin 4400 ng/mL; troponin T 0.65 ng/mL; IL-6 7 pg/mL; ATL 279 IU/L; ALC nadir 700 cells/μL TTE: severely decreased ejection fraction, mild mitral regurgitation, right ventricular dysfunction, coronary artery dilatation. 
CT chest: ground glass opacities and atelectasis. ASA, corticosteroids, IVIG x 1 Discharged after 6 days Patient 5: 33, male, African American, Georgia Obesity, HTN, depression Fever, chest pain, abdominal pain, diarrhea, dark urine x 4 days. Yes/PCR (+) 41 days earlier PCR (+), Ab (+) CRP 182 mg/L; D-dimer 275 ng/mL; ferritin 375 ng/mL; troponin I 1.8 ng/mL; IL-6 74.3 pg/mL; ALT 30 IU/L; ALC nadir 2070 cells/μL CT chest: atelectasis. 
CT abdomen/pelvis: normal. 
TTE: mitral and tricuspid regurgitation. Anticoagulation Discharged after 5 days Patient 6: 22, female, African American, New York None Fever, chills, throat pain, odynophagia x 2 days. No/Testing unknown PCR (+), Ab (+) CRP 355 mg/L; D-dimer 1882 ng/mL; ferritin 378 ng/mL; troponin T 0.06 ng/mL; IL-6 34.8 pg/mL; ALT 119 U/L; ALC nadir 360 cells/μL CT neck: retropharyngeal and parapharyngeal edema. 
EKG: intermittent complete heart block with narrow junctional escape without hemodynamic compromise. 
TTE: ejection fraction 50%. 
CXR: dense bilateral lower lobe air-space disease. Phenylephrine, anticoagulation, corticosteroids Discharged after 19 days Patient 7: 21, female, African American, New York Obesity Fever, fatigue, throat and neck pain, nausea, vomiting x 1 day. Yes/PCR (+) 25 days earlier PCR (+), Ab (+) CRP 319 mg/L; D-dimer 713 ng/mL; ferritin 351 ng/mL; troponin T 0.04 ng/mL; IL-6 56.2 pg/mL; ALT 160 IU/L; ALC nadir 260 cells/μL CT neck: bilateral supraclavicular and cervical lymphadenopathy with no discrete abscess or collection.
CT chest: bilateral patchy ground-glass opacities, pleural effusion. 
TTE: mild to moderate diffuse left ventricular hypokinesis. Mild to moderate decreased left ventricular ejection fraction (40%). Small posterior pericardial effusion. Mild tricuspid and mitral valve regurgitation. Dobutamine, heparin, ASA x1, corticosteroids x2 Discharged after 12 days Patient 8: 47, female, African American, New York None Weakness, sore throat, shortness of breath, decreased exercise tolerance x 3 days. Yes/Testing unknown PCR (+), Ab testing not performed CRP 485 mg/L; D-dimer 1365 ng/mL; ferritin 948 ng/mL; troponin T 0.24 ng/mL; ALT 45 U/L; ALC nadir 1980 cells/μL EKG: first degree AV block and nonspecific T-wave abnormalities. 
TTE: borderline left ventricular ejection fraction (55%). Heparin, convalescent plasma Discharged after 8 days Patient 9: 42, male, Asian, New York Obesity Fever, shortness of breath, cough, diarrhea, poor appetite, dysuria x 5 days. Yes/PCR (+) 37 days earlier PCR (-), Ab testing not performed CRP 387 mg/L; D-dimer 3519 ng/mL; ferritin 7529 ng/mL; troponin T 0.60 ng/mL; ALT 66 U/L; ALC nadir 1740 cells/μL TEE: mildly dilated left ventricle, moderately dilated right ventricle, moderate biventricular hypokinesis, moderately decreased left ventricular ejection fraction (35%).
CXR: bilateral lower lobe opacities/airspace disease. Vasopressors, anticoagulation, corticosteroids Discharged after 9 days Abbreviations: Ab = antibody; ALC = absolute lymphocyte count; ALT = alanine aminotransferase; ASA = aspirin; CRP = C-reactive protein; CT = computed tomography; CXR = chest radiograph; EKG = electrocardiogram; HTN = hypertension; IL-6 = interleukin-6; IVIG = intravenous immunoglobulin; PCR = polymerase chain reaction; TEE = transesophageal echocardiogram; TTE = transthoracic echocardiogram. * Normal ranges for laboratory studies: ALC 1000–4000 cells/μL; ALT 5–30 IU/L; CRP 0–10 mg/L; D-dimer 100,000 ng/mL; ULN = 150 ng/mL for women, 300 ng/mL for men), as well as markers of coagulopathy including D-dimer (275–8691 ng/mL; ULN = 500 ng/mL). Ten patients had absolute lymphocyte counts lower than normal range (range of nadir values 120–2120 cells/μL; lower limit of normal = 1000 cells/μL). SARS-CoV-2 test results. Ten patients received positive SARS-CoV-2 PCR test results at the time of initial assessment for MIS-A, seven of whom also had serologic evidence of infection (positive antibody test results) at that time. Six patients received negative SARS-CoV-2 PCR test results; of those, four had positive anti-SARS-CoV-2 antibody test results when first evaluated. Two patients had positive SARS-CoV-2 PCR test results 14 and 37 days before admission, negative PCR results at the time of admission, and no known antibody testing. Three additional patients had positive SARS-CoV-2 PCR test results 25–41 days before admission and continued positive PCR test results at the time of admission. Treatment. Seven patients were treated with intravenous immunoglobulin, 10 with corticosteroids, and two with the interleukin-6 inhibitor, tocilizumab. Ten patients required intensive care; seven required inotropes or vasopressors, and one required mechanical circulatory support (extracorporeal membrane oxygenation followed by temporary left and right ventricular assist devices). Three patients required endotracheal intubation and mechanical ventilation, and two patients died. Published Case Series Three published case series were identified describing adult patients with manifestations consistent with MIS-A ( 4 – 6 ). One series describes seven previously healthy, young adult men aged 20–42 years who experienced mixed cardiogenic and vasoplegic shock and hyperinflammation along with high SARS-CoV-2 immunoglobulin G antibody titers indicating active or previous infection ( 4 ). Two of the patients identified as African American, two as Hispanic, two as Middle Eastern, and one as White. Four of the seven patients had negative PCR test results for SARS-CoV-2 at the time of admission, all had markedly elevated inflammatory markers and required inotropes or vasopressors, and three required intraaortic balloon pumps. All were treated with corticosteroids and therapeutic anticoagulation. All seven patients recovered and were discharged home after 7 to 18 days of hospitalization with improved cardiovascular function. A second case series describes two patients aged 21 and 50 years who came to medical attention because of large-vessel strokes associated with positive SARS-CoV-2 tests ( 5 ). Information on race/ethnicity of these patients was not reported. These patients had elevated inflammatory markers and minimal respiratory symptoms, consistent with MIS-A. The authors proposed endothelial dysfunction and coagulopathy related to SARS-CoV-2 infection as potential etiologies. Incidence of large-vessel stroke among young adults during this same time the previous year was statistically significantly lower ( 5 ). A third case series describes the pathologic findings of endothelialitis and complement deposition in the vessels of two patients with illness resembling MIS-A (cardiac dysfunction, abdominal signs and symptoms, and rash) associated with positive SARS-CoV-2 test results ( 6 ). Information on race/ethnicity of these patients was not reported. One of these two patients had no underlying medical conditions and recovered; the other had multiple underlying conditions at higher risk for severe COVID-19 and died hours after seeking care. Pathologic findings in this case series were similar to autopsy findings for those of patient 14 (Table 2). Discussion Findings indicate that adult patients of all ages with current or previous SARS-CoV-2 infection can develop a hyperinflammatory syndrome resembling MIS-C. Although hyperinflammation and extrapulmonary organ dysfunction have been described in hospitalized adults with severe COVID-19, these conditions are generally accompanied by respiratory failure ( 7 ). In contrast, the patients described here had minimal respiratory symptoms, hypoxemia, or radiographic abnormalities in accordance with the working case definition, which was meant to distinguish MIS-A from severe COVID-19; only eight of 16 patients had any documented respiratory symptoms before onset of MIS-A. The pathophysiology of MIS in both children and adults is currently unknown. Eight of 27 (30%) adults described in this report and 45% of 440 children with MIS-C reported to CDC through July 29, 2020, ( 1 ) had negative PCR and positive SARS-CoV-2 antibody test results, suggesting MIS-A and MIS-C might represent postinfectious processes. However, in some patients, persistent infection outside the upper respiratory tract is possible; SARS-CoV-2 has been identified in multiple organs including the heart, liver, brain, kidneys, and gastrointestinal tract ( 7 ). Additional proposed mechanisms for extrapulmonary dysfunction in COVID-19 include endothelial damage and thromboinflammation, dysregulated immune responses, and dysregulation of the renin-angiotensin-aldosterone system ( 7 ). The interval between infection and development of MIS-A is unclear, adding to uncertainty regarding whether MIS-A represents a manifestation of acute infection or an entirely postacute phenomenon. In patients with COVID-19, dyspnea is typically experienced a median of 5–8 days and critical illness 10–12 days after onset of symptoms. § In patients who reported typical COVID-19 symptoms before MIS-A onset, MIS-A was experienced approximately 2–5 weeks later. However, eight MIS-A patients reported no preceding respiratory symptoms, making it difficult to estimate when initial infection occurred. Given the high proportion of MIS-C patients with negative PCR testing, clinical guidelines recommend the use of both antibody and viral testing to assist with diagnosis ( 8 – 10 ). In patients with atypical or late manifestations of SARS-CoV-2 infection, including MIS-A, positive antibody results might be crucial to augment clinical recognition of this condition and guide treatment. In addition, the use of a panel of laboratory tests for inflammation, hypercoagulability, and organ damage (e.g., CRP, ferritin, D-dimer, cardiac enzymes, liver enzymes, and creatinine) might assist in the early identification and management of this COVID-19–associated condition. All but one of the patients with MIS-A described in this report belonged to racial or ethnic minority groups. Long-standing health and social inequities have resulted in increased risk for infection and severe outcomes from COVID-19 in communities of color.¶ MIS-C has also been reported disproportionately in these communities (1). Because patients described in this review represent a convenience sample from a small number of jurisdictions, conclusions cannot be made regarding the true burden or determinants of MIS-A in different groups; further research is needed. The majority (24 of 27) of patients with MIS-A survived, similar to those with MIS-C, associated with receiving care in acute, often intensive, health care settings. Because of the potential therapies that might benefit these patients as described in these case reports, clinicians should consider MIS-A within a broader differential diagnosis when caring for adult patients with clinical and laboratory findings consistent with the working MIS-A case definition. The findings in this report are subject to at least three limitations. First, cases described here were voluntarily reported or published and therefore are not representative of the true clinical spectrum or racial/ethnic distribution of this emerging syndrome. Additional cases might not have been reported or published; others might have remained unrecognized because of absence of COVID-like symptoms, lack of antibody testing, or negative test results. Second, the working case definition excludes patients with severe respiratory dysfunction to distinguish MIS-A from severe COVID-19; however, the two conditions might overlap in some cases. Finally, the working case definition for this syndrome is potentially nonspecific, and some patients with other disease processes might have been misclassified as having MIS-A. Clinicians and health departments should consider MIS-A in adults with signs and symptoms compatible with the current working MIS-A case definition. Antibody testing for SARS-CoV-2 might be needed to confirm previous COVID-19 infection in patients who do not have positive SARS-CoV-2 PCR or antigen test results. Findings in this convenience sample emphasize the importance of collecting race/ethnicity data on case reports at the jurisdictional level. As with children, it is important that multidisciplinary care be considered to ensure optimal treatment. In the process of learning more from MIS-A cases, the working case definition might need to be revised in order to systematically conduct a call for cases. Further research is needed to understand the pathogenesis and long-term effects of this newly described condition. Ultimately, the recognition of MIS-A reinforces the need for prevention efforts to limit spread of SARS-CoV-2. Summary What is already known about this topic? Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe complication of SARS-CoV-2 infection in children and adolescents. Since June 2020, several case reports and series have been published reporting a similar multisystem inflammatory syndrome in adults (MIS-A). What is added by this report? Cases reported to CDC and published case reports and series identify MIS-A in adults, who usually require intensive care and can have fatal outcomes. Antibody testing was required to identify SARS-CoV-2 infection in approximately one third of 27 cases. What are the implications for public health practice? Clinical suspicion and indicated SARS-CoV-2 testing, including antibody testing, might be needed to recognize and treat adults with MIS-A. Further research is needed to understand the pathogenesis and long-term effects of this condition. Ultimately, the recognition of MIS-A reinforces the need for prevention efforts to limit spread of SARS-CoV-2.
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                Author and article information

                Journal
                JAMA Netw Open
                JAMA Netw Open
                JAMA Netw Open
                JAMA Network Open
                American Medical Association
                2574-3805
                22 September 2021
                September 2021
                22 September 2021
                : 4
                : 9
                : e2126456
                Affiliations
                [1 ]CDC COVID-19 Response, Division of Emergency Operations, Center for Preparedness and Response, Centers for Disease Control and Prevention, Atlanta, Georgia
                [2 ]Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, Georgia
                Author notes
                Article Information
                Accepted for Publication: July 6, 2021.
                Published: September 22, 2021. doi:10.1001/jamanetworkopen.2021.26456
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Patel P et al. JAMA Network Open.
                Corresponding Author: Pragna Patel, MD, MPH, CDC COVID-19 Response, Division of Emergency Operations, Center for Preparedness and Response, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA 30333 ( plp3@ 123456cdc.gov ).
                Author Contributions: Drs Patel and Abrams had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: Patel.
                Acquisition, analysis, or interpretation of data: All authors.
                Drafting of the manuscript: Patel.
                Critical revision of the manuscript for important intellectual content: All authors.
                Statistical analysis: Patel, DeCuir, Abrams.
                Supervision: Patel, Godfred-Cato, Belay.
                Conflict of Interest Disclosures: None reported.
                Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC).
                Additional Contributions: We recognize all our state and local jurisdiction partners who submit cases to the US CDC through the surveillance system for multisystem inflammatory syndrome (MIS) in children, as well as those who work tirelessly to maintain the system, especially the CDC MIS data team.
                Article
                zoi210775
                10.1001/jamanetworkopen.2021.26456
                8459192
                34550381
                f3ac2c25-c72a-4b2b-9294-e257cc54e8be
                Copyright 2021 Patel P et al. JAMA Network Open.

                This is an open access article distributed under the terms of the CC-BY License.

                History
                : 15 April 2021
                : 6 July 2021
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                Online Only
                Infectious Diseases

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