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      Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

      research-article
      , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., Ph.D., , M.D., , B.S., , B.S., , Ph.D., , Ph.D., , Ph.D., , Ph.D., , Ph.D., , M.D., , M.S., , Ph.D., , M.D., , M.D., , M.D., , Pharm.D. *
      The New England Journal of Medicine
      Massachusetts Medical Society
      Keyword part (code): 18Keyword part (keyword): Infectious DiseaseKeyword part (code): 18_1Keyword part (keyword): Infectious Disease GeneralKeyword part (code): 18_2Keyword part (keyword): VaccinesKeyword part (code): 18_6Keyword part (keyword): Viral InfectionsKeyword part (code): 18_9Keyword part (keyword): Global HealthKeyword part (code): 18_12Keyword part (keyword): Coronavirus , 18, Infectious Disease, Keyword part (code): 18_1Keyword part (keyword): Infectious Disease GeneralKeyword part (code): 18_2Keyword part (keyword): VaccinesKeyword part (code): 18_6Keyword part (keyword): Viral InfectionsKeyword part (code): 18_9Keyword part (keyword): Global HealthKeyword part (code): 18_12Keyword part (keyword): Coronavirus , 18_1, Infectious Disease General, 18_2, Vaccines, 18_6, Viral Infections, 18_9, Global Health, 18_12, Coronavirus

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          Abstract

          Background

          New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

          Methods

          We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29.

          Results

          A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, −6.8 percentage points; 95% confidence interval, −11.3 to −2.4; P=0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% confidence interval, −5.9 to −0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group.

          Conclusions

          Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.)

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          Most cited references39

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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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            Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network — United States, March–June 2020

            Prolonged symptom duration and disability are common in adults hospitalized with severe coronavirus disease 2019 (COVID-19). Characterizing return to baseline health among outpatients with milder COVID-19 illness is important for understanding the full spectrum of COVID-19–associated illness and tailoring public health messaging, interventions, and policy. During April 15–June 25, 2020, telephone interviews were conducted with a random sample of adults aged ≥18 years who had a first positive reverse transcription–polymerase chain reaction (RT-PCR) test for SARS-CoV-2, the virus that causes COVID-19, at an outpatient visit at one of 14 U.S. academic health care systems in 13 states. Interviews were conducted 14–21 days after the test date. Respondents were asked about demographic characteristics, baseline chronic medical conditions, symptoms present at the time of testing, whether those symptoms had resolved by the interview date, and whether they had returned to their usual state of health at the time of interview. Among 292 respondents, 94% (274) reported experiencing one or more symptoms at the time of testing; 35% of these symptomatic respondents reported not having returned to their usual state of health by the date of the interview (median = 16 days from testing date), including 26% among those aged 18–34 years, 32% among those aged 35–49 years, and 47% among those aged ≥50 years. Among respondents reporting cough, fatigue, or shortness of breath at the time of testing, 43%, 35%, and 29%, respectively, continued to experience these symptoms at the time of the interview. These findings indicate that COVID-19 can result in prolonged illness even among persons with milder outpatient illness, including young adults. Effective public health messaging targeting these groups is warranted. Preventative measures, including social distancing, frequent handwashing, and the consistent and correct use of face coverings in public, should be strongly encouraged to slow the spread of SARS-CoV-2. Prolonged illness is well described in adults with severe COVID-19 requiring hospitalization, especially among older adults ( 1 , 2 ). Recently, the number of SARS-CoV-2 infections in persons first evaluated as outpatients have increased, including cases among younger adults ( 3 ). A better understanding of convalescence and symptom duration among outpatients with COVID-19 can help direct care, inform interventions to reduce transmission, and tailor public health messaging. The Influenza Vaccine Effectiveness in the Critically Ill (IVY) Network, a collaboration of U.S. health care systems, is conducting epidemiologic studies on COVID-19 in both inpatient and outpatient settings ( 4 , 5 ). Fourteen predominantly urban academic health systems in 13 states each submitted a list of adults with positive SARS-CoV-2 RT-PCR test results obtained during March 31–June 4, 2020, to Vanderbilt University Medical Center. Site-specific random sampling was then performed on a subset of these patients who were tested as outpatients and included patients tested in the emergency department (ED) who were not admitted to the hospital at the testing encounter and those tested in other outpatient clinics. At 14–21 days from the test date, CDC personnel interviewed the randomly sampled patients or their proxies by telephone to obtain self-reported baseline demographic, socioeconomic, and underlying health information, including the presence of chronic medical conditions. Call attempts were made for up to seven consecutive days, and interviews were conducted in several languages ( 4 ). Respondents were asked to report the number of days they felt unwell before the test date, COVID-19–related symptoms experienced at the time of testing ( 6 ), whether symptoms had resolved by the date of the interview, and whether the patient had returned to their usual state of health. For this data analysis, respondents were excluded if they did not complete the interview, if a proxy (e.g., family member) completed the interview (because of their incomplete knowledge of symptoms), if they reported a previous positive SARS-CoV-2 test (because the reference date for symptoms questions was unclear), or (because this analysis focused on symptomatic persons) if they did not answer symptoms questions or denied all symptoms at testing. Descriptive statistics were used to compare characteristics among respondents who reported returning and not returning to their usual state of health by the date of the interview. Generalized estimating equation regression models with exchangeable correlation structure accounting for clustering by site were fitted to evaluate the association between baseline characteristics and return to usual health, adjusting for potential a priori-selected confounders. Resolution and duration of individual symptoms were also assessed. Statistical analyses were conducted using Stata software (version 16; StataCorp). At least one telephone call was attempted for 582 patients (including 175 [30%] who were tested in an ED and 407 [70%] in non-ED settings), with 325 (56%) interviews completed (89 [27%] ED and 236 [73%] non-ED). Among 257 nonrespondents, 178 could not be reached, 37 requested a callback but could not be reached on further call attempts, 28 refused the interview, and 14 had a language barrier. Among the 325 completed interviews, 31 were excluded: nine (3%) because a proxy was interviewed, 17 (5%) because a previous positive SARS-CoV-2 test was reported, and five (2%) who did not answer the symptoms questions. Two additional respondents were called prematurely at 7 days and were also excluded.* Among the 292 remaining patient respondents, 274 (94%) reported one or more symptoms at testing and were included in this data analysis. Following outpatient testing, 7% (19 of 262 with available data) reported later being hospitalized, a median of 3.5 days after the test date. The median age of symptomatic respondents was 42.5 years (interquartile range [IQR] = 31–54 years), 142 (52%) were female, 98 (36%) were Hispanic, 96 (35%) were non-Hispanic white, 48 (18%) were non-Hispanic black, and 32 (12%) were other non-Hispanic race. Overall, 141 of 264 (53%) with available data reported one or more chronic medical conditions. The median interval from test to interview date was 16 days (IQR = 14–19 days); the median number of days respondents reported feeling unwell before being tested for SARS-CoV-2 was 3 (IQR = 2–7 days). Return to Usual State of Health Among the 270 of 274 interviewees with available data on return to usual health, † 175 (65%) reported that they had returned to their usual state of health a median of 7 days (IQR = 5–12 days) from the date of testing (Table 1). Ninety-five (35%) reported that they had not returned to their usual state of health at the time of interview. The proportion who had not returned to their usual state of health differed across age groups: 26% of interviewees aged 18–34 years, 32% aged 35–49 years, and 47% aged ≥50 years reported not having returned to their usual state of health (p = 0.010) within 14–21 days after receiving a positive test result. Presence of chronic conditions also affected return to health rates; among 180 persons with no or one chronic medical condition, 39 with two chronic medical conditions, and 44 with three or more chronic medical conditions, 28%, 46%, and 57%, respectively, reported not having returned to their usual state of health (p = 0.003) within 14–21 days after having a positive test result. Among respondents aged 18–34 years with no chronic medical condition, 19% (nine of 48) reported not having returned to their usual state of health. Adjusting for other factors, age ≥50 versus 18–34 years (adjusted odds ratio [aOR] = 2.29; 95% confidence interval [CI] = 1.14–4.58) and reporting three or more versus no chronic medical conditions (aOR = 2.29; 95% CI = 1.07–4.90) were associated with not having returned to usual health (Table 2). Obesity (body mass index ≥30 kg per m2) (aOR 2.31; 95% CI = 1.21–4.42) and reporting a psychiatric condition § (aOR 2.32; 95% CI = 1.17–4.58) also were associated with more than twofold odds of not returning to the patient’s usual health after adjusting for age, sex, and race/ethnicity. TABLE 1 Characteristics of symptomatic outpatients with SARS-CoV-2 real-time reverse transcription–polymerase chain reaction (RT-PCR)—positive test results (N = 270)* who reported returning to usual state of health or not returning to usual state of health at an interview conducted 14–21 days after testing — 14 academic health care systems, † United States, March–June 2020 Characteristic Total Returned to usual health, no. (row %) P-value§ Yes (n = 175) No (n = 95) Sex 0.14 Women 140 85 (61) 55 (39) Men 130 90 (69) 40 (31) Age group (yrs) 0.010 18–34 85 63 (74) 22 (26) 35–49 96 65 (68) 31 (32) ≥50 89 47 (53) 42 (47) Race/Ethnicity 0.29 White, non-Hispanic 94 58 (62) 36 (38) Black, non-Hispanic 46 26 (57) 20 (43) Other race, non-Hispanic 32 24 (75) 8 (25) Hispanic 98 67 (68) 31 (32) Insurance (14 missing) 0.69 No 46 31 (67) 15 (33) Yes 210 135 (64) 75 (36) No. of medical conditions (7 missing) 0.003 0 123 87 (71) 36 (29) 1 57 41 (72) 16 (28) 2 39 21 (54) 18 (46) ≥3 44 19 (43) 25 (57) Individual medical conditions (7 missing all) ¶ Hypertension 64 33 (52) 31 (48) 0.018 Obesity (body mass index >30 kg/m2) 51 23 (45) 28 (55) 0.002 Psychiatric condition 49 23 (47) 26 (53) 0.007 Asthma 36 23 (64) 13 (36) 0.99 Diabetes 28 16 (57) 12 (43) 0.43 Immunosuppressive condition 15 6 (40) 9 (60) 0.047 Autoimmune condition 13 7 (54) 6 (46) 0.44 Blood disorder 8 4 (50) 4 (50) 0.47 Chronic kidney disease 7 3 (43) 4 (57) 0.26 Chronic obstructive pulmonary disease 7 4 (57) 3 (43) 0.71 Liver disease 6 4 (67) 2 (33) 1.00 Neurologic condition 6 3 (50) 3 (50) 0.48 Coronary artery disease 4 3 (75) 1 (25) 1.00 Congestive heart failure 2 2 (100) 0 (0) 0.54 * 294 patients responded to an interview 2–3 weeks after testing, did not report a previous positive SARS-CoV-2 test before the reference test, and answered questions about symptoms. Of these, 276 (94%) reported one or more symptoms at the time of SARS-CoV-2 RT-PCR testing, with 272 (99%) reporting whether they had returned to their usual state of health by the time of the interview. Two additional patients excluded who were called at 7 days, with 270 included here. † Patients were randomly sampled from fourteen academic healthcare systems in 13 states (University of Washington [Washington], Oregon Health and Sciences University [Oregon], University of California Los Angeles and Stanford University [California], Hennepin County Medical Center [Minnesota], Vanderbilt University [Tennessee], Ohio State University [Ohio], Wake Forest University [North Carolina], Montefiore Medical Center [New York], Beth Israel Deaconess Medical Center and Baystate Medical Center [Massachusetts], Intermountain Healthcare [Utah/Idaho], University of Colorado Hospital [Colorado], and Johns Hopkins University [Maryland]). § Respondents who reported returning to usual health and respondents who reported not returning to usual health were compared using the chi-square test or Fisher's exact test. ¶ Excluding seven (3%) patients who did not answer questions about chronic underlying medical conditions; for those who answered questions about underlying conditions, some respondents were missing data on obesity (two), neurologic conditions (one), and psychiatric conditions (one). TABLE 2 Characteristics associated with not returning to usual health among symptomatic outpatients with SARS-CoV-2 real-time reverse transcription–polymerase chain reaction (RT-PCR)–positive test results (N = 270)* reported at an interview conducted 14–21 days after testing — 14 academic health care systems, † United States, March–June 2020 Characteristic Odds of not returning to “usual health” at 14–21 days after testing Unadjusted odds ratio (95% CI)§ Adjusted odds ratio (95% CI)§,¶ Age group (yrs) 18–34 Referent Referent 35–49 1.40 (0.73–2.67) 1.38 (0.71–2.69) ≥50 2.64 (1.39–5.00) 2.29 (1.14–4.58) Sex Women Referent Referent Men 0.68 (0.41–1.13) 0.80 (0.46–1.38) Race/Ethnicity White, non-Hispanic Referent Referent Black, non-Hispanic 1.23 (0.60–2.53) 1.13 (0.53–2.45) Other, non-Hispanic 0.53 (0.21–1.31) 0.63 (0.24–1.61) Hispanic 0.74 (0.40–1.34) 0.83 (0.44–1.58) No. of medical conditions 0 Referent Referent 1 0.94 (0.47–1.89) 0.74 (0.35–1.55) 2 2.09 (1.00–4.38) 1.50 (0.68–3.33) ≥3 3.19 (1.56–6.50) 2.29 (1.07–4.90) Individual medical conditions** Hypertension 1.98 (1.12–3.52) 1.30 (0.67–2.51) Obesity (BMI >30 kg/m2) 2.65 (1.42–4.95) 2.31 (1.21–4.42) Psychiatric condition 2.42 (1.29–4.56) 2.32 (1.17–4.58) Asthma 1.00 (0.48–2.08) 1.02 (0.47–2.20) Diabetes 1.38 (0.62–3.05) 1.06 (0.46–2.44) Immunosuppressive condition 2.84 (0.98–8.26) 2.33 (0.77–7.04) Autoimmune condition 1.55 (0.51–4.76) 1.05 (0.32–3.46) Blood disorder 1.82 (0.45–7.45) 1.43 (0.33–6.24) Chronic kidney disease 2.42 (0.53–11.05) 2.36 (0.48–11.51) Chronic obstructive pulmonary disease 1.34 (0.29–6.12) 0.70 (0.14–3.48) Liver disease 0.88 (0.16–4.90) 0.72 (0.12–4.25) Neurologic condition 1.78 (0.35–9.01) 1.23 (0.23–6.62) Coronary artery disease 0.58 (0.06–5.70) 0.48 (0.05–4.92) Congestive heart failure — — Abbreviations: BMI = body mass index; CI = confidence interval. * 294 patients responded to 14–21-day interview, did not report a previous positive SARS-CoV-2 test before the reference test, and answered questions about symptoms; 276 (94%) of these reported one or more symptoms at the time of SARS-CoV-2 RT-PCR testing, with 272 (99%) reporting whether they had returned to their usual state of health by the time of the interview. Two additional patients who were called at 7 days were excluded, with 270 included here. † Patients were randomly sampled from academic healthcare systems in 13 states (University of Washington [Washington], Oregon Health and Sciences University [Oregon], University of California Los Angeles and Stanford University [California], Hennepin County Medical Center [Minnesota], Vanderbilt University [Tennessee], Ohio State University [Ohio], Wake Forest University [North Carolina], Montefiore Medical Center [New York], Beth Israel Deaconess Medical Center and Baystate Medical Center [Massachusetts], Intermountain Healthcare [Utah/Idaho], University of Colorado Hospital [Colorado], and Johns Hopkins University [Maryland]). § For this analysis, generalized estimation equation (GEE) models with exchangeable correlation structure were used to estimate the association between characteristics and the odds of not returning to usual health by the date of the 14–21-day interview. GEE models were used to account for clustering of cases by site. 95% CIs including 1.00 are not considered statistically significant. ¶ In adjusted GEE models for age, sex, race/ethnicity, and number of chronic medical conditions, the other variables were used to adjust for potential confounders. Models for individual conditions (e.g., hypertension) were adjusted for age, sex, and race/ethnicity. ** Medical conditions are not exclusive and individual patients could have more than one chronic medical condition. Resolution of Symptoms and Duration Among the 274 symptomatic outpatients, the median number of symptoms was seven of 17 listed in the interview tool (IQR = 5–10), with fatigue (71%), cough (61%), and headache (61%) those most commonly reported (Figure). Among respondents who reported fever and chills on the day of testing, these resolved in 97% and 96% of respondents, respectively. Symptoms least likely to have resolved included cough (not resolved in 43% [71 of 166]) and fatigue (not resolved in 35% [68 of 192]); among 90 who reported shortness of breath at the time of testing, this symptom had not resolved in 26 (29%). The median interval to symptom resolution among those who reported individual symptoms at the time of testing but not at the time of the interview ranged from 4 to 8 days from the test date, with the longest intervals reported for loss of smell (median = 8 days; IQR = 5–10.5 days) and loss of taste (median = 8 days; IQR = 4–10 days). Among respondents who reported returning to their usual state of health, 34% (59 of 175) still reported one or more of the 17 queried COVID-related symptoms at the time of the interview. FIGURE Self-reported symptoms at the time of positive SARS-CoV-2 reverse transcription–polymerase chain reaction (RT-PCR) testing results and unresolved symptoms 14–21 days later among outpatients (N = 274)* — 14 academic health care systems, † United States, March–June 2020 * 294 patients responded to 14–21-day interview, did not report a previous positive SARS-CoV-2 test before the reference test, and answered questions about symptoms; 276 (94%) of these reported one or more symptoms at the time of SARS-CoV-2 RT-PCR testing; those who were interviewed at 7 days were excluded, with 274 included here. † Patients were randomly sampled from 14 academic health care systems in 13 states (University of Washington [Washington], Oregon Health and Sciences University [Oregon], University of California Los Angeles and Stanford University [California], Hennepin County Medical Center [Minnesota], Vanderbilt University [Tennessee], Ohio State University [Ohio], Wake Forest University [North Carolina], Montefiore Medical Center [New York], Beth Israel Deaconess Medical Center and Baystate Medical Center [Massachusetts], Intermountain Healthcare [Utah/Idaho], University of Colorado Hospital [Colorado], and Johns Hopkins University [Maryland]). The figure is a bar chart showing self-reported symptoms at the time of positive SARS-CoV-2 reverse transcription–polymerase chain reaction testing results and unresolved symptoms 14–21 days later among outpatients (N = 274), using data from 14 academic health care systems in the United States, during March–June 2020. Discussion Most studies to date have focused on symptoms duration and clinical outcomes in adults hospitalized with severe COVID-19 ( 1 , 2 ). This report indicates that even among symptomatic adults tested in outpatient settings, it might take weeks for resolution of symptoms and return to usual health. Not returning to usual health within 2–3 weeks of testing was reported by approximately one third of respondents. Even among young adults aged 18–34 years with no chronic medical conditions, nearly one in five reported that they had not returned to their usual state of health 14–21 days after testing. In contrast, over 90% of outpatients with influenza recover within approximately 2 weeks of having a positive test result ( 7 ). Older age and presence of multiple chronic medical conditions have previously been associated with illness severity among adults hospitalized with COVID-19 ( 8 , 9 ); in this study, both were also associated with prolonged illness in an outpatient population. Whereas previous studies have found race/ethnicity to be a risk factor for severe COVID-19 illness ( 10 ), this study of patients whose illness was diagnosed in an outpatient setting did not find an association between race/ethnicity and return to usual health although the modest number of respondents might have limited our ability to detect associations. The finding of an association between chronic psychiatric conditions and delayed return to usual health requires further evaluation. These findings have important implications for understanding the full effects of COVID-19, even in persons with milder outpatient illness. Notably, convalescence can be prolonged even in young adults without chronic medical conditions, potentially leading to prolonged absence from work, studies, or other activities. The findings in this report are subject to at least three limitations. First, nonrespondents might have differed from survey respondents; for example, those with more severe illness might have been less likely to respond to telephone calls if they were subsequently hospitalized and unable to answer the telephone. Second, symptoms that resolved before the test date or that commenced after the date of testing were not recorded in this survey. Finally, as a telephone survey, this study relied on patient self-report and might have been subject to incomplete recall or recall bias. Nonhospitalized COVID-19 illness can result in prolonged illness and persistent symptoms, even in young adults and persons with no or few chronic underlying medical conditions. Public health messaging should target populations that might not perceive COVID-19 illness as being severe or prolonged, including young adults and those without chronic underlying medical conditions. Preventative measures, including social distancing, frequent handwashing, and the consistent and correct use of face coverings in public, should be strongly encouraged to slow the spread of SARS-CoV-2. Summary What is already known about this topic? Relatively little is known about the clinical course of COVID-19 and return to baseline health for persons with milder, outpatient illness. What is added by this report? In a multistate telephone survey of symptomatic adults who had a positive outpatient test result for SARS-CoV-2 infection, 35% had not returned to their usual state of health when interviewed 2–3 weeks after testing. Among persons aged 18–34 years with no chronic medical conditions, one in five had not returned to their usual state of health. What are the implications for public health practice? COVID-19 can result in prolonged illness, even among young adults without underlying chronic medical conditions. Effective public health messaging targeting these groups is warranted.
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              Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial

              Coronavirus disease 2019 (COVID-19) continues to spread rapidly worldwide. Neutralizing antibodies are a potential treatment for COVID-19.
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                Author and article information

                Journal
                N Engl J Med
                N Engl J Med
                nejm
                The New England Journal of Medicine
                Massachusetts Medical Society
                0028-4793
                1533-4406
                16 December 2021
                16 December 2021
                : NEJMoa2116044
                Affiliations
                From IMAT Oncomédica, Monteria, Colombia (A.J.B.); the Department of Public Health, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil (M.M.G.S.); Jongaie Research, Pretoria, South Africa (D.B.M.); Medical Research Institute, St. Petersburg, Russia (E.K.); Advanced Research for Health Improvement, Immokalee, FL (A.G.); Lung Center of the Philippines, Quezon City, Philippines (V.D.R.); Hospital Universitario La Paz, IdiPAZ, Madrid (A.M.-Q.); Clinical Pharmacology Unit, Hadassah–Hebrew University Medical Center, Jerusalem (Y.C.); and Merck, Kenilworth, NJ (A.W.-D., M.L.B., J.D., A. Pedley, C.A., J.S., J.A.G., H.H.S., R.T., H.W., A. Paschke, J.R.B., M.G.J., C.D.A.).
                Author notes
                Dr. De Anda can be contacted at Merck, 309 Sumneytown Pike, North Wales, PA 19454.
                [*]

                The members of the MOVe-OUT study group are listed in the Supplementary Appendix, available at NEJM.org.

                Article
                NJ202112163860601
                10.1056/NEJMoa2116044
                8693688
                34914868
                e9d78cc3-3d3a-4e9c-b21f-6b7e320fefe3
                Copyright © 2021 Massachusetts Medical Society. All rights reserved.

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                Funded by: Merck, FundRef http://dx.doi.org/10.13039/100004334;
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