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Rapid expansion, slightly slower decay, and a sharp peak define typical shedding episode morphology. A, We separated 1020 episodes by duration and took median HSV DNA quantity obtained at each time point during episodes to generate stereotypical curves for each of the durations. Episodes are assumed to start at 12 hours before first positive swab result and to end 12 hours after the last positive swab result. B, Connected percentiles for episodes of 4 days duration, including median values (solid line), and 5th and 95th percentiles (dotted lines).
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Herpes simplex virus type 2 (HSV-2) reactivations in the genital tract are responsible for mucocutaneous lesions and transmission and manifest as discrete shedding episodes.
We analyzed duration, peak copy number, and expansion and decay rates of 1020 shedding episodes in 531 immunocompetent HSV-2-seropositive persons from whom daily swabs of genit...
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... of genital herpes was 8 years (IQR, 2–16 years; range, 0–38 years). The cohort was sampled for 106 person-years (per-person median, 62 days; IQR, 56–99 days), and genital swab samples were available from 14 685 days (92%). Sensitivity analyses were performed, limiting included data to a maximum of 30 days per participant (15 930 study days). Of 531 participants, 381 (72%) had at least 1 episode. We identified 1809 separate episodes, of which 1020 were of certain duration, and 1695 were included after interval censoring. We separated episodes into subsets according to duration in days, and calculated median HSV DNA load for each day of the episode, to generate generic episode curves for episodes. Shedding episodes had a characteristic morphology with steep up- ward slope, sharp peak, and more gradual decrease (Figure 1) irrespective of maximal genomic copy or duration. We demonstrated the cumulative effect of all episodes in a histogram showing shedding frequency in quantitative strata. Of 14 685 total swab samples, 2658 (18%) contained HSV DNA. A similar proportion of swab samples ( 3%) contained 10 2 –10 3 , 10 3 –10 4 , 10 4 –10 5 , or 10 6 –10 7 HSV DNA copies/mL; 3.48% of swab samples contained 10 5 –10 6 HSV DNA copies/mL, and only 0.5% of swab samples contained . 10 8 HSV DNA copies/mL (Figure 2). We observed significant heterogeneity in episode duration (Figure 3). Of 1695 episodes analyzed, the median duration was 3 days (IQR, 1–8 days), with 28.8% lasting 1 day and 19.5% lasting . 9 days. There was a wide range of peak viral production with median peak copy number of 10 4.8 HSV DNA copies/mL (geometric mean, 10 4.9 HSV DNA copies/mL). Of 1020 episodes of known duration, 27% peaked at , 10 3 HSV DNA copies/mL. There was a relatively constant proportion of peak copy numbers (10%–15%) in each quantitative stratum of 10 3 –10 8 HSV DNA copies/mL (Figure 4 A ). Only 6% of episodes peaked at . 10 8 HSV DNA copies/mL. We observed a positive association between episode duration and peak copy number (Figure 4 B ). Duration was 1.4 days longer (95% confidence interval [CI], 1.3–1.6 days) for each 1-log increase in maximum genomic copy number ( P , .001). For 1020 episodes, we calculated the median first positive copy number of 10 3.8 HSV DNA copies/mL, which translates to an expansion rate of 7.6 logs per day during the first 12 hours of an episode, although the rate may not have been constant during that time. The frequency of first positive swab result values was similar in the 3 strata (10 3 –10 6 HSV DNA copies), suggesting exponential growth during this expansion phase. However, because of the high percentage of episodes that peaked at , 10 3 HSV DNA copies/mL, more first positive swab samples contained 10 2 –10 3 HSV DNA copies/mL (34%) than 10 3 –10 4 HSV DNA copies/mL (17%). This may also suggest that viral expansion is slower during the initial hours of an episode and increases until HSV DNA copy number surpasses 10 3 copies/mL (Figure 5, A and B ). A lower frequency of first positive swab samples was in the strata with . 10 6 HSV DNA copies/mL. If viral expansion hy- pothetically remained constant throughout the first 24 hours at a mean rate of 7.6 logs per day, there would have been an equivalent proportion of swab samples during the early stratum (10 3 –10 4 HSV DNA copies/mL) and the later stratum (10 8 –10 9 HSV DNA copies/mL). The decrease in frequency from 17% to 2% between these 2 strata suggests that exponential viral expansion rate rapidly decreases during the first 24 hours of an episode. For the 1020 episodes, median regression slope from 12 hours before episode initiation to episode peak was 5.0 logs per day ( , 7.6 logs per day during the first 12 hours of an episode), indicating a decreasing viral expansion rate after the first 12 hours of an episode. Decelerating exponential expansion is also evident in Figure 1. For the 1020 episodes, the median last positive copy number was 10 3.1 HSV DNA copies/mL. The calculated mean rate of decay was –6.2 logs per day during the final 12 hours of the episode. A greater proportion of last positive swab samples contained 10 2 –10 3 HSV DNA copies/mL (48%) than 10 3 –10 4 HSV DNA copies/mL (23%), which may suggest that viral decay rate is slower during the final few hours than during the final 12 hours of an episode. This may also reflect that many episodes never exceed 10 3 HSV DNA copies/mL. The frequency of last positive swab samples decreased at each successive strata . 104 HSV DNA copies/mL, indicating that exponential viral decay rate continually decreased during the last 24 hours. Nevertheless, decay rate remained sufficiently high to terminate each episode (Figure 5, A and B ). The median regression slope from peak to 12 hours after the last positive swab result was –3.6 logs per day (smaller absolute value than 2 6.2 logs during the last 12 hours of an episode). Therefore, decay rate increased substantially from peak to termination (Figure 1), despite an apparent slight decrease during the final 24 hours. Episode decay occurred more slowly than expansion (Figure 1). Juxtaposed histograms of first and last positive swab copy number revealed that a larger proportion of first positive swab results occurred at higher copy numbers (Figure 5, A and B ). Moreover, the absolute value of median slope from initiation to peak was greater than from peak to termination (5.0 vs –3.6 logs/d). Long episodes often had multiple peaks as an important feature (Figure 6 A ). Of 1020 episodes, 198 (19%) had nonmonotonic decay (decrease of at least 0.5 log, followed by increase of at least 0.5 log). Episode duration correlated with likelihood of nonmonotonic decay (Figure 6 B ). Episodes with nonmonotonic decay were longer (mean, 10.7 vs 2.5 days), had higher peaks (mean, 7.0 vs 4.4 log 10 HSV DNA copies/mL), higher first swab copy number (mean, 5.5 vs 4.0 log 10 HSV DNA copies/mL), and lower peak to termination slope (mean, –1.0 vs –4.6 logs per day), despite no difference in last swab copy number (mean, 3.4 vs 3.4 log 10 HSV DNA copies/mL). Three hundred thirty-six (33%) of 1020 episodes occurred while genital lesions were present; genital lesions were noted on 6158 (11%) of 58 299 days and on 2835 (38%) of 7248 days when swab samples were positive for HSV DNA. Shedding episodes with lesions were longer (median, 5 vs 1 days; mean, 6.8 vs 2.9 days; P , .001) and had higher peak copy number (median, 6.7 vs 3.6 log 10 HSV DNA copies/mL; P , .001), first copy number (median, 5.5 vs 3.2 log 10 HSV DNA copies/mL; P , .001), and last copy number (median, 3.5 vs 2.9 log 10 HSV DNA copies/mL; P , .001), compared with nonlesional episodes. Using a generalized estimating equation, we explored whether expansion and decay rates can be described generally for all episodes or whether rates vary by episode duration and must be described separately for longer and shorter episodes. Among episodes without multiple peaks, expansion and decay rates were mildly associated with episode duration. Among 299 episodes lasting for . 2 days with only monotonic decay, regression expansion rate decreased by 0.9 log per day for each 1-day increase in episode duration (from 6.6 at 3 days duration to 4.8 at 5 days duration; P , .001). Decay rate also decreased by 0.5 logs per day for each 1-day increase in episode duration (from 2 3.3 at 3 days duration to 2 2.2 at 5 days duration; P , .001). Episode characteristics (first, last, and peak HSV DNA copy number; expansion and decay rate [logs/d]; duration; and monotonicity) did not differ between HSV-1–seropositive and –seronegative persons or between men and women, with the exception of last swab copy number, which was 0.22 logs lower in men than in women (95% CI, 2 .38 to 2 .06; P 5 .007). All episode characteristics, including expansion and decay rates, were similar according to time since acquisition ( # 1 year vs . 1 year). Only a small percentage of each characteristic’s variability (first [1.9%], last [13.0%], and peak [3.7%] copy number; expansion [9.3%] and decay rate [8.3%]; duration [1.2%]; and probability of monotonicity [2.5%]) could be attributed to individual characteristics. Our analysis of a large, diverse cohort of patients with HSV-2 infection provides, to our knowledge, the first detailed kinetic evaluation of mucosal HSV-2 infection in the healthy host. HSV-2 infection reactivations vary substantially in and among individuals according to duration and peak HSV DNA copy number, 2 measures that strongly correlate. Episodes with higher viral production are more commonly associated with genital lesion formation and nonmonotonic viral decay [1]. Regardless of peak copy number, episodes expand extremely rapidly, with subsequent rapid deceleration, followed by sharp decay, leading to a stereotypical episode appearance with sharp peaks. Duration of the expansion phase varies among episodes, and some episodes are eliminated within hours [1]. However, even during prolonged lesional episodes, the exponential rate of expansion invariably decelerates during the first 24 hours. Moreover, exponential decay rate increases dramatically from episode peak to termination. During the final 24 hours of an episode, exponential decay rate may actually decrease slightly, although decay rate remains sufficiently high to ensure termination of viral replication. Although these observations most obviously pertain to viral kinetics, they indirectly highlight the importance of the mucosal host immune response in containment of viral shedding. The rapid cessation of expansion phase and accelerated decay phase of episodes suggest that the peripheral immune response must be continually primed to rapidly eliminate HSV-infected cells. In a previous study [11], we used a mathematical model to indicate that the most likely mechanism to explain high frequency of annual genital episodes in HSV-2–infected persons is nearly constant release of low numbers of ...
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... median, 62 days; IQR, 56–99 days), and genital swab samples were available from 14 685 days (92%). Sensitivity analyses were performed, limiting included data to a maximum of 30 days per participant (15 930 study days). Of 531 participants, 381 (72%) had at least 1 episode. We identified 1809 separate episodes, of which 1020 were of certain duration, and 1695 were included after interval censoring. We separated episodes into subsets according to duration in days, and calculated median HSV DNA load for each day of the episode, to generate generic episode curves for episodes. Shedding episodes had a characteristic morphology with steep up- ward slope, sharp peak, and more gradual decrease (Figure 1) irrespective of maximal genomic copy or duration. We demonstrated the cumulative effect of all episodes in a histogram showing shedding frequency in quantitative strata. Of 14 685 total swab samples, 2658 (18%) contained HSV DNA. A similar proportion of swab samples ( 3%) contained 10 2 –10 3 , 10 3 –10 4 , 10 4 –10 5 , or 10 6 –10 7 HSV DNA copies/mL; 3.48% of swab samples contained 10 5 –10 6 HSV DNA copies/mL, and only 0.5% of swab samples contained . 10 8 HSV DNA copies/mL (Figure 2). We observed significant heterogeneity in episode duration (Figure 3). Of 1695 episodes analyzed, the median duration was 3 days (IQR, 1–8 days), with 28.8% lasting 1 day and 19.5% lasting . 9 days. There was a wide range of peak viral production with median peak copy number of 10 4.8 HSV DNA copies/mL (geometric mean, 10 4.9 HSV DNA copies/mL). Of 1020 episodes of known duration, 27% peaked at , 10 3 HSV DNA copies/mL. There was a relatively constant proportion of peak copy numbers (10%–15%) in each quantitative stratum of 10 3 –10 8 HSV DNA copies/mL (Figure 4 A ). Only 6% of episodes peaked at . 10 8 HSV DNA copies/mL. We observed a positive association between episode duration and peak copy number (Figure 4 B ). Duration was 1.4 days longer (95% confidence interval [CI], 1.3–1.6 days) for each 1-log increase in maximum genomic copy number ( P , .001). For 1020 episodes, we calculated the median first positive copy number of 10 3.8 HSV DNA copies/mL, which translates to an expansion rate of 7.6 logs per day during the first 12 hours of an episode, although the rate may not have been constant during that time. The frequency of first positive swab result values was similar in the 3 strata (10 3 –10 6 HSV DNA copies), suggesting exponential growth during this expansion phase. However, because of the high percentage of episodes that peaked at , 10 3 HSV DNA copies/mL, more first positive swab samples contained 10 2 –10 3 HSV DNA copies/mL (34%) than 10 3 –10 4 HSV DNA copies/mL (17%). This may also suggest that viral expansion is slower during the initial hours of an episode and increases until HSV DNA copy number surpasses 10 3 copies/mL (Figure 5, A and B ). A lower frequency of first positive swab samples was in the strata with . 10 6 HSV DNA copies/mL. If viral expansion hy- pothetically remained constant throughout the first 24 hours at a mean rate of 7.6 logs per day, there would have been an equivalent proportion of swab samples during the early stratum (10 3 –10 4 HSV DNA copies/mL) and the later stratum (10 8 –10 9 HSV DNA copies/mL). The decrease in frequency from 17% to 2% between these 2 strata suggests that exponential viral expansion rate rapidly decreases during the first 24 hours of an episode. For the 1020 episodes, median regression slope from 12 hours before episode initiation to episode peak was 5.0 logs per day ( , 7.6 logs per day during the first 12 hours of an episode), indicating a decreasing viral expansion rate after the first 12 hours of an episode. Decelerating exponential expansion is also evident in Figure 1. For the 1020 episodes, the median last positive copy number was 10 3.1 HSV DNA copies/mL. The calculated mean rate of decay was –6.2 logs per day during the final 12 hours of the episode. A greater proportion of last positive swab samples contained 10 2 –10 3 HSV DNA copies/mL (48%) than 10 3 –10 4 HSV DNA copies/mL (23%), which may suggest that viral decay rate is slower during the final few hours than during the final 12 hours of an episode. This may also reflect that many episodes never exceed 10 3 HSV DNA copies/mL. The frequency of last positive swab samples decreased at each successive strata . 104 HSV DNA copies/mL, indicating that exponential viral decay rate continually decreased during the last 24 hours. Nevertheless, decay rate remained sufficiently high to terminate each episode (Figure 5, A and B ). The median regression slope from peak to 12 hours after the last positive swab result was –3.6 logs per day (smaller absolute value than 2 6.2 logs during the last 12 hours of an episode). Therefore, decay rate increased substantially from peak to termination (Figure 1), despite an apparent slight decrease during the final 24 hours. Episode decay occurred more slowly than expansion (Figure 1). Juxtaposed histograms of first and last positive swab copy number revealed that a larger proportion of first positive swab results occurred at higher copy numbers (Figure 5, A and B ). Moreover, the absolute value of median slope from initiation to peak was greater than from peak to termination (5.0 vs –3.6 logs/d). Long episodes often had multiple peaks as an important feature (Figure 6 A ). Of 1020 episodes, 198 (19%) had nonmonotonic decay (decrease of at least 0.5 log, followed by increase of at least 0.5 log). Episode duration correlated with likelihood of nonmonotonic decay (Figure 6 B ). Episodes with nonmonotonic decay were longer (mean, 10.7 vs 2.5 days), had higher peaks (mean, 7.0 vs 4.4 log 10 HSV DNA copies/mL), higher first swab copy number (mean, 5.5 vs 4.0 log 10 HSV DNA copies/mL), and lower peak to termination slope (mean, –1.0 vs –4.6 logs per day), despite no difference in last swab copy number (mean, 3.4 vs 3.4 log 10 HSV DNA copies/mL). Three hundred thirty-six (33%) of 1020 episodes occurred while genital lesions were present; genital lesions were noted on 6158 (11%) of 58 299 days and on 2835 (38%) of 7248 days when swab samples were positive for HSV DNA. Shedding episodes with lesions were longer (median, 5 vs 1 days; mean, 6.8 vs 2.9 days; P , .001) and had higher peak copy number (median, 6.7 vs 3.6 log 10 HSV DNA copies/mL; P , .001), first copy number (median, 5.5 vs 3.2 log 10 HSV DNA copies/mL; P , .001), and last copy number (median, 3.5 vs 2.9 log 10 HSV DNA copies/mL; P , .001), compared with nonlesional episodes. Using a generalized estimating equation, we explored whether expansion and decay rates can be described generally for all episodes or whether rates vary by episode duration and must be described separately for longer and shorter episodes. Among episodes without multiple peaks, expansion and decay rates were mildly associated with episode duration. Among 299 episodes lasting for . 2 days with only monotonic decay, regression expansion rate decreased by 0.9 log per day for each 1-day increase in episode duration (from 6.6 at 3 days duration to 4.8 at 5 days duration; P , .001). Decay rate also decreased by 0.5 logs per day for each 1-day increase in episode duration (from 2 3.3 at 3 days duration to 2 2.2 at 5 days duration; P , .001). Episode characteristics (first, last, and peak HSV DNA copy number; expansion and decay rate [logs/d]; duration; and monotonicity) did not differ between HSV-1–seropositive and –seronegative persons or between men and women, with the exception of last swab copy number, which was 0.22 logs lower in men than in women (95% CI, 2 .38 to 2 .06; P 5 .007). All episode characteristics, including expansion and decay rates, were similar according to time since acquisition ( # 1 year vs . 1 year). Only a small percentage of each characteristic’s variability (first [1.9%], last [13.0%], and peak [3.7%] copy number; expansion [9.3%] and decay rate [8.3%]; duration [1.2%]; and probability of monotonicity [2.5%]) could be attributed to individual characteristics. Our analysis of a large, diverse cohort of patients with HSV-2 infection provides, to our knowledge, the first detailed kinetic evaluation of mucosal HSV-2 infection in the healthy host. HSV-2 infection reactivations vary substantially in and among individuals according to duration and peak HSV DNA copy number, 2 measures that strongly correlate. Episodes with higher viral production are more commonly associated with genital lesion formation and nonmonotonic viral decay [1]. Regardless of peak copy number, episodes expand extremely rapidly, with subsequent rapid deceleration, followed by sharp decay, leading to a stereotypical episode appearance with sharp peaks. Duration of the expansion phase varies among episodes, and some episodes are eliminated within hours [1]. However, even during prolonged lesional episodes, the exponential rate of expansion invariably decelerates during the first 24 hours. Moreover, exponential decay rate increases dramatically from episode peak to termination. During the final 24 hours of an episode, exponential decay rate may actually decrease slightly, although decay rate remains sufficiently high to ensure termination of viral replication. Although these observations most obviously pertain to viral kinetics, they indirectly highlight the importance of the mucosal host immune response in containment of viral shedding. The rapid cessation of expansion phase and accelerated decay phase of episodes suggest that the peripheral immune response must be continually primed to rapidly eliminate HSV-infected cells. In a previous study [11], we used a mathematical model to indicate that the most likely mechanism to explain high frequency of annual genital episodes in HSV-2–infected persons is nearly constant release of low numbers of viral particles from sensory nerve endings at the dermal-epidermal junction in the genital tract. After a single epithelial ...
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... in HSV load by 0.5 logs after a prior decrease in the episode of at least 0.5 logs) and episodes with and without associated genital lesions. We used generalized estimating equations to assess associations between episode duration, maximum copy number, and rate of increase and decrease in the same individual [18]. We measured individual correlation for shedding characteristics with use of variance components analysis and examined episode characteristics with use of covariates, including sex, time since acquisition, and HSV-1 coinfection. Noncentrally distributed measures were log transformed before analysis. We included 531 HSV-2–seropositive persons who contributed at least 30 days of genital swabbing and diaries. Two hundred twenty-one participants (42%) were men. The median age was 39 years (interquartile range [IQR], 31–48 years; range, 20–76 years). Two hundred thirty-three participants (44%) were also infected with HSV-1, whereas 437 (82%) reported a history of recognized genital lesions. The median time since acquisition for persons with recollection of their first episode of genital herpes was 8 years (IQR, 2–16 years; range, 0–38 years). The cohort was sampled for 106 person-years (per-person median, 62 days; IQR, 56–99 days), and genital swab samples were available from 14 685 days (92%). Sensitivity analyses were performed, limiting included data to a maximum of 30 days per participant (15 930 study days). Of 531 participants, 381 (72%) had at least 1 episode. We identified 1809 separate episodes, of which 1020 were of certain duration, and 1695 were included after interval censoring. We separated episodes into subsets according to duration in days, and calculated median HSV DNA load for each day of the episode, to generate generic episode curves for episodes. Shedding episodes had a characteristic morphology with steep up- ward slope, sharp peak, and more gradual decrease (Figure 1) irrespective of maximal genomic copy or duration. We demonstrated the cumulative effect of all episodes in a histogram showing shedding frequency in quantitative strata. Of 14 685 total swab samples, 2658 (18%) contained HSV DNA. A similar proportion of swab samples ( 3%) contained 10 2 –10 3 , 10 3 –10 4 , 10 4 –10 5 , or 10 6 –10 7 HSV DNA copies/mL; 3.48% of swab samples contained 10 5 –10 6 HSV DNA copies/mL, and only 0.5% of swab samples contained . 10 8 HSV DNA copies/mL (Figure 2). We observed significant heterogeneity in episode duration (Figure 3). Of 1695 episodes analyzed, the median duration was 3 days (IQR, 1–8 days), with 28.8% lasting 1 day and 19.5% lasting . 9 days. There was a wide range of peak viral production with median peak copy number of 10 4.8 HSV DNA copies/mL (geometric mean, 10 4.9 HSV DNA copies/mL). Of 1020 episodes of known duration, 27% peaked at , 10 3 HSV DNA copies/mL. There was a relatively constant proportion of peak copy numbers (10%–15%) in each quantitative stratum of 10 3 –10 8 HSV DNA copies/mL (Figure 4 A ). Only 6% of episodes peaked at . 10 8 HSV DNA copies/mL. We observed a positive association between episode duration and peak copy number (Figure 4 B ). Duration was 1.4 days longer (95% confidence interval [CI], 1.3–1.6 days) for each 1-log increase in maximum genomic copy number ( P , .001). For 1020 episodes, we calculated the median first positive copy number of 10 3.8 HSV DNA copies/mL, which translates to an expansion rate of 7.6 logs per day during the first 12 hours of an episode, although the rate may not have been constant during that time. The frequency of first positive swab result values was similar in the 3 strata (10 3 –10 6 HSV DNA copies), suggesting exponential growth during this expansion phase. However, because of the high percentage of episodes that peaked at , 10 3 HSV DNA copies/mL, more first positive swab samples contained 10 2 –10 3 HSV DNA copies/mL (34%) than 10 3 –10 4 HSV DNA copies/mL (17%). This may also suggest that viral expansion is slower during the initial hours of an episode and increases until HSV DNA copy number surpasses 10 3 copies/mL (Figure 5, A and B ). A lower frequency of first positive swab samples was in the strata with . 10 6 HSV DNA copies/mL. If viral expansion hy- pothetically remained constant throughout the first 24 hours at a mean rate of 7.6 logs per day, there would have been an equivalent proportion of swab samples during the early stratum (10 3 –10 4 HSV DNA copies/mL) and the later stratum (10 8 –10 9 HSV DNA copies/mL). The decrease in frequency from 17% to 2% between these 2 strata suggests that exponential viral expansion rate rapidly decreases during the first 24 hours of an episode. For the 1020 episodes, median regression slope from 12 hours before episode initiation to episode peak was 5.0 logs per day ( , 7.6 logs per day during the first 12 hours of an episode), indicating a decreasing viral expansion rate after the first 12 hours of an episode. Decelerating exponential expansion is also evident in Figure 1. For the 1020 episodes, the median last positive copy number was 10 3.1 HSV DNA copies/mL. The calculated mean rate of decay was –6.2 logs per day during the final 12 hours of the episode. A greater proportion of last positive swab samples contained 10 2 –10 3 HSV DNA copies/mL (48%) than 10 3 –10 4 HSV DNA copies/mL (23%), which may suggest that viral decay rate is slower during the final few hours than during the final 12 hours of an episode. This may also reflect that many episodes never exceed 10 3 HSV DNA copies/mL. The frequency of last positive swab samples decreased at each successive strata . 104 HSV DNA copies/mL, indicating that exponential viral decay rate continually decreased during the last 24 hours. Nevertheless, decay rate remained sufficiently high to terminate each episode (Figure 5, A and B ). The median regression slope from peak to 12 hours after the last positive swab result was –3.6 logs per day (smaller absolute value than 2 6.2 logs during the last 12 hours of an episode). Therefore, decay rate increased substantially from peak to termination (Figure 1), despite an apparent slight decrease during the final 24 hours. Episode decay occurred more slowly than expansion (Figure 1). Juxtaposed histograms of first and last positive swab copy number revealed that a larger proportion of first positive swab results occurred at higher copy numbers (Figure 5, A and B ). Moreover, the absolute value of median slope from initiation to peak was greater than from peak to termination (5.0 vs –3.6 logs/d). Long episodes often had multiple peaks as an important feature (Figure 6 A ). Of 1020 episodes, 198 (19%) had nonmonotonic decay (decrease of at least 0.5 log, followed by increase of at least 0.5 log). Episode duration correlated with likelihood of nonmonotonic decay (Figure 6 B ). Episodes with nonmonotonic decay were longer (mean, 10.7 vs 2.5 days), had higher peaks (mean, 7.0 vs 4.4 log 10 HSV DNA copies/mL), higher first swab copy number (mean, 5.5 vs 4.0 log 10 HSV DNA copies/mL), and lower peak to termination slope (mean, –1.0 vs –4.6 logs per day), despite no difference in last swab copy number (mean, 3.4 vs 3.4 log 10 HSV DNA copies/mL). Three hundred thirty-six (33%) of 1020 episodes occurred while genital lesions were present; genital lesions were noted on 6158 (11%) of 58 299 days and on 2835 (38%) of 7248 days when swab samples were positive for HSV DNA. Shedding episodes with lesions were longer (median, 5 vs 1 days; mean, 6.8 vs 2.9 days; P , .001) and had higher peak copy number (median, 6.7 vs 3.6 log 10 HSV DNA copies/mL; P , .001), first copy number (median, 5.5 vs 3.2 log 10 HSV DNA copies/mL; P , .001), and last copy number (median, 3.5 vs 2.9 log 10 HSV DNA copies/mL; P , .001), compared with nonlesional episodes. Using a generalized estimating equation, we explored whether expansion and decay rates can be described generally for all episodes or whether rates vary by episode duration and must be described separately for longer and shorter episodes. Among episodes without multiple peaks, expansion and decay rates were mildly associated with episode duration. Among 299 episodes lasting for . 2 days with only monotonic decay, regression expansion rate decreased by 0.9 log per day for each 1-day increase in episode duration (from 6.6 at 3 days duration to 4.8 at 5 days duration; P , .001). Decay rate also decreased by 0.5 logs per day for each 1-day increase in episode duration (from 2 3.3 at 3 days duration to 2 2.2 at 5 days duration; P , .001). Episode characteristics (first, last, and peak HSV DNA copy number; expansion and decay rate [logs/d]; duration; and monotonicity) did not differ between HSV-1–seropositive and –seronegative persons or between men and women, with the exception of last swab copy number, which was 0.22 logs lower in men than in women (95% CI, 2 .38 to 2 .06; P 5 .007). All episode characteristics, including expansion and decay rates, were similar according to time since acquisition ( # 1 year vs . 1 year). Only a small percentage of each characteristic’s variability (first [1.9%], last [13.0%], and peak [3.7%] copy number; expansion [9.3%] and decay rate [8.3%]; duration [1.2%]; and probability of monotonicity [2.5%]) could be attributed to individual characteristics. Our analysis of a large, diverse cohort of patients with HSV-2 infection provides, to our knowledge, the first detailed kinetic evaluation of mucosal HSV-2 infection in the healthy host. HSV-2 infection reactivations vary substantially in and among individuals according to duration and peak HSV DNA copy number, 2 measures that strongly correlate. Episodes with higher viral production are more commonly associated with genital lesion formation and nonmonotonic viral decay [1]. Regardless of peak copy number, episodes expand extremely rapidly, with subsequent rapid deceleration, followed by sharp decay, leading to a stereotypical episode appearance with sharp peaks. Duration of the ...
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... type-common primers to the HSV gene encoding glycoprotein B [15]: Type-specific PCR assay was not performed, because in prior studies, , 10% of swab samples were likely to test HSV-1 positive [1]. An internal control was included to ensure that negative swab samples were not caused by inhibition. Laboratory personnel were blinded to clinical data. We defined each shedding episode according to peak copy number, expansion rate, and decay rate and used frequency histograms to describe ranges of values for all episodes [16]. For each measure, we only included episodes of known duration (preceded and followed by at least 2 negative swab results). We estimated duration by the number of consecutive swab samples containing at least 150 copies/mL of HSV (preceded and followed by 2 negative swab results). Because swab samples were obtained every 24 hours, episodes could have initiated within 0–24 hours before the first positive swab result of the episode and terminated within 0–24 hours after the last positive swab result. We assumed that swab timing was independent from timing of the episode and, therefore, that the midpoint of this interval would provide an unbiased estimate of duration [17]. Therefore, for duration, we assumed that episodes began 12 hours before the first positive swab result and ended 12 hours after the last positive swab result. Occasionally, only missed swab samples separated successive episodes; using survival analysis with interval censoring, we combined such episodes to form a single episode with longer maximum duration. Survival analysis was used because the longest episodes were most likely to have missing swab samples. We defined peak episode copy number as the greatest quantity of HSV DNA copies/mL during an episode. Because of rapid kinetics of viral expansion, values for the first positive swab result were, in part, a reflection of duration of the episode. Therefore, we assumed that median episode duration was 12 hours at the first positive swab result. We calculated median exponential expansion slope during the first 12 hours of an episode by dividing the median value for the first positive swab result by 0.5 days. Because of rapid kinetics of viral decay, values for the last positive swab result reflected remaining time in the episode at the time of the swab. Expo- nential slope of decay during the final 12 hours of an episode was calculated by dividing the median last positive swab result value by 0.5 days. We calculated rate of increase from initiation to peak of each episode by computing linear regression line slope over copy numbers up to and including maximum copy and setting time of the most proximal negative swab result at 0.5 days before the first positive. We calculated rate of decrease from peak to termination by setting time of termination to 0.5 days after the last positive result. We calculated a median for each slope on the basis of results from all episodes. We performed separate analyses of episode characteristics for episodes with and without nonmonotonic decay (defined as an increase in HSV load by 0.5 logs after a prior decrease in the episode of at least 0.5 logs) and episodes with and without associated genital lesions. We used generalized estimating equations to assess associations between episode duration, maximum copy number, and rate of increase and decrease in the same individual [18]. We measured individual correlation for shedding characteristics with use of variance components analysis and examined episode characteristics with use of covariates, including sex, time since acquisition, and HSV-1 coinfection. Noncentrally distributed measures were log transformed before analysis. We included 531 HSV-2–seropositive persons who contributed at least 30 days of genital swabbing and diaries. Two hundred twenty-one participants (42%) were men. The median age was 39 years (interquartile range [IQR], 31–48 years; range, 20–76 years). Two hundred thirty-three participants (44%) were also infected with HSV-1, whereas 437 (82%) reported a history of recognized genital lesions. The median time since acquisition for persons with recollection of their first episode of genital herpes was 8 years (IQR, 2–16 years; range, 0–38 years). The cohort was sampled for 106 person-years (per-person median, 62 days; IQR, 56–99 days), and genital swab samples were available from 14 685 days (92%). Sensitivity analyses were performed, limiting included data to a maximum of 30 days per participant (15 930 study days). Of 531 participants, 381 (72%) had at least 1 episode. We identified 1809 separate episodes, of which 1020 were of certain duration, and 1695 were included after interval censoring. We separated episodes into subsets according to duration in days, and calculated median HSV DNA load for each day of the episode, to generate generic episode curves for episodes. Shedding episodes had a characteristic morphology with steep up- ward slope, sharp peak, and more gradual decrease (Figure 1) irrespective of maximal genomic copy or duration. We demonstrated the cumulative effect of all episodes in a histogram showing shedding frequency in quantitative strata. Of 14 685 total swab samples, 2658 (18%) contained HSV DNA. A similar proportion of swab samples ( 3%) contained 10 2 –10 3 , 10 3 –10 4 , 10 4 –10 5 , or 10 6 –10 7 HSV DNA copies/mL; 3.48% of swab samples contained 10 5 –10 6 HSV DNA copies/mL, and only 0.5% of swab samples contained . 10 8 HSV DNA copies/mL (Figure 2). We observed significant heterogeneity in episode duration (Figure 3). Of 1695 episodes analyzed, the median duration was 3 days (IQR, 1–8 days), with 28.8% lasting 1 day and 19.5% lasting . 9 days. There was a wide range of peak viral production with median peak copy number of 10 4.8 HSV DNA copies/mL (geometric mean, 10 4.9 HSV DNA copies/mL). Of 1020 episodes of known duration, 27% peaked at , 10 3 HSV DNA copies/mL. There was a relatively constant proportion of peak copy numbers (10%–15%) in each quantitative stratum of 10 3 –10 8 HSV DNA copies/mL (Figure 4 A ). Only 6% of episodes peaked at . 10 8 HSV DNA copies/mL. We observed a positive association between episode duration and peak copy number (Figure 4 B ). Duration was 1.4 days longer (95% confidence interval [CI], 1.3–1.6 days) for each 1-log increase in maximum genomic copy number ( P , .001). For 1020 episodes, we calculated the median first positive copy number of 10 3.8 HSV DNA copies/mL, which translates to an expansion rate of 7.6 logs per day during the first 12 hours of an episode, although the rate may not have been constant during that time. The frequency of first positive swab result values was similar in the 3 strata (10 3 –10 6 HSV DNA copies), suggesting exponential growth during this expansion phase. However, because of the high percentage of episodes that peaked at , 10 3 HSV DNA copies/mL, more first positive swab samples contained 10 2 –10 3 HSV DNA copies/mL (34%) than 10 3 –10 4 HSV DNA copies/mL (17%). This may also suggest that viral expansion is slower during the initial hours of an episode and increases until HSV DNA copy number surpasses 10 3 copies/mL (Figure 5, A and B ). A lower frequency of first positive swab samples was in the strata with . 10 6 HSV DNA copies/mL. If viral expansion hy- pothetically remained constant throughout the first 24 hours at a mean rate of 7.6 logs per day, there would have been an equivalent proportion of swab samples during the early stratum (10 3 –10 4 HSV DNA copies/mL) and the later stratum (10 8 –10 9 HSV DNA copies/mL). The decrease in frequency from 17% to 2% between these 2 strata suggests that exponential viral expansion rate rapidly decreases during the first 24 hours of an episode. For the 1020 episodes, median regression slope from 12 hours before episode initiation to episode peak was 5.0 logs per day ( , 7.6 logs per day during the first 12 hours of an episode), indicating a decreasing viral expansion rate after the first 12 hours of an episode. Decelerating exponential expansion is also evident in Figure 1. For the 1020 episodes, the median last positive copy number was 10 3.1 HSV DNA copies/mL. The calculated mean rate of decay was –6.2 logs per day during the final 12 hours of the episode. A greater proportion of last positive swab samples contained 10 2 –10 3 HSV DNA copies/mL (48%) than 10 3 –10 4 HSV DNA copies/mL (23%), which may suggest that viral decay rate is slower during the final few hours than during the final 12 hours of an episode. This may also reflect that many episodes never exceed 10 3 HSV DNA copies/mL. The frequency of last positive swab samples decreased at each successive strata . 104 HSV DNA copies/mL, indicating that exponential viral decay rate continually decreased during the last 24 hours. Nevertheless, decay rate remained sufficiently high to terminate each episode (Figure 5, A and B ). The median regression slope from peak to 12 hours after the last positive swab result was –3.6 logs per day (smaller absolute value than 2 6.2 logs during the last 12 hours of an episode). Therefore, decay rate increased substantially from peak to termination (Figure 1), despite an apparent slight decrease during the final 24 hours. Episode decay occurred more slowly than expansion (Figure 1). Juxtaposed histograms of first and last positive swab copy number revealed that a larger proportion of first positive swab results occurred at higher copy numbers (Figure 5, A and B ). Moreover, the absolute value of median slope from initiation to peak was greater than from peak to termination (5.0 vs –3.6 logs/d). Long episodes often had multiple peaks as an important feature (Figure 6 A ). Of 1020 episodes, 198 (19%) had nonmonotonic decay (decrease of at least 0.5 log, followed by increase of at least 0.5 log). Episode duration correlated with likelihood of nonmonotonic decay (Figure 6 B ). Episodes with nonmonotonic decay were longer (mean, 10.7 vs 2.5 days), had higher ...
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Citations
... In the complicated reaction steps of the LAMP, GCrich targets may cause unexpected dimers between the primers themselves or between the primers and amplicons. According to a previous study, viral shedding of HSV-2 frequently occurred at rates of 10 5.2 copies/mL (10 2.2 copies/µL) and exhibited high infectivity [30,31]. Therefore, our LAMP assay displays adequate sensitivity to detect a transmissible number of BV. ...
Herpes B virus (BV) is a zoonotic virus which can be transmitted from macaques to humans, which is often associated with high mortality rates. Because macaques often exhibit asymptomatic infections, individuals who come into contact with these animals face unexpected risks of BV infections. A serological test is widely performed to investigate BV infections. However, the assay’s sensitivity and specificity appeared to be inadequate, and it does not necessarily indicate ongoing viral shedding. Here, we developed LAMP and qPCR assays aiming to detect BVs with a high sensitivity and specificity in various macaque species and validated them using oral swab samples collected from 97 wild cynomolgus macaques living in Thailand. Our LAMP and qPCR assays detected more than 50 and 10 copies of the target sequences per reaction, respectively. The LAMP assay could detect BV within 25 min, indicating its advantages for the rapid detection of BV. Collectively, our findings indicated that both assays developed in this study exhibit advantages and usefulness for BV surveillance and the diagnosis of BV infections in macaques. Furthermore, for the first time, we determined the partial genome sequences of BVs detected in cynomolgus macaques in Thailand. Phylogenetic analysis revealed the species-specific evolution of BV within macaques.
... In the complicated reaction steps of LAMP, GC-rich targets may cause unexpected dimers between the primers themselves or between the primers and amplicons. According to a previous study, viral shedding of HSV-2 frequently occurred at rates of 10 5.2 copies/ml (10 2.2 copies/µl) and exhibited high infectivity [30,31]. Therefore, our LAMP assay displays adequate sensitivity to detect a transmissible number of BV. ...
Herpes B virus (BV) is a zoonotic virus which can be transmitted from macaques to humans, which is often associated with high mortality rates. Because macaques often exhibit asymptomatic infections, individuals who come into contact with these animals face unexpected risks of BV infections. Serological test is widely performed to investigate BV infections. However, the assay’s sensitivity and specificity appeared to be inadequate, and it does not necessarily indicate ongoing viral shedding. Here, we developed LAMP and qPCR assays aiming to detect BVs with high sensitivity and specificity in various macaque species and validated them using oral swab samples collected from 97 wild cynomolgus macaques living in Thailand. Our LAMP and qPCR assays detected more than 50 and 10 copies of the target sequences per reaction, respectively. The LAMP assay could detect BV within 25 min, indicating its advantages for the rapid detection of BV. Collectively, our findings indicated that both assays developed in this study exhibit advantages and usefulness for BV surveillance and diagnosis of BV infections in macaques. Furthermore, for the first time, we determined the partial genome sequences of BVs detected in cynomolgus macaques in Thailand. Phylogenetic analysis revealed the species-specific evolution of BV within macaques.
... Question 2 was addressed for SARS-CoV-2 in Gandhi et al. [14]. Both questions were indirectly addressed by exploring the microscopic dynamics of infection by poliomyelitis viruses [15], Moloney sarcoma virus [16,17], and herpes simplex virus-2 [18]. It is common for a person not to be able to avoid sharing limited space with other people. ...
... and their crossing point, described by Eq.(18), are marked by circles. At the left of the crossing point,π (N c = 1) >π (N c = ∞) and at the right of the crossing point,π (N c = 1) <π (N c = ∞). ...
A primary concern in epidemics is to minimize the probability of contagion, often resorting to reducing the number of contacted people. However, the success of that strategy depends on the shape of the dose-response curve, which relates the response of the exposed person to the pathogen dose received from surrounding infected people. If the reduction is achieved by spending more time with each contacted person, the pathogen charge received from each infected individual will be larger. The extended time spent close to each person may worsen the expected response if the dose-response curve is convex for small doses. This is the case when the expected response is negligible below a certain dose threshold and rises sharply above it. This study proposes a mathematical model to calculate the expected response and uses it to identify the conditions when it would be advisable to reduce the contact time with each individual even at the cost of increasing the number of contacted people.
... Episodes of shedding are clustered together and last a median of 3 days, with longer shedding episodes in the presence of a lesion, lasting a mean of 6.8 days ( Fig. 6) (Wald et al. 1995;Schiffer et al. 2011). However, shedding occurs most frequently in the absence of genital symptoms or lesions ("subclinical shedding") (Wald et al. 1995;Tronstein et al. 2011). ...
... During each 30-day series of at-home swab collection, participants were instructed to rub a sterile swab over the entire genital region (i.e. vaginal or penile area, followed by external anal area; this encompasses the entire anogenital area), as in prior studies of genital HSV shedding [16,53]. For surveillance of oral shedding, participants were instructed to rub a sterile swab across the entire oral area (i.e. ...
Herpes simplex virus (HSV) causes chronic infection in the human host, characterized by self-limited episodes of mucosal shedding and lesional disease, with latent infection of neuronal ganglia. The epidemiology of genital herpes has undergone a significant transformation over the past two decades, with the emergence of HSV-1 as a leading cause of first-episode genital herpes in many countries. Though dsDNA viruses are not expected to mutate quickly, it is not yet known to what degree the HSV-1 viral population in a natural host adapts over time, or how often viral population variants are transmitted between hosts. This study provides a comparative genomics analysis for 33 temporally-sampled oral and genital HSV-1 genomes derived from five adult sexual transmission pairs. We found that transmission pairs harbored consensus-level viral genomes with near-complete conservation of nucleotide identity. Examination of within-host minor variants in the viral population revealed both shared and unique patterns of genetic diversity between partners, and between anatomical niches. Additionally, genetic drift was detected from spatiotemporally separated samples in as little as three days. These data expand our prior understanding of the complex interaction between HSV-1 genomics and population dynamics after transmission to new infected persons.
... Our estimate of a rapid viral peak and subsequent slower decline has been demonstrated in prior mathematical models of SARS-CoV-2 infection and other respiratory viruses, such as respiratory syncytial virus, human rhinovirus, and H1N1, using molecular detection as well as chronic nonrespiratory viral infections, such as herpes simplex virus. 29,[41][42][43][44][45] Our observation of a lower viral load at the initiation of viral shedding with a peak viral load shortly after shedding onset suggests a rapid viral production after acquisition. The transition from the peak to viral decay occurs quickly, and the magnitude of the peak correlates with the duration of the shedding episode (intense and extended infection). ...
Importance
The SARS-CoV-2 viral trajectory has not been well characterized in incident infections. These data are needed to inform natural history, prevention practices, and therapeutic development.
Objective
To characterize early SARS-CoV-2 viral RNA load (hereafter referred to as viral load) in individuals with incident infections in association with COVID-19 symptom onset and severity.
Design, Setting, and Participants
This prospective cohort study was a secondary data analysis of a remotely conducted study that enrolled 829 asymptomatic community-based participants recently exposed (<96 hours) to persons with SARS-CoV-2 from 41 US states from March 31 to August 21, 2020. Two cohorts were studied: (1) participants who were SARS-CoV-2 negative at baseline and tested positive during study follow-up, and (2) participants who had 2 or more positive swabs during follow-up, regardless of the initial (baseline) swab result. Participants collected daily midturbinate swab samples for SARS-CoV-2 RNA detection and maintained symptom diaries for 14 days.
Exposure
Laboratory-confirmed SARS-CoV-2 infection.
Main Outcomes and Measures
The observed SARS-CoV-2 viral load among incident infections was summarized, and piecewise linear mixed-effects models were used to estimate the characteristics of viral trajectories in association with COVID-19 symptom onset and severity.
Results
A total of 97 participants (55 women [57%]; median age, 37 years [IQR, 27-52 years]) developed incident infections during follow-up. Forty-two participants (43%) had viral shedding for 1 day (median peak viral load cycle threshold [Ct] value, 38.5 [95% CI, 38.3-39.0]), 18 (19%) for 2 to 6 days (median Ct value, 36.7 [95% CI, 30.2-38.1]), and 31 (32%) for 7 days or more (median Ct value, 18.3 [95% CI, 17.4-22.0]). The cycle threshold value has an inverse association with viral load. Six participants (6%) had 1 to 6 days of viral shedding with censored duration. The peak mean (SD) viral load was observed on day 3 of shedding (Ct value, 33.8 [95% CI, 31.9-35.6]). Based on the statistical models fitted to 129 participants (60 men [47%]; median age, 38 years [IQR, 25-54 years]) with 2 or more SARS-CoV-2–positive swab samples, persons reporting moderate or severe symptoms tended to have a higher peak mean viral load than those who were asymptomatic (Ct value, 23.3 [95% CI, 22.6-24.0] vs 30.7 [95% CI, 29.8-31.4]). Mild symptoms generally started within 1 day of peak viral load, and moderate or severe symptoms 2 days after peak viral load. All 535 sequenced samples detected the G614 variant (Wuhan strain).
Conclusions and Relevance
This cohort study suggests that having incident SARS-CoV-2 G614 infection was associated with a rapid viral load peak followed by slower decay. COVID-19 symptom onset generally coincided with peak viral load, which correlated positively with symptom severity. This longitudinal evaluation of the SARS-CoV-2 G614 with frequent molecular testing serves as a reference for comparing emergent viral lineages to inform clinical trial designs and public health strategies to contain the spread of the virus.
... However, it also suggests that HSV-1 has evolved an efficient mechanism to shed progeny virions in the tissues associated with transmission. Although HSV-1 shedding has not been well studied, clues to this process can be gleaned from work on HSV-2 shedding that has been carried for more than 20 years by investigators at the University of Washington (UW) [8,13,[96][97][98][99][100][101]. A groundbreaking initial study enlisted HSV-2-positive individuals to swab their genitalia over the course of many weeks and provide the samples to the clinic for PCR-detection of virus [101]. ...
... Since then, the HSV-2 shedding studies at UW have advanced in several ways and continue to lead to new insights. First, sampling protocols were broadened to increase the frequency of testing as well as the spatial detail of the anatomical surfaces assayed (e.g., in some studies, individuals swabbed >20 distinct but contiguous areas of their epithelia) [97,99]. A key insight to emerge from this work was that HSV-2 reactivation is extremely heterogenous, even in a single individual, in regards to the location, strength, and duration of the events. ...
Herpes simplex virus type 1, or HSV-1, is a widespread human pathogen that replicates in epithelial cells of the body surface and then establishes latent infection in peripheral neurons. When HSV-1 replicates, viral progeny must be efficiently released to spread infection to new target cells. Viral spread occurs via two major routes. In cell-cell spread, progeny virions are delivered directly to cellular junctions, where they infect adjacent cells. In cell-free release, progeny virions are released into the extracellular milieu, potentially allowing the infection of distant cells. Cell-cell spread of HSV-1 has been well studied and is known to be important for in vivo infection and pathogenesis. In contrast, HSV-1 cell-free release has received less attention, and its significance to viral biology is unclear. Here, I review the mechanisms and regulation of HSV-1 cell-free virion release. Based on knowledge accrued in other herpesviral systems, I argue that HSV-1 cell-free release is likely to be tightly regulated in vivo. Specifically, I hypothesize that this process is generally suppressed as the virus replicates within the body, but activated to high levels at sites of viral reactivation, such as the oral mucosa and skin, in order to promote efficient transmission of HSV-1 to new human hosts.
... Our estimate of a rapid viral peak and subsequent slower decline has been demonstrated in prior mathematical models of SARS-CoV-2 infection and other respiratory viruses using molecular detection such as RSV, HRV, H1N1, as well as chronic non-respiratory viral infections such as HSV. 37,47,[49][50][51][52][53] Our observation of lower viral load at the initiation of viral shedding with a peak viral load shortly after shedding onset suggests a rapid viral production following viral acquisition. The transition from the peak to the viral decay occurs quickly and the magnitude of the peak viral seems to dictate the duration of the shedding episode (intense and extended infection). ...
Importance: SARS-CoV-2 viral trajectory has not been well-characterized in documented incident infections. These data will inform SARS-CoV-2 natural history, transmission dynamics, prevention practices, and therapeutic development.
Objective: To prospectively characterize early SARS-CoV-2 viral shedding in persons with incident infection.
Design: Prospective cohort study.
Setting: Secondary data analysis from a multicenter study in the U.S.
Participants: The samples derived from a randomized controlled trial of 829 community-based asymptomatic participants recently exposed (<96 hours) to persons with SARS-CoV-2. Participants collected daily mid-turbinate swabs for SARS-CoV-2 detection by polymerase-chain-reaction and symptom diaries for 14-days. Persons with negative swab for SARS-CoV-2 at baseline who developed infection during the study were included in the analysis.
Exposure: Laboratory-confirmed SARS-CoV-2 infection.
Main outcomes and measures: The observed SARS-CoV-2 viral shedding characteristics were summarized and shedding trajectories were examined using a piece-wise linear mixed-effects modeling. Whole viral genome sequencing was performed on samples with cycle threshold (Ct)<34.
Results: Ninety-seven persons (57% women, median age 37-years) developed incident infections during 14-days of follow-up. Two-hundred fifteen sequenced samples were assigned to 15 lineages that belonged to the G614 variant. Forty-two (43%), 18(19%), and 31(32%) participants had viral shedding for 1 day, 2-6 days, and >7 days, with median peak viral load Ct of 38.5, 36.7, and 18.3, respectively. Six (6%) participants had 1-6 days of observed viral shedding with censored duration. The peak average viral load was observed on day 3 of viral shedding. The average Ct value was lower, indicating higher viral load, in persons reporting COVID-19 symptoms than asymptomatic. Using the statistical model, the median time from shedding onset to peak viral load was 1.4 days followed by a median of 9.7 days before clearance.
Conclusions and Relevance: Incident SARS-CoV-2 G614 infection resulted in a rapid viral load peak followed by slower decay and positive correlation between peak viral load and shedding duration; duration of shedding was heterogeneous. This longitudinal evaluation of the SARS-CoV-2 G614 variant with frequent molecular testing may serve as a reference for comparing emergent viral lineages to inform clinical trial designs and public health strategies to contain the spread of the virus.
... There is no way to predict the timing of viral shedding (i.e., viral release from the skin), nor to intentionally trigger a reactivation to allow precise sample collection on a clinicallycontrolled timeline ( Johnston and Corey, 2015). Thus most studies on the natural ecology of HSV shedding have utilized repeated sample collections, spanning days or weeks, in order to document the rate and frequency of viral shedding and lesions ( Johnston et al., 2014;Ramchandani et al., 2016;Schiffer et al., 2011;van Velzen et al., 2013). ...
Over the last two decades, the viromes of our closest relatives, the African great apes (AGA), have been intensively studied. Comparative approaches have unveiled diverse evolutionary patterns, highlighting both stable host-virus associations over extended evolutionary timescales and much more recent viral emergence events. In this chapter, we summarize these findings and outline how they have shed a new light on the origins and evolution of many human-infecting viruses. We also show how this knowledge can be used to better understand the evolution of human health in relation to viral infections.
... There is no way to predict the timing of viral shedding (i.e., viral release from the skin), nor to intentionally trigger a reactivation to allow precise sample collection on a clinically-controlled timeline (Johnston and Corey, 2015). Thus most studies on the natural ecology of HSV shedding have utilized repeated sample collections, spanning days or weeks, in order to document the rate and frequency of viral shedding and lesions (Johnston et al., 2014;Ramchandani et al., 2016;Schiffer et al., 2011;van Velzen et al., 2013). ...
Herpes simplex viruses (HSV) cause chronic infection in humans that are characterized by periodic episodes of mucosal shedding and ulcerative disease. HSV causes millions of infections world-wide, with lifelong bouts of viral reactivation from latency in neuronal ganglia. Infected individuals experience different levels of disease severity and frequency of reactivation. There are two distantly related HSV species, with HSV-1 infections historically found most often in the oral niche and HSV-2 infections in the genital niche. Over the last two decades, HSV-1 has emerged as the leading cause of first-episode genital herpes in multiple countries. While HSV-1 has the highest level of genetic diversity among human alpha-herpesviruses, it is not yet known how quickly the HSV-1 viral population in a human host adapts over time, or if there are population bottlenecks associated with viral reactivation and/or transmission. It is also unknown how the ecological environments in which HSV infections occur influence their evolutionary trajectory, or that of co-occurring viruses and microbes. In this review, we explore how HSV accrues genetic diversity within each new infection, and yet maintains its ability to successfully infect most of the human population. A holistic examination of the ecological context of natural human infections can expand our awareness of how HSV adapts as it moves within and between human hosts, and reveal the complexity of these lifelong human-virus interactions. These insights may in turn suggest new areas of exploration for other chronic pathogens that successfully evolve and persist among their hosts.
