Preeclampsia causes significant maternal and perinatal morbidity. Genetic factors seem to affect the onset of the disease. We aimed to investigate whether the polygenic risk score for blood pressure  is associated with preeclampsia, its subtypes, and BP values during pregnancy.The analyses were performed in the FINNPEC study (Finnish Genetics of Pre-Eclampsia Consortium) cohort of 1514 preeclamptic and 983 control women. In a case-control setting, the data were divided into percentiles to compare women with high BP-PRS  or low BP-PRS (≤5th percentile) to others. Furthermore, to evaluate the effect of BP-PRS on BP, we studied 3 cohorts: women with preeclampsia, hypertensive controls, and normotensive controls.P=0.009), and women with low BP-PRS presented with preeclampsia less frequently than others . HBP-PRS was associated with an increased risk for preeclampsia . Furthermore, women with HBP-PRS presented with recurrent preeclampsia and preeclampsia with severe features more often.BP values were higher in women with HBP-PRS throughout the pregnancy. Preeclampsia was more common in women with HBP-PRS compared with others (71.8% and 60.1%, respectively; Our results suggest that HBP-PRS is associated with an increased risk of preeclampsia, recurrent preeclampsia, and preeclampsia with severe features. Furthermore, women with HBP-PRS present higher BP values during pregnancy. The results strengthen the evidence pointing toward the role of genetic variants associated with BP regulation in the etiology of preeclampsia, especially its more severe forms. This study is among the first to investigate the role of polygenic risk scores (PRSs) in the onset of preeclampsia (PE).Our results show the association between PRS for for blood pressure (BP) and gestational BP values and highlight the increased risk for PE in women with the highest BP-PRS. Our study is, to our knowledge, the first to note the association between certain PE subtypes (PE with severe features and recurrent PE) and BP-PRS.Women whose genetics predispose them to higher BP values are also at higher risk for PE and its more severe forms. The use of BP-PRS as a predictive tool is a target for further research.1 Risks of stillbirth, preterm birth, and intrauterine growth restriction increase in hypertensive disorders of pregnancy.4 Preeclampsia is a systemic vascular disorder involving endothelial dysfunction,5 oxidative stress, and immunologic intolerance.6 Hypertensive disorders of pregnancy are risk factors for maternal and offspring cardiovascular morbidity.3 With efficient predicting methods, early diagnosis and in some cases even disease prevention could be possible, leading to improved maternal and neonatal outcome.7Preeclampsia affects 2% to 8% of pregnancies in developed countries and is defined by new-onset hypertension and proteinuria after 20 weeks of gestation, or, in the absence of proteinuria, impaired organ function or subjective symptoms of preeclampsia.8 Preeclampsia is considered to be associated with severe symptoms if significantly increased blood pressure (BP) level (≥160/110 mm Hg) is combined with severe headache, visual disturbances, impaired liver function, renal insufficiency, pulmonary edema, or thrombocytopenia.1 Early-onset preeclampsia,10 preeclampsia with severe features,11 as well as recurrent preeclampsia14 are strongly related to chronic hypertension and future cardiovascular disease (CVD) risk.Preeclampsia has multiple subtypes with different etiologies. Early-onset preeclampsia manifests before 34+0 weeks of gestation.15 preeclampsia in the family was shown to increase the risk of preeclampsia 3-fold. In a recent study by the InterPregGen consortium, the maternal single-nucleotide polymorphism heritability of preeclampsia on the liability scale in Europeans was shown to be 38.1%, and certain maternal DNA variants were identified as risk factors for preeclampsia.16 Variants of these genes have previously been associated with BP17 and body mass index.19 The consortium previously reported the first genetic variants in fetal genomes predisposing mothers to preeclampsia.20 In addition, epigenetic changes have been suggested to account for the onset of preeclampsia.22The genetics of underlying preeclampsia is incompletely understood. However, a family history of preeclampsia increases the risk, suggesting a genetic background. In a systematic review,23 PRSs are an extended method as opposed to traditional genetic risk scores in which only genome-wide significant associations are taken into account in calculating the score.24 In a recent study, the PRS for hypertension was shown to be associated with preeclampsia.16 This suggests that women genetically susceptible to hypertension might be at a higher risk for preeclampsia.A polygenic risk score (PRS) demonstrates an individual’s genetic risk of a disease affected by multiple genetic variants. A PRS is formed as a weighted sum of the risk alleles found in genome-wide association studies to be associated with the disease.This study had 2 aims. First, we evaluated the impact of PRS for BP (BP-PRS) on the risks of preeclampsia, its subtypes, and other hypertensive disorders of pregnancy in a case-control setting. Another aim of the study was to assess the effect of BP-PRS on BP during pregnancy.Because of the sensitive nature of the data collected for this study, requests to access the data set from qualified researchers may be sent to H.L. at the Tampere University. Data requests may require further review by national register authorities and ethical committees. A.K. had access to all data.25 Our study included those women whose genetic data were available. After the cohort description was published, additional women were included since their data were processed in accordance with the FINNPEC study protocol. Our study, therefore, includes more women than reported in the original cohort description, a total of 1514 women in the preeclampsia group and 983 women as controls. All participants provided written informed consent, and the FINNPEC study protocol was approved by the coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (149/EO/2007).Nulliparous and multiparous women with a singleton pregnancy were recruited at 5 university hospitals in Finland during 2008 to 2011 in the FINNPEC study (Finnish Genetics of Pre-Eclampsia Consortium). A detailed description of the FINNPEC cohort has been published elsewhere.8 Preeclampsia with severe features was diagnosed with either markedly increased BP (≥160/110 mm Hg) or severe proteinuria (≥5 g/24 hours) combined with subjective symptoms and, preferably, objective findings referring to a severe disease form.8Preeclampsia was defined as hypertension (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg) and proteinuria occurring after 20+0 weeks of gestation. Proteinuria was defined as urinary excretion of ≥0.3 g protein in a 24-hour specimen or 0.3 g/L or two ≥1+ readings on a dipstick in a random urine determination in the absence of urinary tract infection. Preeclampsia was classified as early onset if diagnosed before 34+0 weeks of gestation.The FINNPEC cohort includes data on participating women and their pregnancies, including detailed data on BP and maternal biological samples. BP information was obtained from maternity cards or hospital records. Measurements were performed by medical professionals.26 The genome option of Plink was used to test for unexpected genetic relationships in duplicated samples, triads, and dyads. Samples with unresolved sex mismatch, a missingness rate >5%, or heterozygosity rate ±4 SDs were omitted. Also samples with non-Finnish ancestry based on MDS analysis were excluded. Variants with a missing call rate >2%, Hardy-Weinberg equilibrium P<1×10−6, or minor allele count <3 were removed. The genotyped samples were then prephased using the Eagle 2.3.5 software27 and imputed with Beagle, version 4.1,28 using a population-specific reference panel SiSu v3 imputation reference panel, which consisted of 3775 whole-genome sequenced individuals of Finnish ancestry.FINNPEC samples have been genotyped using the Infinium Global Screening Array-24 v2.0 BeadChip  at the Institute for Molecular Medicine Finland FIMM Technology Centre . Preimputation quality control has been performed with Plink, versions 1.07 and 1.9.29 which recalculates single-nucleotide polymorphism weights from genome-wide association study summary statistics and a linkage disequilibrium reference panel by utilizing a Bayesian regression framework and placing continuous shrinkage priors on single-nucleotide polymorphism effect sizes. In the PRS-CS pipeline, default parameters and a European linkage disequilibrium reference panel with 1.1 million variants derived from samples from the 1000 Genomes Project30 were used. Input weights came from the publicly available genome-wide association study for SBP.17 A total of 1 073 588 genetic variants common for the FINNPEC cohort and the linkage disequilibrium reference panel were included in the PRSs.We built a BP-PRS with the PRS-CS software,31To assess the effect of high BP-PRS (HBP-PRS) or low BP-PRS (LBP-PRS) on the risk of preeclampsia and hypertensive disorders in a case-control setting, the participants were divided into percentiles based on their BP-PRS: women with HBP-PRS (>95th percentile) were compared with those with LBP-PRS, and women with LBP-PRS (≤5th percentile) were compared with those with HBP-PRS. PRS was categorized into HBP-PRS and LBP-PRS percentiles for ease of interpretation.To evaluate BP levels in cohorts, 1514 women experiencing preeclampsia were compared with 2 control groups. Women with chronic hypertension, gestational hypertension or gestational proteinuria were counted as hypertensive controls (n=219), whereas normotensive controls (n=764) presented none of these. Women with preeclampsia in a previous but not in the current pregnancy were excluded from both control groups to control for potential confounding in genetic samples. In the cohort setting, we investigated the differences in BP values in the 3 cohorts between women with HBP-PRS and others and between women with LBP-PRS and others.In this study, we used BP measurements from the first antenatal visit and the highest BP throughout the pregnancy. Furthermore, we calculated BP change as BP measured at first antenatal visit subtracted from the highest BP during pregnancy. We calculated whether BP-PRS correlates with BP values during pregnancy.t test and 1-way ANOVA were used to compare means where appropriate, and for skewed distributions, the Kruskal-Wallis test was used. The χ2 test was used to analyze the associations between the categorical variables. Binary logistic regression was used to calculate odds ratios (ORs) with 95% CIs. Women with preeclampsia were compared with controls (dependent variable), whereas HBP-PRS and LBP-PRS were used as independent variables. A linear regression model was used to adjust results of BP value comparisons using BP-PRS for age, body mass index, and principal components. Homoscedasticity of errors was assessed by plotting the residuals.Statistical analyses were performed using IBM SPSS for Windows, version 27 . Women with HBP-PRS were compared with those whose BP-PRS was lower, and similarly, women with LBP-PRS were compared with those whose BP-PRS was higher. BP values were compared in a similar manner and, in addition, in 3 groups . Correlations were calculated using the Pearson method. Normally distributed quantitative data are expressed as means and SD, whereas medians and quartiles are reported for skewed distributions. Categorical data are shown in percentages. The normality of continuous variables was assessed with the Kolmogorov-Smirnov test. Student Preeclamptic women and hypertensive controls were older and more obese compared with normotensive control women Table . There wWomen with HBP-PRS (>95th percentile) displayed higher BP values throughout pregnancy compared with women with LBP-PRS Table .Table S1). The difference in BPs remained statistically significant after adjusting for age, body mass index, and genetic principal components. The increase in BP from the first antenatal visit to highest measured BP did not differ between women with HBP-PRS or LBP-PRS when analyzed within subgroups. Figure Among women experiencing preeclampsia, those with HBP-PRS displayed higher BP values throughout pregnancy compared with those with LBP-PRS Table S. The difP=0.009), and women with HBP-PRS were more often hypertensive . Additionally, women with HBP-PRS were less often normotensive compared with women with LBP-PRS . In the preeclamptic group, those with HBP-PRS more often displayed preeclampsia with severe features  or recurrent preeclampsia  compared with those with LBP-PRS. Table Women with HBP-PRS (>95th percentile) had preeclampsia more often compared with women whose BP-PRS was lower . However, when the first antenatal BP value was included in the model, the association between HBP-PRS and preeclampsia was not statistically significant .Women with LBP-PRS (≤5th percentile) had lower BP values throughout pregnancy compared with women with HBP-PRS. Moreover, the increase in BP from the first antenatal visit to the highest measured BP was smaller in women with LBP-PRS Table .Table S2). The difference in BP values remained statistically significant after adjusting for age, body mass index, and genetic principal components. Figure In the preeclamptic group, BP values were significantly lower in women with LBP-PRS compared with others, but BP change did not show the same tendency Table S. The difP<0.001). Women with LBP-PRS had hypertensive disorders less often  and were more often normotensive  compared with those with HBP-PRS. Additionally, in the preeclampsia group, women with LBP-PRS less frequently had preeclampsia with severe features compared with those with HBP-PRS . Table Women with LBP-PRS (≤5th percentile) had preeclampsia less frequently than those with HBP-PRS . After including the first antenatal BP value in the model, the negative association between LBP-PRS and preeclampsia remained statistically significant .P<0.001). A similar correlation was seen between the highest measured BP and HBP-PRS . There was a positive correlation between BP-PRS and BP values. Correlation coefficients varied between 0.216 and 0.293 (P<0.001) and were convergent for both SBP and DBP values.BP values from the first antenatal visit correlated with BP-PRS  compared with others. Additionally, women with LBP-PRS (BP-PRS ≤5th percentile) were affected less frequently than others. Recurrent preeclampsia and preeclampsia with severe features were more common in women with HBP-PRS compared with others. BP values were higher in women with HBP-PRS, and the difference was observed throughout the pregnancy.16 and in previous studies, genetic variants related to hypertension have been shown to be associated with preeclampsia.17 In our study, along with the increase in preeclampsia risk, women with HBP-PRS also had higher BP values and the difference was already seen in the first antenatal visit. After adjusting for preeclampsia risk with the first antenatal BP value in women with HBP-PRS and other women, the association between HBP-PRS and preeclampsia was not statistically significant. Hence, the increase in the preeclampsia risk in women with HBP-PRS seems to be more strongly associated with prepregnancy BP levels. In our data, HBP-PRS was associated with preeclampsia with severe features and recurrent preeclampsia, supporting the evidence of genetic background in these subtypes, whereas milder forms of the disease might be linked to preexisting complex maternal conditions, such as obesity and diabetes.32 However, in our study, the incidence of early-onset preeclampsia was not associated with BP-PRS. This highlights the intricate nature of preeclampsia subtypes and the need for further research. Additionally, although LBP-PRS is associated with lower risk for preeclampsia, the background of the disease is complex and heterogenic in nature, and due to this, the use of BP-PRS as a predictive factor in these women cannot be justified.This study supports the evidence that women genetically susceptible to hypertension have an increased risk for preeclampsia in their pregnancies. In a recent meta-analysis, BP-PRS was linked to a higher risk for preeclampsia,10 preeclampsia with severe features,11 and recurrent preeclampsia14 are subtypes strongly related to chronic hypertension and future CVD risk.33 In preeclampsia, and probably these subtypes in particular, there seems to also be prepregnancy endothelial dysfunction35 influencing women’s increased risk for future CVD. In our study, HBP-PRS was associated with an increased risk for recurrent preeclampsia and preeclampsia with severe features. Thus, women with HBP-PRS might be in increased risk for a future CVD as well. In our study, the difference in BP values between women with HBP-PRS compared with others was already seen in the first antenatal visit. This might imply that these women have constantly higher BP values than those with LBP-PRS. Obviously, this might be one explanation for these women’s higher risk for CVD although preeclampsia-related vascular changes and other factors are involved. The role of BP-PRS in identifying women at higher risk for cardiometabolic complications could be a target for further investigation.Early-onset preeclampsia,A major strength of this study is the precise BP data covering the whole pregnancy and BP measurements performed by medical professionals. In the FINNPEC data, preeclampsia diagnoses were retrospectively confirmed by a study nurse and physician to improve reliability of the diagnoses. The genetic data of the cohort are comprehensive, and investigation focusing on PRS allows for exploring large amounts of genetic information. Our case-control cohort is not matched, and only multiple pregnancies and women under the age of 18 years were excluded from the FINNPEC cohort. Consequently, our cohort represents the general obstetric population.Additionally, a few limitations should be acknowledged. The FINNPEC cohort was recruited from the Finnish university hospitals. Due to this, the cohort might represent women with more severe symptoms or earlier disease than the general obstetric population. On the other hand, the most severe cases might not be recruited due to urgent deliveries after hospital referral. We used BP-PRS in our analyses; however, genetic variants other than BP-related ones may affect the onset of the disease. Furthermore, the hypertensive control group in our study was relatively small, impairing the power of our data. The study population was genetically mainly Finnish; thus our results cannot be directly generalized to other ethnicities. Finally, the effect of antihypertensive medications on BP could not be evaluated in our data, leading to a possible underestimation of maximum BP values and BP changes in the preeclampsia and hypertensive control groups.38 Identifying women with the highest risk for these complications would offer an opportunity to affect the risk factors for preeclampsia, which would also be beneficial regarding future CVD risk. The role of BP-PRS in the prediction of preeclampsia is an important target for future research. To our knowledge, few studies have investigated PRS and predisposition to hypertensive disorders of pregnancy. The results of a previous study have been convergent with our findings.16 Further research to confirm these results is needed. Combining maternal, paternal, and offspring PRS and their relationship to pregnancy outcomes, as well as associations between CVD-PRS and preeclampsia, provides interesting subjects for future research.This study demonstrated that women with HBP-PRS are more likely to develop preeclampsia and display higher BP values during pregnancy. Additionally, LBP-PRS is associated with a decreased risk for preeclampsia. Moreover, women with HBP-PRS are affected more often by preeclampsia with severe features and recurrent preeclampsia. In clinical practice, identifying women with higher risk for preeclampsia would offer new insights for early diagnosis and more efficient management. Additionally, women with hypertensive pregnancy complications are more likely to develop CVD in the future.We appreciate the expert technical assistance of Eija Kortelainen and late Susanna Mehtälä and contribution of the members and assisting personnel of the FINNPEC study group (Finnish Genetics of Pre-Eclampsia). In addition, we thank Prof Teemu Niiranen for his valuable comments on the manuscript.The FINNPEC study (Finnish Genetics of Pre-Eclampsia) was supported by the Jane and Aatos Erkko Foundation, Juho Vainio Foundation, Päivikki and Sakari Sohlberg Foundation, Academy of Finland, research funds of the University of Helsinki, government special state subsidy for the health sciences for the Hospital District of Helsinki and Uusimaa, Finska Läkaresellskapet, Liv och Hälsa Foundation, NovoNordisk Foundation, Finnish Foundation for Pediatric Research, Emil Aaltonen Foundation, Sigrid Juselius Foundation, and the Finnish Foundation for Laboratory Medicine.None.


This sequential, prospective meta-analysis sought to identify risk factors among pregnant and postpartum women with COVID-19 for adverse outcomes related to disease severity, maternal morbidities, neonatal mortality and morbidity, and adverse birth outcomes.We prospectively invited study investigators to join the sequential, prospective meta-analysis via professional research networks beginning in March 2020.Eligible studies included those recruiting at least 25 consecutive cases of COVID-19 in pregnancy within a defined catchment area.We included individual patient data from 21 participating studies. Data quality was assessed, and harmonized variables for risk factors and outcomes were constructed. Duplicate cases were removed. Pooled estimates for the absolute and relative risk of adverse outcomes comparing those with and without each risk factor were generated using a 2-stage meta-analysis.We collected data from 33 countries and territories, including 21,977 cases of SARS-CoV-2 infection in pregnancy or postpartum. We found that women with comorbidities  vs those without were at higher risk for COVID-19 severity and adverse pregnancy outcomes . Participants with COVID-19 and HIV were 1.74 times  more likely to be admitted to the intensive care unit. Pregnant women who were underweight before pregnancy were at higher risk of intensive care unit admission , ventilation , and pregnancy-related death . Prepregnancy obesity was also a risk factor for severe COVID-19 outcomes including intensive care unit admission , ventilation , any critical care , and pneumonia . Anemic pregnant women with COVID-19 also had increased risk of intensive care unit admission  and death .We found that pregnant women with comorbidities including diabetes mellitus, hypertension, and cardiovascular disease were at increased risk for severe COVID-19–related outcomes, maternal morbidities, and adverse birth outcomes. We also identified several less commonly known risk factors, including HIV infection, prepregnancy underweight, and anemia. Although pregnant women are already considered a high-risk population, special priority for prevention and treatment should be given to pregnant women with these additional risk factors. Pregnant women are at risk for severe SARS-CoV-2 complications, and those with comorbidities might be at even higher risk for adverse outcomes. Furthermore, some vaccines and treatments are only recommended for those at highest risk. There is no global consensus about what risk factors signify such risk. Heterogeneity in the design and analysis of published studies and limited global data further complicate definitive guidance.We pooled individual patient data from 21 studies  and found that comorbidities, nutritional status, and older maternal age were associated with severe COVID-19–related outcomes , adverse pregnancy outcomes, and fetal/neonatal morbidity and mortality.We pooled and reanalyzed data from global collaborators. We assessed high-priority risk factors and 24 consistently defined maternal and newborn outcomes. Given the large sample, including data from low- and middle-income countries, we generated estimates on rare outcomes  and risk factors  where data have been lacking.,Since the onset of the novel COVID-19 pandemic, the World Health Organization (WHO) and the Centers for Disease Control and Prevention classified pregnant women as a group at higher risk of severe complications from SARS-CoV-2 infection compared with nonpregnant people.,,Initial evidence showed that SARS-CoV-2 infection during pregnancy is linked to increased likelihood of adverse maternal, fetal, and neonatal outcomes.,Among pregnant women, multiple risk factors for severe SARS-CoV-2 infection have been identified.In the general population, nutritional status has been introduced as a potential risk factor for severe COVID-19. A meta-analysis of 7 studies (N=9912) found that among people with COVID-19, those with anemia had 2.44 higher odds of severe illness compared with nonanemic people.There is an urgent need to pool high-quality and internationally representative data assessing the underlying risk factors and outcomes linked to COVID-19 in pregnancy. Currently, scarcity of similarly collected and analyzed data hampers our ability to make strong recommendations for the introduction and prioritization of new pharmaceutical interventions in pregnancy. The primary aim of this sequential, prospective meta-analysis (sPMA) is to accrue harmonized global data to inform policy and practice, grounded in the epidemiology of COVID-19 in the pregnancy, peripartum, and postnatal periods.This study aimed to identify risk factors among pregnant and postpartum women with SARS-CoV-2 infection for adverse outcomes related to: (1) disease severity; (2) maternal morbidities; (3) fetal and neonatal mortality and morbidity; and (4) adverse birth outcomes.We registered the protocol for this prospective meta-analysis via the International Prospective Register of Systematic Reviews (PROSPERO) (ID: 188955) in May 2020, and the full protocol has been published elsewhere.Not all of those who are pregnant or give birth identify as women; throughout this document, the term “pregnant women” should be taken to be inclusive of all persons who have the biological capability to carry a pregnancy regardless of gender identity.Eligible studies include registries and single- or multisite cohort studies that recruited pregnant and recently postpartum women with confirmed or suspected COVID-19. They must have enrolled at least 25 women within a defined catchment area. We included data from those with infection onset up to 42 days after the pregnancy outcome.We invited principal investigators of studies of COVID-19 in pregnancy to join the sPMA via professional research networks and collaborations with key stakeholder networks.Following identification of eligible studies, investigators shared individual patient data (IPD) with the technical team for review and analysis. The technical team processed data to review data quality, identify outliers, and reconstruct variables to align with harmonized definitions of outcomes as defined in our protocol. We shared results with investigators for review and approval. For study sites unable to share IPD directly, the technical team worked with investigators to implement a common set of Stata codes to complete the same process of review, data quality checks, and harmonization.In cases where studies collected data from overlapping catchment areas, we worked with investigators to identify and remove potential duplicates from the analysis. Because of the harmonization process and removal of overlapping data, there are some differences between our study results and those of the original published studies; these differences are summarized in Table S1.We used an adapted Newcastle–Ottawa scale to review study quality and risk of bias for each participating study; criteria for determination of high or low risk for each study design element are presented in Table S2.We examined 24 outcomes related to: (1) COVID-19 severity; (2) maternal morbidities; (3) fetal and neonatal morbidity and mortality; and (4) adverse birth outcomes. Specific definitions of each outcome—and 4 alternative outcomes used in sensitivity analyses—are presented in Table S3. The definition of maternal, fetal, and neonatal death and adverse birth outcomes were based on WHO case definitions.The sPMA steering committee, on the basis of expert opinion, identified 9 high-priority maternal risk factors including comorbidities, nutritional status, age, parity, and COVID-19 symptomatic status. Comorbidities included preexisting diabetes mellitus, hypertension, cardiovascular disease, and HIV coinfection.2) and obesity (BMI ≥30 kg/m2). Both risk factors were compared with a reference group of participants who were of normal weight or overweight before pregnancy . Anemia was diagnosed on the basis of a hemoglobin measurement <11 g/dL at the time of COVID-19 diagnosis.Nutrition-related risk factors included body mass index (BMI) and anemia. We relied on prepregnancy BMI to determine the category for each participant, and we examined 2 risk factors: underweight  and older maternal age (35–45 years). Both groups were compared with a reference group of women aged 20 to 34 years. Lastly, we considered being symptomatic for COVID-19, as opposed to having no symptoms, as a risk factor for the outcomes of interest.We used a standard set of analysis codes to calculate study-specific estimates, comparing those with and without each risk factor  for each participating study. Within each study, individual participants were excluded from the analysis if they were missing data on the risk factor of interest. Any study missing >25% of the data on an outcome of interest was excluded from that specific analysis.,We applied a 2-stage IPD meta-analytic framework to generate pooled absolute risks and RRs, with 95% CI for each risk factor–outcome pair when there were ≥3 studies with available data. We presented unadjusted estimates because the goal of this study was to present descriptive epidemiologic data among a group of people (pregnant women with COVID-19 and their infants), rather than to examine a causal relationship.We excluded studies with 0 total events from that particular analysis. In case of 0 events within a risk factor subgroup, we applied a continuity correction of 0.5 when calculating pooled absolute risks. For pooled RRs, we applied a continuity correction of the inverse number of events in the opposite group within the same study for the risk factor–outcome pair. All meta-analyses were conducted in Stata, version 16.1 .We included data from 21 studies conducted across 33 countries and territories  with data from 21,977 cases of confirmed or suspected SARS-CoV-2 infections in pregnancy or the postpartum period. This iteration of the analysis included data from any study that met eligibility criteria and was able to share data by December 2021 . One stuCases occurred between January 2020 and December 2021 . More thThe mean maternal age across studies was 29.4 years, ranging from 26 years in Kenya  and India (H.D.) to 32 years in Italy . Among the 18 studies that recorded gestational age at SARS-CoV-2 infection, 11 recruited most of their participants in the third trimester; 10 of these studies included people in the postpartum period. The Nachega (multicountry Africa) and Yang (China) studies were composed entirely of patients hospitalized for COVID-19; the Knight (United Kingdom) and Poon  studies were composed entirely  of patients hospitalized for COVID-19, labor and delivery, or other causes .Detailed risk of bias ratings for each participating study are presented in summary in Table S4 and in detail in Table S5. Studies generally had moderate-to-low risk of bias according to the adapted Newcastle–Ottawa scale criteria, with 15 of 21 studies earning at least 4 out of 5 or 4 out of 6 stars across all outcome categories where that study was included in the analysis. The most common cause for high risk of bias rating was related to representativeness of the study population; 5 of 21 studies did not collect data on the reason for screening for individual patients. Another 8 studies primarily used methods to identify cases that were deemed to be at higher risk of bias . In total, 13 of 21 studies had elevated risk of bias in this area.Overall event incidence for each site is shown in We found that pregnant women with COVID-19 who also had chronic illnesses, including diabetes mellitus, hypertension, and cardiovascular disease, were at higher risk for most outcomes related to COVID-19 severity, and pregnancy-related death . Risk ofPregnant women with COVID-19 and one of these chronic conditions were at higher risk for maternal morbidity, including placental abruption, preeclampsia, preeclampsia or eclampsia, hypertensive disorders of pregnancy, preterm labor, and any cesarean delivery. Those with hypertension or cardiovascular disease were also at increased risk of having an intrapartum cesarean delivery. Infants born to mothers with both COVID-19 and one of these chronic conditions were at higher risk for mortality  and NICU admission. These infants were more likely to be born preterm, have low birthweight, and be small for gestational age.Although less data were available on HIV coinfection with COVID-19 during pregnancy, we found that coinfection increased the risk of severe COVID-19 disease . Among p2 were at increased risk for ICU admission , ventilation , and pneumonia , but not for pregnancy-related death  (Table S11).We found increased risk of COVID-19 severity among pregnant and postpartum people who were either obese or underweight compared with those who were normal to overweight before pregnancy . PregnanPregnant women who were underweight prepregnancy had >5 times increased risk for ICU admission  or any critical care , >9 times increased risk for ventilation , and nearly 3 times increased risk for pneumonia  compared with pregnant women who were normal to overweight prepregnancy (Table S12). Although this was based on a small sample size, underweight pregnant women with COVID-19 were found to have a sharply increased risk of pregnancy-related death .Prepregnancy obesity was also associated with increased risks for maternal morbidity such as preeclampsia , any hypertensive disorders of pregnancy , any cesarean delivery , and intrapartum cesarean delivery  . PrepregAlthough data were limited, we found an increased risk of COVID-19 severity among pregnant women with anemia at the time of COVID-19 diagnosis compared with those without anemia . Those wOlder maternal age (35–45 years) was associated with multiple COVID-19–associated adverse outcomes compared with those aged 20 to 34 years . Older mCompared with pregnant women with COVID-19 aged 20 to 34 years, younger pregnant women (15–19 years) were at increased risk for preeclampsia or eclampsia  (Table S15). Infants born to younger women with COVID-19 had higher risks of stillbirth, perinatal death, and neonatal death. Younger women with COVID-19 were also more likely to experience adverse pregnancy outcomes, including moderate preterm birth , very low-birthweight infants , and small-for-gestational-age infants .Overall, we found limited differences in risks of adverse outcomes among primiparous compared with multiparous pregnant women with COVID-19 . PrimipaWe found increased risks for adverse outcomes related to COVID-19 severity among pregnant women with symptomatic infection compared with those with asymptomatic SARS-CoV-2 infection, including ICU admission, any critical care, and pneumonia (Table S17). However, most other outcomes related to maternal morbidity, fetal and neonatal mortality and morbidity, and adverse birth outcomes were similar across symptomatic and asymptomatic groups, with a few exceptions. Pregnant women with symptomatic COVID-19 were more likely to have an intrapartum cesarean delivery  compared with those with asymptomatic infection (Table S18).We also found increased risk of preterm and moderate preterm birth among symptomatic pregnant women . However, when we restricted to only pregnant women with infection onset before 37 weeks’ gestation for preterm birth and before 34 weeks’ gestation for moderate preterm birth, we found that asymptomatic pregnant women had an increased risk of preterm and moderate preterm birth  compared with symptomatic pregnant women.As in the general population, we found that pregnant women with comorbidities including diabetes mellitus, hypertension, cardiovascular disease, and obesity were at increased risk for severe COVID-19–related outcomes, as well as for maternal morbidities and adverse birth outcomes, compared with pregnant women without these comorbidities. Given pooled global data, we also identified several less commonly known risk factors for pregnant women with COVID-19, including HIV coinfection, being underweight at the start of pregnancy, and anemia at the time of COVID-19 diagnosis.,We found that among pregnant women with COVID-19, those living with HIV were nearly twice as likely to be admitted to the ICU or need critical care. Women living with HIV already have greater likelihood of antenatal, delivery, and postpartum complications, including preterm birth, cesarean delivery, postpartum sepsis, venous thromboembolism, postpartum infection, and mortality.A recent systematic review of SARS-CoV-2 infection among people living with HIV in the general population found strong evidence that HIV is a risk factor for both SARS-CoV-2 infection and for mortality owing to COVID-19; that review did not examine pregnant and postpartum women as a subgroup of interest.,Undernutrition in pregnant women with COVID-19 was identified as an important risk factor for COVID-19 severity and adverse birth outcomes. Underweight pregnant women had elevated risks for severe COVID-19 and pregnancy-related death, and for moderately preterm, very low-birthweight, and small-for-gestational-age infants. In addition, being anemic during pregnancy increased the risk for pregnancy-related death, ICU admission, and stillbirth. Although the results for anemia were based on 4 studies, the effect estimates for severe COVID-19 were consistent with those reported in a recent meta-analysis highlighting linkages between low hemoglobin, hypoxia, respiratory organ dysfunction, and severe outcomes from COVID-19 infection in the general population.We found that pregnant women with any COVID-19 symptoms were at increased risk for ICU admission, ventilation, cesarean delivery, and preterm birth compared with asymptomatic pregnant women on the basis of a large sample size of global studies. Although a previous systematic review of published literature examined this question, data on symptomatic compared with asymptomatic SARS-CoV-2 infection in pregnancy were only available for a small subset of studies and participants in this review .However, in a sensitivity analysis restricted only to participants infected before 37 weeks’ gestation, we found that asymptomatic pregnant women are more likely than symptomatic pregnant women to have a preterm birth. These seemingly conflicting results may be related to features of study sampling; for example, this difference may be because of the large percentage of asymptomatic participants who are identified during screening at labor and delivery. Across the 10 studies included in the restricted analysis, 64% of infants born to asymptomatic participants were identified at ≥37 weeks’ gestation vs 26% of infants born to symptomatic participants.IPD meta-analyses are considered the gold-standard method for generating aggregate estimates. Here, we standardized data quality assessment and harmonized definitions of risk factors and outcomes. This is especially valuable for outcomes such as stillbirth, preterm birth, and perinatal mortality, which have varying definitions globally. We included data from 33 countries and territories, including many low- and middle-income countries, whereas the bulk of the published literature on COVID-19 in pregnancy comes from middle- or high-income countries. Therefore, by pooling global data we were able to investigate risk factors such as HIV status, undernutrition, and anemia, which are more common in low-income countries, but for which individual studies may not have adequate power to draw meaningful conclusions. We were also able to identify risks linked to rare outcomes such as pregnancy-related death and stillbirth.Our study had several limitations. First, the studies contributing to the IPD meta-analysis recruited participants differently, varying from hospital-based surveillance to universal screening during antenatal care. Furthermore, representativeness of the sample was deemed to be at elevated risk of bias for most studies because of limited information about identification and screening at the individual patient level or the use of identification strategies that are only somewhat representative of the population of interest. Some studies only recruited women admitted to the hospital with COVID-19 infection, whereas others included both symptomatic and asymptomatic women who tested positive for the infection. Given the heterogeneity of the sampling frames between studies, it is not possible to draw inferences about the absolute risk of adverse outcomes. The heterogeneity in baseline rates of adverse outcomes globally further complicates interpretation of the absolute risks. However, the RRs comparing those with and without the risk factors of interest generally seemed consistent between sites, and heterogeneity was relatively low for pooled estimates. In addition, although this analysis pooled a large, global sample of pregnant and postpartum women with COVID-19, half of the overall sample for critical care outcomes  was derived from the Mexican National Registry, which collected no information on maternal morbidity, birth, or neonatal outcomes. This analysis also did not examine risk factors related to social determinants of health, which may exacerbate the biological risk factors identified in this analysis.,,,,We identified risk factors for adverse maternal morbidities and fetal and neonatal outcomes among pregnant women with COVID-19, and these are generally consistent with risk factors for adverse pregnancy outcomes including preexisting diabetes mellitus or hypertension,Although pregnant women are already considered a high-risk population by the WHO and should be given equitable access to safe and effective preventives and therapeutics, special priority should be given to pregnant women with additional risk factors, including those related to chronic and infectious comorbidities, nutritional status, and maternal age. These data strongly support the need for access to vaccines and treatments for SARS-CoV-2 infection for pregnant women, prioritizing those with risk factors for severe illness and adverse birth outcomes.


Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the dysregulated production and uncontrolled proliferation of mature and maturing granulocytes. CML has the potential to cause secondary immunodeficiency in affected patients. COVID-19 infection has been associated with worse outcomes in immunocompromised patients, including patients with hematologic cancers, requiring hospitalization. Herein we present a 61-year-old male with known COVID-19 infection who presented for the evaluation of acute hypoxic respiratory failure and was found to have marked leukocytosis of 125,000. The patient was eventually diagnosed with CML, and his respiratory failure resolved with conventional COVID-19 pneumonia treatment. With this case report, we hope to assist clinicians in the workup of marked leukocytosis in the setting of COVID-19 pneumonia and aim to help clinicians in the management of patients admitted with COVID-19 pneumonia and concomitant CML. Chronic myeloid leukemia (CML) is a clonal disorder of hematopoiesis that arises in a hematopoietic stem or early progenitor cell . The cliThis is a 61-year-old male with no significant past medical history who presented for evaluation of hypoxia. The patient’s home pulse oximeter revealed an oxygen saturation ranging in the mid to high 80% for the past day prior to admission. He also complained of cough, worsening shortness of breath, rhinorrhea, nausea, and vomiting of non-bloody and non-bilious contents for two weeks prior to admission. Of note, the patient tested positive for COVID-19, three days prior to admission. The patient was not vaccinated against COVID-19. 3/µL), microcytic anemia, thrombocytopenia, elevated bands, myelocytes, metamyelocytes, and promyelocytes as seen in Table Physical exam was notable for hypoxia on room air (oxygen saturation 88%), bilateral diffuse rales across all lung fields, and hepatosplenomegaly. The repeat COVID-19 test by polymerase chain reaction was positive. His laboratory results revealed marked leukocytosis  with partial aberrant CD56 expression and loss of CD13, CD16, and CD11b. Blasts were around 1% of total cells analyzed, expressing CD34, CD117, CD13, and human leukocyte antigen-DR (HLA-DR). B cells appeared polytypic, and T cells showed no aberrant loss of T-cell antigen, suggesting a myeloproliferative neoplasm. A subsequent fluorescence in-situ hybridization (FISH) showed a BCR-ABL1 fusion in 87% of cells confirming the diagnosis of CML.The patient was placed on supplemental oxygen , remdesivir for five days, and Intravenous dexamethasone 6 mg for 10 days. The patient was gradually weaned off supplemental oxygen and was able to maintain oxygen saturation in the mid to high 90% on room air on day 9 of hospitalization. The treatment for CML was deferred during his hospital stay. The patient was discharged after 12 days of hospitalization and was symptom-free. He was instructed to follow up with the local cancer center to establish care for the CML.CML is a clonal hematopoietic stem cell neoplasm characterized by the overproduction of myeloid cells ,6. SeconMost patients with CML present in the indolent or chronic phase ,5. CommoTyrosine kinase inhibitors (TKIs) are the initial treatment of choice for most patients with CML -12. HydrCML is a clonal hematopoietic stem cell neoplasm with the potential to cause secondary immunodeficiency in affected patients. Recent studies and clinical observations have demonstrated a poor outcome for immunodeficient patients hospitalized with COVID-19 infection. The approach to managing CML with concomitant COVID-19 pneumonia is still under review. With this case report, we hope to assist clinicians in the workup of marked leukocytosis in the setting of COVID-19 pneumonia and aim to help clinicians in the management of patients admitted with COVID-19 pneumonia and concomitant CML.


The aim of this study was to review our management experience of ruptured abdominal aortic aneurysms (RAAAs) using an endovascular aneurysm repair (EVAR)-only strategy, and discuss the feasibility of this strategy.A retrospective analysis of clinical data was performed in patients with RAAAs from January 2009 to October 2020. Our strategy toward operative treatment for RAAAs evolved from an EVAR-selected (from January 2009 to April 2014) to an EVAR-only (from May 2014 to October 2020) strategy. Baseline characteristics, thirty-day mortality, perioperative complications, and long-term outcomes of patients were compared between the two periods.P = 0.79). Systolic blood pressure ≤70 mmHg  and abdominal compartment syndrome  were identified as independent risk factors responsible for 30-day mortality. After 5 years, 47.5%  of patients in the EVAR-selected group were still alive versus 49.1%  of patients in the EVAR-only group (P = 0.29).A total of 93 patients undergoing emergent RAAA repair were eventually included. The overall operation rate in RAAAs at our centre was 70.5% (93/132). In the EVAR-only period, all 53 patients underwent ruptured endovascular aneurysm repair (rEVAR). However, only 47.5% (19/40) of patients in the EVAR-selected period underwent rEVAR, and the remaining 21 patients underwent emergent open surgery. Thirty-day mortality in the EVAR-only group was 22.6% (12/53) compared with 25.0% (10/40) for the EVAR-selected group (The EVAR-only strategy has allowed rEVAR to be used in nearly all the RAAAs with similar mortality comparing with the EVAR-selected strategy. Due to the avoidance of operative modality selection, the EVAR-only strategy was associated with a more simplified algorithm, less influence on haemodynamics, and a shorter operation and recovery time. The mortality rates of ruptured abdominal aortic aneurysms (RAAAs) following open surgical repair (OSR) remain high despite advances in surgical and anaesthetic techniques . The safEver since the results of three RCTs  on OSR versus rEVAR appeared in early 2010s , 4, 9. AA retrospective review of the database of images and electronic medical records was performed to identify patients who received a diagnosis of RAAA between January 2009 and October 2020 at our centre. Clinical data including patient demographics, coexisting medical conditions, patient status upon admission, computed tomography angiography (CTA) images, laboratory test results, surgery details, postoperative complications, and long-term follow-up results were collected. Exclusion criteria included the following: (1) suprarenal RAAAs; (2) ruptured Crawford type I–IV thoracoabdominal aortic aneurysms; (3) symptomatic AAAs without retroperitoneal haematoma or leakage of the contrast agent on preoperative CTA; (4) ruptured isolated iliac artery aneurysms; (5) abdominal aortic pseudoaneurysms without aneurysmal dilatation of the infrarenal abdominal aortic wall; and (6) RAAAs in patients who previously underwent EVAR. Patients meeting any one of these criteria were excluded from the analysis of this study. The rest of the patients receiving a diagnosis of RAAA were then included in the current study. This study was approved by the Committee for the Protection of Human Subjects at Zhongshan Hospital, Fudan University. All patients participating in the study signed an informed consent document.From January 2009 to October 2020, treatment conditions and resources for RAAAs at our centre included the following: (1) a green channel in the emergency room for priority treatment of RAAAs; (2) availability of CTA in the emergency room within 15 min of raising a request; (3) a fully trained on-call multidisciplinary team including vascular surgeons, emergency department physicians, anaesthesiologists, operating room staff, and surgical intensive care unit (sICU) doctors; this team was capable of treating vascular emergencies throughout the day; (4) a fully equipped hybrid operating room used independently by vascular surgeons; (5) priority given for treating RAAAs in the hybrid operating room; (6) at least three brands of endografts with complete specifications stocked in the hybrid operating room; (7) all emergent RAAA repair procedures performed by senior vascular surgeons competent in open and endovascular techniques.From January 2009 to April 2014, we implemented an “EVAR-selected” strategy. The rEVAR procedure was performed in a highly selected patient population during this period, and selection was based on patient’s haemodynamic conditions, neck anatomy, and the senior vascular surgeon’s preference. Haemodynamic instability was defined as a systolic blood pressure ≤70 mmHg for more than 10 min; patients with a systolic blood pressure >70 mmHg were considered haemodynamically stable in the current study. Favourable proximal aneurysm neck anatomy was defined when the well-accepted IFU criteria of endografts were met, which were as follows: (1) proximal neck length ≥10 mm; (2) proximal neck angulation <60°; and (3) proximal neck diameter <32 mm. A hostile proximal neck was defined if any one of the above mentioned criteria were not met. During this period, a rEVAR was performed as the first-choice treatment only in haemodynamically stable patients with a favourable proximal neck. As for haemodynamically unstable patients, the administration of rEVAR was dependent on the personal experience of the senior vascular surgeon. Notably, due to our abundant experience in elective EVAR  for treaFrom May 2014 to September 2020, the strategy for the management of patients with RAAAs could be summarised as “EVAR-only.” Briefly, once the diagnosis of an infrarenal RAAA was established, a rEVAR would be immediately prepared for these patients, regardless of their haemodynamic status and the anatomic conditions of the proximal aneurysm neck. Therefore, rEVAR was the only technique used to repair RAAAs during this period.The diagnosis of a RAAA was established when a retroperitoneal haematoma or leakage of the contrast agent was found around a true AAA on CT images. All the patients received CT imaging in the transferring hospital or at our emergency room. An expeditious CTA was mandatory for the haemodynamically stable patients. For the haemodynamically unstable patients, hypotensive haemostasis with strict limitation of fluid infusion was implemented to maintain a target systolic blood pressure of 80–100 mmHg. Surgical interventions including balloon occlusion were performed only when informed consent was obtained from the patients or their family members.Emergent open surgery was performed under general anaesthesia. A transperitoneal RAAA repair was utilised in our centre. In haemodynamically unstable patients, transfemoral balloon occlusion of the aorta was considered before anaesthesia induction. Heparin was used selectively according to the patients’ coagulation conditions. When primary abdominal closure was deemed unfeasible due to intestinal oedema, vacuum-pack temporary abdominal wound management with delayed closure was used.A rEVAR was performed in a hybrid operation room by surgeons with extensive experience in elective EVAR. Transfemoral descending aortic balloon occlusion was performed in haemodynamically unstable patients. The anaesthesia method  for the following rEVAR procedures was determined by anaesthetists and vascular surgeons, and was mainly based on the degree of dysphoria and haemodynamic conditions in these patients. Technical success was defined as the successful deployment of the endograft into the target segment of the artery without type I and III endoleaks at complete angiogram. Additionally, decompression laparotomy was not performed at the same stage during the rEVAR procedure as during OSR.Patients undergoing rAAA repair were admitted to the sICU. Maintenance of acid-base balance, correction of coagulation function, and improvement of the haemodynamic parameters were the three main goals of our therapy; this aspect has been described in our previous study .Abdominal compartment syndrome (ACS) was defined as an intraluminal bladder pressure value of ≥20 mmHg with a new organ dysfunction . For patients with ACS, vascular surgeons and sICU physicians codetermined whether a laparotomy decompression was indicated, mainly according to patients’ tolerance to open surgery, coagulation functions, and willingness of their family members. Patients surviving to discharge after RAAA repair were routinely followed up by CTA at 3, 6, and 12 months, and annually thereafter.2 test, and the t-test was used to analyse continuous variables. Statistical significance was defined as a P-value < 0.05. Univariate and multivariate logistic analyses were used to identify potential independent risk factors of 30-day mortality after emergent repair of RAAAs and the occurrence of ACS after rEVAR. The multivariate logistic model included all variables that exhibited significant differences at the level of P < 0.05 in the univariate analysis. Kaplan–Meier analysis was performed to estimate the long-term survival, and the difference between the EVAR-selected and EVAR-only periods was analysed using the log-rank test. Statistical analysis was performed using the SPSS 23 software .The primary outcome was 30-day all-cause mortality. Secondary outcomes included in-hospital all-cause mortality, postoperative complications during a 30-day postoperative period, and the length of the sICU and hospital stay. Continuous variables were expressed as mean ± SD, and categorical variables were expressed as frequencies and percentages. Categorical variables were compared between groups using the χA total of 132 patients with RAAAs treated at our institution between January 2009 and October 2020 were identified . Among tDemographic and aneurysmal characteristics were similar between patients in the EVAR-selected and EVAR-only periods. Hostile proximal necks  were fouP < 0.01).Technical success of the aneurysm repair was achieved in all patients in the EVAR-selected period. Technical failure occurred in four patients  in the EVAR-only period due to persistent type Ia endoleaks at completion angiogram. Open surgery conversion was not performed in these four patients considering their state of haemorrhagic shock. Patients in the EVAR-only period had significantly less operative time and lower blood transfusion needs . When weP = 0.79). There was also no significant difference (P = 0.93) in in-hospital mortality between the EVAR-only  and EVAR-selected  periods  compared with 25.0% (10/40) in the EVAR-selected period  were independent risk factors of 30-day mortality in the current cohort of patients.Univariate logistic regression analysis showed loss of consciousness  at admission, SBP ≤90 mmHg, serum creatinine >186 mmol/L, Hb ≤60 g/L, and ACS were risk factors related to 30-day mortality . NotablyP = 0.02) and Hb <90 g/L  were identified as independent risk predictors of ACS . After 5 years, 47.5%  of patients in the EVAR-selected period were still alive versus 49.1%  of patients in the EVAR-only period (P = 0.29).There were 29 and 38 patients surviving to discharge in the EVAR-selected and EVAR-only periods, respectively. The median follow-up time was 61 months  in the EVAR-selected period and 39 months  in the EVAR-only period. The Kaplan–Meier analysis showed no significant difference in mid-term survival between the two periods , which, to some extent, implied that the superior efficacy of rEVAR for RAAAs in historical reports might be attributed to this new technique rather than to patient selection. However, the implementation of this radical EVAR-only approach for RAAAs has not been reported at other centres. In the current study, the 30-day mortality in the EVAR-only period was lower than that in the EVAR-selected period, although the difference was not statistically significant. Additionally, similar long-term survival rates were observed between the two periods, which was not reported in the previous study by Meyer et al.  (P = 0.23) (P = 1.00) (P = 0.09), and the 3-year mortality was observed to be significantly lower in EVAR-suitable patients ; an aneurysm neck diameter >29 mm was found to be an independent risk factor of overall mortality. In the IMPROVE trial  . However = 0.23) . As for  = 1.00) . HoweverVE trial , no assoAbdominal compartment syndrome was a common complication in patients with RAAAs. rEVAR was associated with a higher incidence of postoperative ACS compared with OSR due to the untreated retroperitoneal haematoma. A meta-analysis of ACS after rEVAR by Karkos et al. estimated that the ACS rate might be higher than 20% with improved awareness and vigilant monitoring , 21, thiThe current study has several limitations, including its retrospective design which could have biassed patient selection. Second, despite the relatively large sample size of the present study, it remains too limited to generate more convincing statistical results. Third, our study extended over 11 years. There may have been learning curves for using some techniques during this period, as reflected by the fact that a significantly higher proportion of rEVAR cases in the later period were performed using local anaesthesia, percutaneous access, and bifurcated endografts. Additionally, endograft evolution during the past decade might have had a sizeable influence on the favourable outcomes in the EVAR-only period . HoweverThe EVAR-only strategy has allowed rEVAR to be used in nearly all the RAAAs with similar mortality comparing with the EVAR-selected strategy. Due to the avoidance of operative modality selection, the EVAR-only strategy was associated with a more simplified algorithm, less influence on haemodynamics, and a shorter operation and recovery time. Prospective validation of the EVAR-only strategy is required at more experienced vascular centres.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.This study design was approved by the Ethics Committee for the Protection of Human Subjects at Zhongshan Hospital, Fudan University, Shanghai, China. All included patients were informed about the nature of the study and gave their written informed consent.GF, JY, TS, TY, BR, YF, TP, and ZL collected the data. GF and JY wrote the manuscript. GF, JY, ZD, and WF critically reviewed the manuscript and contributed significantly to discussion. All authors contributed to the article and approved the submitted version.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) may cause damage to the cardiovascular system during the acute phase of the infection. However, recent studies reported mid- to long-term subtle cardiac injuries after recovering from acute coronavirus disease 2019 (COVID-19). This study aimed to determine the relationship between the severity of chest computed tomography (CT) lesions and the persistence of subtle myocardial injuries at mid-term follow-up of patients who recovered from COVID-19 infection.All patients with COVID-19 were enrolled prospectively in this study. Sensitive troponin T (hsTnT) and chest CT scans were performed on all patients during the acute phase of COVID-19 infection. At the mid-term follow-up, conventional transthoracic echocardiograph and global longitudinal strain (GLS) of the left and right ventricles (LV and RV) were determined and compared between patients with chest CT scan lesions of < 50% (Group 1) and those with severe chest CT scan lesions of greater or equal to 50% (Group 2).p = 0.013 and p = 0.011, respectively). LV GLS value of more than −18 was noted in 43% of all the patients, and an RV GLS value of more than −20 was observed in 48% of them. The group with severe chest CT scan lesions included more patients with reduced LV GLS and reduced RV GLS than the group with mild chest CT scan lesions .The mean age was 55 ± 14 years. Both LV GLS and RV GLS values were significantly decreased in group 2  could be recommended in patients recovering from COVID-19 to detect subtle LV and RV lesions. Coronavirus disease 2019 (COVID-19) is an emergent infection caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-COV 2)  measurement is recommended.Many studies , 4 showeThis study aimed to reveal cardiac abnormalities at mid-term follow-up in patients who recovered from COVID-19 by using LV GLS and RV GLS values. It also compared the degree of LV GLS and RV GLS alteration between patients already having severe chest computed tomography (CT) scan lesions ≥ 50% and those with chest CT scan lesions < 50% at the acute phase of infection.This is a cohort study conducted in the three COVID centers from January 2021 to March 2021.We enrolled a cohort of recovered patients from COVID-19 infection from three COVID-19 centers.Diagnosis of COVID-19 was confirmed by the presence of a real time reverse –transcription polymerase chain reaction (RT-PCR).Patients who did not agree to participate were not included.Patients with pulmonary embolism, a high-sensitivity cardiac troponin (hs-cTn) serum level> the 99th percentile (0.014 ng/mL)  during tAll the patients underwent a clinical examination, that is, blood tests including hs-cTn, C-reactive protein, D-dimers, hematocrit, serum creatinine, and N-terminal prohormone of the brain natriuretic peptide (NT-proBNP).A chest CT scan was performed within the first 14 days from the onset of the symptoms. TTE with longitudinal strain study was performed 3 months after recovery .Patients were divided into two groups. Group 1: those with Chest CT scan lesions < 50% and Group 2: those with chest CT scan lesions equal to or >50%.Demographic, biological, and scanner data were collected from patients during hospitalization in the COVID-19 units.At 3 months of follow-up, TTE  was performed on all participants by the same operator. Conventional TTE parameters, including LV end-systolic and end-diastolic diameters (LVESD and LVEDD), interventricular septum (IVS), and LV ejection fraction (LVEF), were measured. Diastolic LV function was evaluated. RV systolic function was measured by using peak right ventricular systolic myocardial velocity (S wave) and tricuspid annular plane systolic excursion (TAPSE). The atrial areas and systolic pulmonary blood pressure (SPBP) were measured. Offline speckle tracking analyses were performed in all participants using Echopac software version 112 and based on apical views of two, three, and four chambers for the LV study. GLS was obtained after tracking the endocardial borders and by calculating the mean peak systolic strain values of the 17 segments. LV GLS and bull's eye plot were obtained . A valuet-test was performed to compare means in two independent samples. The non-normally distributed data were presented as median with interquartile range (IQR) and compared by the Mann-Whitney U-test. A p-value of < 0.05 was considered statistically significant.Statistical analysis was performed using Statistical Program for Social Sciences (SPSS) version 20.0. Categorical variables were presented as frequency rates and percentages. The Chi-Square test (χ2 test) or the Fisher exact test were used to compare frequencies. The Kolmogorov–Smirnov test was used to confirm the normal distribution of continuous variables. The normally distributed data were expressed as mean ± standard deviation (SD), and Student's The cohort of patients is a part of the research protocol (IORG 00093738 N°102/OMB 0990-0279) approved by the Hospital Ethics Committee of the Faculty of Medicine of Monastir. The study was conducted in accordance with Good Clinical Practice conditions and standard ethical considerations.All participants had signed informed consent.A total of 147 patients were initially enrolled. Of which, 37 were excluded due to the exclusion criteria. Thus, a total of 111 patients were included in the final analysis. A total of 55 patients (49.55%) had mild chest CT scan lesions (group 1) and 56 patients (50.45%) had severe chest CT scan lesions (group 2) as shown in p = 0.05). Baseline data of the overall population and the two groups are presented in No significant differences were noted between the two groups regarding all epidemiological characteristics except for smoking status and diabetes mellitus. Compared to group 1, a higher prevalence of ground glass opacity was noted in group 2 . Group 2 included more patients with reduced LV GLS  and RV GLS  compared to group 1.At 3 months of follow-up, TTE was performed on all participants. All echocardiographic measurements are reported in Patients with COVID-19 showed myocardial involvement that could be due to SARS-CoV-2 virus lesions or could be a sequela of myocardial inflammation. Myocardial involvement induced by SARS-CoV-2 infection is an important indicator for long-term prognosis.p = 0.013 and p = 0.011, respectively).The present study aimed to determine residual cardiac injury at mid-term follow-up among hospitalized patients who recovered from COVID-19 and had no biological stigmata of myocardial injury, according to the severity of the previous pulmonary lesion. The results showed that, compared to group 1(mild chest CT scan lesions), both mean LV GLS and RV GLS were significantly decreased in the patients with severe chest CT scan lesions compared to those with no severe pulmonary lesions (To the best of our knowledge, this is the first study evaluating the relationship between biventricular strain in patients who recovered from COVID-19 and lung injury severity. According to a previous study, cardiovascular injuries due to COVID-19 infection could be manifested by acute coronary syndrome, myocarditis, arrhythmia, hypertension, and pericarditis , 7–9. InPrevious studies showed that preserved LVEF in patients with COVID-19 is associated with a decreased LV GLS, suggestive of occult myocardial injury, which is a marker of poor prognoses such as heart failure and mortality . DespiteThere are some limitations to our study. The first limitation is that the three-dimension echocardiography and circumferential and radial strain were not performed. The second limitation is that the echocardiography was not performed during the acute phase of COVID-19 infection. Moreover, cardiac magnetic resonance imaging and cardiac CT imaging were not performed.This study showed that patients with severe CT scan pulmonary lesions were more likely to develop sub-clinical myocardial damage at mid-term follow-up, despite the absence of biological stigmata of myocardial injury. Early detection of sub-clinical myocardial dysfunction with speckle tracking echocardiography could be beneficial to ensure early management in patients recovered from COVID-19 infection. Further studies are required to determine the prognostic value of myocardial strain and the long-term evolution of this subclinical myocardial dysfunction in patients after COVID-19.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by khochtali Ines. The Ethics Committee waived the requirement of written informed consent for participation.IC, RK, HA, and TL were actively involved in data collection and processing. IC, NF, and MA were involved in manuscript preparation. AB, SC, KB, and FM were involved in manuscript reviewing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Improved life expectancy is increasing the number of older adults who suffer from motor-cognitive decline. Unfortunately, conventional balance exercise programs are not tailored to patients with cognitive impairments, and exercise adherence is often poor due to unsupervised settings. This study describes the acceptability and feasibility of a sensor-based in-home interactive exercise system, called tele-Exergame, used by older adults with mild cognitive impairment (MCI) or dementia. Our tele-Exergame is specifically designed to improve balance and cognition during distractive conditioning while a telemedicine interface remotely supervises the exercise, and its exercises are gamified balance tasks with explicit augmented visual feedback. Fourteen adults with MCI or dementia  participated and completed exergame twice weekly for six weeks at their homes. Before and after 6 weeks, participants’ acceptance was assessed by Technology Acceptance Model (TAM) questionnaire, and participants’ cognition and anxiety level were evaluated by the Montreal Cognitive Assessment (MoCA) and Beck Anxiety Inventory (BAI), respectively. Results support acceptability, perceived benefits, and positive attitudes toward the use of the system. The findings of this study support the feasibility, acceptability, and potential benefit of tele-Exergame to preserve cognitive function among older adults with MCI and dementia. Motor and cognitive decline are common in older adults; they are closely associated and often interact because of shared brain networks ,2. By 20Multiple systematic reviews have shown that various combinations of motor and cognitive training can improve motor-cognitive abilities in older adults for short (hours to days) and long (weeks to months) periods ,13,14,15Most technology-based motor-cognitive training systems use virtual reality (VR) or video games (exergames), which offer immersive and interactive training or intervention regimens . These technology-based systems enable the providing of biofeedback  or different levels of complexity of motor and cognitive tasks. Indeed, two systematic reviews have highlighted the beneficial effects of VR or exergame-based physical-cognitive training compared to conventional physical-cognitive training regimens in older adults with mild cognitive impairment (MCI) or dementia ,17. HoweRecognizing these limitations and recent efforts to advance telehealth and telerehabilitation, we describe the design and development of a tele-Exergame system and assess the acceptance of interactive tele-Exergame by older adults with MCI or dementia. American Telemedicine Association defines tele-rehabilitation as delivering rehabilitation services via information and communication technologies (ICT) . Based oThis study adopts one of the most influential user acceptance and behavior analysis models, the Technology Acceptance Model (TAM), to analyze the factors influencing older adults with dementia’s acceptance of the tele-Exergame system. The TAM is a theoretical model that suggests that when a user is presented with a novel technology or application, a number of factors influence their behavioral intention to use the technology. The most influential factors are the perception of ease-of-use, and the usefulness of the technology perceived by the user. Recently, Mishra et al. 2022) used a TAM-based questionnaire to determine the acceptability of technology-driven solutions to facilitate dementia caregiving . Similar22 used aWe also describe cognition and anxiety levels in older adults with MCI or dementia after 6 weeks of in-home exergaming exercises. Previous studies assessed cognition and anxiety in combination with TAM constructs to identify any moderating effect of cognitive decline or high anxiety on responses to the TAM-based questionnaire. Key features of our tele-Exergame system include: (1) easy to use, (2) relatively inexpensive, (3) providing scalable physical-cognitive training, (4) storing user’s motor and cognitive performance, (5) providing feedback remotely, and (6) monitoring training compliance and progress remotely.TM, that was designed and developed for people with MCI or dementia. Tele-FootXTM consists of a motion sensor module  and a tablet  equipped with a custom application.TM includes a triaxial accelerometer (±2 g) and gyroscope (±2000 deg/s), a microprocessor to process sensor data, and a Bluetooth module for wireless data acquisition. LEGSysTM computes 3D rotation using the Kalman filter and quaternion approach, which is described in detail in our previous publications [TM are transmitted to the tablet via Bluetooth with high efficiency and zero package loss.LEGSysications ,24,25. TTM automatically when the sensor is detected, (2) administering two types of exercises , (3) providing instructions using audio, images, and texts for the use of the tablet and LEGSysTM, (4) displaying user’s motion on the table’s screen by mapping the user’s leg or foot movements to dial’s displacements . Potential participants were recruited from the Baylor College of Medicine’s affiliated outpatient clinics or communities . Eligible participants were: (1) 65 years or older, (2) had clinically diagnosed MCI or dementia or had cognitive decline confirmed by the Montreal Cognitive Assessment (MoCA); the cutoff score on the MoCA was 25 or lower, (3) could walk at least 20 m with or without walking assistance, (4) were living independently in a residential home with a caregiver/informant, and (5) were willing and able to provide informed consent.Exclusion criteria were as follows: (1) immobility or major mobility disorder or inability to engage safely in the proposed weight-bearing exercise program ; (2) severe cognitive impairment (MoCA score < 16); (3) other neurological conditions associated with cognitive impairment such as stroke, Parkinson disease, and head injury; (4) any clinically significant psychiatric condition, current drug or alcohol abuse, or laboratory abnormality that would interfere with the ability to participate in the study; and (5) major hearing/visual impairment. The study protocol was approved by the local Institutional Review Boards at Baylor College of Medicine (Protocols: H-44913). All participants read and signed a consent form prior to the study.Demographics collected from all participants included age, gender, and body mass index (BMI). The following clinical information was also collected, such as high blood pressure, heart disease, musculoskeletal problems, stroke, depression, sleep problems, diabetes, osteoarthritis, rheumatoid arthritis, cancer, urinary tract problem, digestive problem, hearing problem, walking assistance use, fall history in the past year, daily prescription medications, and daily over-the-counter medications. Furthermore, all participants were assessed for their fear of falling using the Falls Efficacy Scale-International (FES-I) questionnaire ,27 and tThe clinical psychologist (M.Y.) at Baylor College of Medicine confirmed the diagnosis of mild cognitive impairment or dementia. A trained research assistant interviewed the potential candidate for the study participation face to face. After confirming the satisfaction of the inclusion and exclusion criteria, informed consent was obtained, and the individual with dementia or MCI and their caregiver (if available) were trained with the tele-Exergame system. The clinical assessments, including administration of MoCA, BAI, CES-D, TAM questionnaire, and FES-I, were carried out in-clinic by the same research assistant.At the beginning of 6 weeks of in-home exergaming exercises with the proposed tele-Exergame system, acceptance of tele-Exergame and participant’s cognition and anxiety were assessed . To assess the acceptance of tele-Exergame by participants, the TAM questionnaire , which is an intention-based model developed to evaluate user’s acceptance and user satisfaction with technology, was used . The TAMTM) at the top of their foot for foot flexion exercises and the middle of their upper leg for leg raising exercises. After completing 6 weeks of in-home exergaming exercises, all participants were assessed for their acceptance of tele-Exergame, cognition, and anxiety by using the TAM questionnaire, MoCA, and BAI questionnaire .All participants performed exergaming exercises  with the proposed tele-Exergame system twice per week for 6 consecutive weeks at their home. All participants were instructed to perform leg raising or foot flexion exercises for approximately 30 min every day. Participants were asked to wear the motion sensor , medium (0.50–0.79), large (0.80–1.29), and very large (above 1.30) [p < 0.05 level.Outcome measures included Likert scale points for each question of the TAM, MoCA score, and BAI score for two assessment periods . Statistical analysis was conducted using SPSS . A paired t-test was conducted to compare all outcome measures  between two assessment periods . In addition, an effect size was calculated for all outcome measures using Cohen’s ve 1.30) . Statist2, respectively. The average FES-I and CES-D scores were 25.7 ± 6.7 and 11.8 ± 10.7, respectively. A total of 35.7% and 28.6% of participants were identified as having a high concern of falling  and at risk for clinical depression (CES-D score ≥ 16).The results showed that participants agreed on user-friendliness and ease of use while performing in-home exergaming exercises with the proposed tele-Exergame system . The Likert scale values were significantly decreased for the exergaming adherence (Q1) and increased for the participants’ level of interest while performing in-home exergaming exercises (Q2). The Likert scale values were significantly increased for Q3–Q9, which indicates that participants benefitted from performing in-home exergaming exercises to improve their physical and mental functions and quality of work. Specifically, participants felt significantly more energetic (Q3), improved self-awareness (Q4), increased mental alertness (Q5), improved quality of work (Q6), improved overall body functions (Q7), increased stamina (Q8), and improved flexibility (Q9) after 6 weeks of in-home exergaming exercises. Participants’ general attitude toward using the proposed tele-Exergame system was significantly increased. They indicated a willingness to perform similar or advanced exergaming exercises again (Q10), and they were satisfied with performing in-home exergaming exercises with the proposed tele-Exergame system (Q11). The Cohen’s d effect size was observed as large (0.80–1.29) for eight questions  and very large (above 1.30) for three questions .Additionally, participants and their families also commented positively on the proposed tele-Exergame system and performing in-home exergaming exercises. For example, they mentioned that it was “Easy to learn how to use tablet and sensors. Believes it will improve her flexibility.”, “She likes that she is able to interact with modern technology because she does not have a computer at home”, “Exercises were the perfect intensity. Not too hard and not too easy.”, “She believes it will make her muscles more toned.”, “Believes that it improved his walking and ankle strength.”, “It gave me something to do every day. Motivated him to be more active and achieve the star rewards.”, etc.This proof-of-concept phase I clinical study aimed to design and develop an interactive tele-Exergame system, and quantitatively and qualitatively assess the acceptance of an interactive tele-Exergame by older adults with MCI or dementia. This study also quantitatively evaluated cognition and anxiety levels after completing 6 weeks of in-home exergaming exercises by older adults with MCI or dementia. The results showed that older adults with MCI or dementia experienced interactive exergaming exercises as interesting and motivating. Older adults with MCI or dementia indicated that they were able to use the proposed tele-Exergame system easily and considered it user-friendly. The exercises provided were inspired by the validated Buerger-Allen exercise program to prevent ankle deconditioning and improve walking capability . NotablyThe core innovation of the proposed system is the use of gamified safe balance tasks in an interactive environment, immediate and sensitive feedback about the user’s performance, and a motivating effect due to game-based features ,35,36,37A major advantage of the proposed solution is its ability to improve access to care and health equity among older adults suffering from cognitive impairment. Many (40 to 80%) geriatric patients in rehabilitation are cognitively impaired ,43. ConvA systematic review  on the uRecent clinical studies and meta-analyses indicate that technology-based motor-cognitive training systems are feasible and can improve motor-cognitive functions in older adults with MCI or dementia, comparable to conventional clinical motor-cognitive training. For example, a systematic review and meta-analysis found that computerized cognitive training incorporating a VR system or using videogames provided by Nintendo Wii improved global cognition, attention, and working memory in older adults with MCI or dementia . AnotherOur tele-Exergame system has several advantages over existing VR- or videogame-based systems or exergame systems using Kinect. It uses a relatively inexpensive motion sensor to measure user’s motion in real time and support motor-cognitive exercises. Notably, our tele-Exergame system enables the remote monitoring of exercise progress and adherence, and remote coaching and consultation via an integrated video call. This functionality could potentially contribute to enhancing the health care providers’ knowledge about the patients by facilitating patient education and establishing shared goal setting and action planning for rehabilitation interventions. Furthermore, our custom application can be implemented on smartphones that are already universal and ubiquitous all around the world. In 2011, the smartphone’s penetration rate is approximately 97% in the United States and continues to increase worldwide ,57. PeopThe limitations of the present study are a relatively small sample size, and the lack of a control group . An additional limitation is a relatively short period of in-home exergaming exercises . A recent systematic review and meta-analysis reported that the number of interventions ranged from 1 to 3 days per week, and the longest exercise duration was 16 weeks . DespiteThis study is the first step toward implementing a tele-medicine based and interactive home-based exercise program tailored for people with MCI or dementia. The proposed exergaming technology supports cognitive-motor exercises that have been designed to improve balance and cognition during distractive conditioning. It also enables remote monitoring of exercise progress and adherence as well as remote coaching and consultation. The results showed the feasibility and acceptability of home-based and self-administered interventions for people with MCI and dementia. While the results are preliminary, they support the potential effectiveness in engaging older adults with MCI and dementia in regular cognitively demanding exercise tasks at home, which potentially helps improve or preserve cognitive function and reduce anxiety. These encouraging results pave the way for future randomized control trials (RCT) to demonstrate the effectiveness of encouraging this home-based exercise program to improve cognitive and motor functions in older adults with MCI and dementia.This study was a phase I of a larger randomized control trial described in clinicaltrials.gov (Identifier: NCT05235113). In the next phase study (Phase II), we plan to examine the effectiveness of a 12-week tele-Exergame program using a RCT design, with additional primary and secondary outcomes including motor performance , mobility , cognition, patient reported outcomes , and risk of falling. The eventual goal is to provide a self-administered, remotely supervised home-exercise program for older adults with MCI or dementia to help them preserve cognitive-motor function while reducing the consequences of cognitive-motor decline such as reduced mobility, falls, anxiety, depression, and reduced independency.


Efforts to understand the impact of SARS-CoV-2 variants, vaccine status, and treatment on the development and persistence of Long COVID have intensified.We report 4 sequential cases from a post-COVID cohort study demonstrating variability in outcomes following differentially timed nirmatrelvir therapy, received as part of clinical care.In the first case, the participant experienced symptomatic rebound and developed Long COVID despite early initiation of antiviral therapy. In the next 2 cases, participants reported improvement in persistent COVID symptoms when nirmatrelvir was taken 25 and 60 days following initial symptom onset. In the final case, an individual with presumed Long COVID for 2 years reported substantial improvement in chronic symptoms when taking nirmatrelvir following SARS-CoV-2 re-infection.These anecdotes suggest that systematic study of antiviral therapy for Long COVID is warranted. Many individuals do not fully recover from acute SARS-CoV-2 infection . Efforts to prevent or reverse this potentially disabling syndrome are just now emerging. Here, we report 4 cases in which individuals were treated with nirmatrelvir/ritonavir at various stages following infection. We believe these cases provide rationale for studying antiviral therapies in people with Long COVID.Participants were sequential volunteers in the UCSF Long-term Impact of Infection with Novel Coronavirus (LIINC) study (NCT04362150), who enrolled because of a history of Long-COVID symptoms and reported a history of nirmatrelvir/ritonavir use. The study was approved by the UCSF Institutional Review Board. Volunteers provided written informed consent prior to collection of clinical data and consented to the presentation of their cases.2  and reduced maximum heart rate  consistent with chronotropic incompetence.A 48-year-old man with a past medical history of presumed Bechet's disease and taking colchicine developed fever, worsening headache, and pharyngitis in Spring 2022. He had previously received 2 doses of the mRNA-1273 SARS-CoV-2 vaccine and 1 dose of the BNT162b2 vaccine; the most recent was 5 months prior. A rapid antigen test was positive, as was a confirmatory PCR test. He was prescribed a 5-day course of nirmatrelvir/ritonavir, which he initiated within 24 hours of symptom onset, and experienced rapid improvement in his systemic symptoms. However, approximately 4 days following completion of the 5-day course, he experienced rebound symptoms with recurrence of fever, fatigue, rhinorrhea, cough, chest pain, rash on his upper and lower extremities, and trouble concentrating (“brain fog”). During this period, he wore a personal fitness device which recorded certain physiologic measurements including heart rate, respiratory rate, and change from baseline body temperature . ApproxiA 42-year-old man with no significant medical history developed rhinorrhea and pharyngitis in early 2022, followed by fatigue, myalgia, and a pruritic rash on his upper extremities and groin that persisted for approximately 10 days. He had previously received 3 doses of the BNT162b2 SARS-CoV-2 vaccine; the most recent was 2 months prior. A SARS-CoV-2 antigen test was positive when performed 2 days after symptom onset; multiple additional antigen tests were subsequently positive. On Day 11, an antigen test was negative, and all of his symptoms resolved. Approximately 2 weeks later, he experienced new onset of severe myalgia and bone pain across his upper body, which he described as post-exertional soreness in the absence of exertion. There was an associated increase in fatigue, as well as heightened awareness of breathing (described as “lung soreness”). These symptoms persisted, and he contacted his primary care doctor for evaluation approximately 10 days later. At this visit, he noted that he was experiencing ongoing fatigue, and described being at 80% of his pre-COVID baseline health. Laboratory testing was notable only for vitamin D insufficiency (25 ng/mL); a chest X-ray showed no abnormalities.Approximately 7 weeks following initial symptom onset, his symptoms worsened. He experienced ongoing myalgia, severe fatigue, post-exertional malaise, and trouble concentrating (“brain fog”). These symptoms profoundly affected his ability to perform his activities of daily living, and he felt substantially debilitated, reporting that he was at 40%-50% of his pre-COVID baseline health, and that he was spending the majority of the day resting. He began to seek care for Long COVID because he was concerned about the duration of his symptoms. As his symptoms continued to worsen, he was re-exposed to SARS-CoV-2 when his spouse and children tested positive on antigen tests. A repeat antigen test was negative, but he experienced further worsening of his symptoms which his provider attributed to possible re-infection with SARS-CoV-2. In this context, he received a prescription for nirmatrelvir/ritonavir.Within days of re-exposure, the patient began to note an improvement in his persistent symptoms, while his family members continued to experience worsening symptoms. After symptomatic improvement for 1-2 days, he initiated a 5-day course of nirmatrelvir/ritonavir. During this period, he continued to experience improvement in his symptoms. While they have not resolved entirely as of 2 weeks later, he reports that he is gradually approaching his baseline health.A 43-year-old woman with no significant medical history developed cough and pharyngitis in Spring 2022. She had previously received 3 doses of the BNT162b2 SARS-CoV-2 vaccine; the most recent was 4 months prior. While a PCR test was initially negative, she and one of her children subsequently tested positive on an antigen test 5 days later. She did not initially receive antiviral therapy. Over the course of the subsequent 3 weeks, she began to experience worsening fatigue and malaise, with associated myalgia and trouble concentrating (“brain fog”); 3 weeks following initial symptom onset she was spending the majority of the day resting and was unable to easily complete her activities of daily living. She received a prescription for nirmatrelvir/ritonavir, which she began 25 days following initial symptom onset. One day following completion of therapy, she experienced improvement in her fatigue symptoms. While she has residual shortness of breath and myalgias, she has now been able to re-engage with the usual activities of daily living.In March 2020, a 47-year-old physician with a history of asthma developed an acute viral illness characterized by 12 days of sore throat, fatigue, diarrhea, and myalgia while working on an inpatient COVID-19 ward. She was not tested for SARS-CoV-2 infection due to the lack of availability of nucleic acid testing and the absence of fever, cough, or recent travel to China, which were strict criteria for testing during this time period. While many of her acute symptoms improved and she returned to work, she subsequently experienced progressive symptoms which included worsening myalgia, trouble concentrating (“brain fog”), chest pain, chronic diarrhea, and intermittent debilitating fatigue which persisted over the subsequent 20 months; this was presumed to represent Long COVID. She received 3 doses of the BNT162b2 SARS-CoV-2 vaccine with minimal change in her symptoms, although the third dose resulted in a week of intensified chest pain. Her Long Covid symptoms continued to progress to the point that she decided to take a leave of absence from work in early Winter 2022. Two months later, she was re-infected with SARS-CoV-2 and prescribed nirmatrelvir/ritonavir given her elevated risk for severe disease. She began treatment on Day 2 of her acute re-infection. She reported that within two days of initiating therapy, she began to experience relief from her chronic Long COVID symptoms, with substantial improvement in myalgia, diarrhea, and chest pain.As the SARS-CoV-2 pandemic continues to evolve, efforts to understand variability in COVID-19 recovery, as well as the impact of factors including viral variants, vaccine status, and COVID-19 treatment on the development and persistence of Long COVID symptoms have intensified. This case series demonstrates that variability in the timing of antiviral therapy as well as other potential determinants of Long COVID may be associated with different outcomes and underscores the need for systematic study of antiviral therapy for this disease condition during both the acute and convalescent stages.It has been suggested that the viral burden during acute infection may be an important determinant of Long COVID,  and thatA related hypothesis is that SARS-CoV-2 may persist for weeks to months in some individuals, causing inflammation, local tissue damage, and end-organ disease. –11 If thAn additional factor in 2 of these cases was re-exposure and/or re-infection events; in one case the individual began to experience improvement in Long COVID symptoms which had until that point been escalating. Although vaccines are likely to reduce the risk of developing Long COVID,  there arAlthough this case series is limited by a lack of intensive physiologic and laboratory measurements throughout the disease course, we believe these clinical anecdotes are informative as investigators try to understand the pathophysiology that drives the development and persistence of Long COVID. They suggest that antiviral therapy and/or antigen re-exposure could potentially alter the complex interplay between viral replication and the host immune response that likely underlies this syndrome but raise concern that brief early antiviral therapy alone may be insufficient to prevent the development of Long COVID.