Solving the puzzle of Long Covid.

Long Covid provides an opportunity to understand how acute infections cause chronic disease.

Fluctuating risk of acute kidney injury-related mortality for four weeks after exposure to air pollution: A multi-country time-series study in 6 countries.

BACKGROUND: Recent studies have reported that air pollution is related to kidney diseases. However, the global evidence on the risk of death from acute kidney injury (AKI) owing to air pollution is limited. Therefore, we investigated the association between short-term exposure to air pollution-particulate matter ≤ 2.5 µm (PM2.5), ozone (O3), and nitrogen dioxide (NO2)-and AKI-related mortality using a multi-country dataset. METHODS: This study included 41,379 AKI-related deaths in 136 locations in six countries during 1987-2018. A novel case time-series design was applied to each air pollutant during 0-28 lag days to estimate the association between air pollution and AKI-related deaths. Moreover, we calculated AKI deaths attributable to non-compliance with the World Health Organization (WHO) air quality guidelines. RESULTS: The relative risks (95% confidence interval) of AKI-related deaths are 1.052 (1.003, 1.103), 1.022 (0.994, 1.050), and 1.022 (0.982, 1.063) for 5, 10, and 10 µg/m3 increase in lag 0-28 days of PM2.5, warm-season O3, and NO2, respectively. The lag-distributed association showed that the risk appeared immediately on the day of exposure to air pollution, gradually decreased, and then increased again reaching the peak approximately 20 days after exposure to PM2.5 and O3. We also found that 1.9%, 6.3%, and 5.2% of AKI deaths were attributed to PM2.5, warm-season O3, and NO2 concentrations above the WHO guidelines. CONCLUSIONS: This study provides evidence that public health policies to reduce air pollution may alleviate the burden of death from AKI and suggests the need to investigate the several pathways between air pollution and AKI death.

Long-term outcomes following hospital admission for COVID-19 versus seasonal influenza: a cohort study.

BACKGROUND: Previous comparative analyses of people admitted to hospital for COVID-19 versus influenza evaluated the risk of death, hospital readmission, and a narrow set of health outcomes up to 6 months following infection. We aimed to do a comparative evaluation of both acute and long-term risks and burdens of a comprehensive set of health outcomes following hospital admission for COVID-19 or seasonal influenza. METHODS: For this cohort study we used the health-care databases of the US Department of Veterans Affairs to analyse data from 81 280 participants admitted to hospital for COVID-19 between March 1, 2020, and June 30, 2022, and 10 985 participants admitted to hospital for seasonal influenza between Oct 1, 2015, and Feb 28, 2019. Participants were followed up for up to 18 months to comparatively evaluate risks and burdens of death, a prespecified set of 94 individual health outcomes, ten organ systems, overall burden across all organ systems, readmission, and admission to intensive care. Inverse probability weighting was used to balance the baseline characteristics. Cox and Poisson models were used to generate estimates of risk on both the relative scale and absolute scale as the event rate and disability-adjusted life-years (DALYs) per 100 persons. FINDINGS: Over 18 months of follow-up, compared to seasonal influenza, the COVID-19 group had an increased risk of death (hazard ratio [HR] 1·51 [95% CI 1·45-1·58]), corresponding to an excess death rate of 8·62 (95% CI 7·55-9·44) per 100 persons in the COVID-19 group versus the influenza group. Comparative analyses of 94 prespecified health outcomes showed that COVID-19 had an increased risk of 68·1% (64 of 94) pre-specified health outcomes; seasonal influenza was associated with an increased risk of 6·4% (six of 94) pre-specified health outcomes, including three out of four pre-specified pulmonary outcomes. Analyses of organ systems showed that COVID-19 had a higher risk across all organ systems except for the pulmonary system, the risk of which was higher in seasonal influenza. The cumulative rates of adverse health outcomes across all organ systems were 615·18 (95% CI 605·17-624·88) per 100 persons in COVID-19 and 536·90 (527·38-544·90) per 100 persons in seasonal influenza, corresponding to an excess rate of 78·72 (95% CI 66·15-91·24) per 100 persons in COVID-19. The total number of DALYs across all organ systems were 287·43 (95% CI 281·10-293·59) per 100 persons in the COVID-19 group and 242·66 (236·75, 247·67) per 100 persons in the seasonal influenza group, corresponding to 45·03 (95% CI 37·15-52·90) higher DALYs per 100 persons in COVID-19. Decomposition analyses showed that in both COVID-19 and seasonal influenza, there was a higher burden of health loss in the post-acute than the acute phase; and comparatively, except for the pulmonary system, COVID-19 had a higher burden of health loss across all other organ systems than seasonal influenza in both the acute and post-acute phase. Compared to seasonal influenza, COVID-19 also had an increased risk of hospital readmission (excess rate 20·50 [95% CI 16·10-24·86] per 100 persons) and admission to intensive care (excess rate 9·23 [6·68-11·82] per 100 persons). The findings were consistent in analyses comparatively evaluating risks in seasonal influenza versus COVID-19 by individuals' respective vaccination status and in those admitted to hospital during the pre-delta, delta, and omicron eras. INTERPRETATION: Although rates of death and adverse health outcomes following hospital admission for either seasonal influenza or COVID-19 are high, this comparative analysis shows that hospital admission for COVID-19 was associated with higher long-term risks of death and adverse health outcomes in nearly every organ system (except for the pulmonary system) and significant cumulative excess DALYs than hospital admission for seasonal influenza. The substantial cumulative burden of health loss in both groups calls for greater prevention of hospital admission for these two viruses and for greater attention to the care needs of people with long-term health effects due to either seasonal influenza or SARS-CoV-2 infection. FUNDING: US Department of Veterans Affairs.

Postacute sequelae of COVID-19 at 2 years.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to postacute sequelae in multiple organ systems, but evidence is mostly limited to the first year postinfection. We built a cohort of 138,818 individuals with SARS-CoV-2 infection and 5,985,227 noninfected control group from the US Department of Veterans Affairs and followed them for 2 years to estimate the risks of death and 80 prespecified postacute sequelae of COVID-19 (PASC) according to care setting during the acute phase of infection. The increased risk of death was not significant beyond 6 months after infection among nonhospitalized but remained significantly elevated through the 2 years in hospitalized individuals. Within the 80 prespecified sequelae, 69% and 35% of them became not significant at 2 years after infection among nonhospitalized and hospitalized individuals, respectively. Cumulatively at 2 years, PASC contributed 80.4 (95% confidence interval (CI): 71.6-89.6) and 642.8 (95% CI: 596.9-689.3) disability-adjusted life years (DALYs) per 1,000 persons among nonhospitalized and hospitalized individuals; 25.3% (18.9-31.0%) and 21.3% (18.2-24.5%) of the cumulative 2-year DALYs in nonhospitalized and hospitalized were from the second year. In sum, while risks of many sequelae declined 2 years after infection, the substantial cumulative burden of health loss due to PASC calls for attention to the care needs of people with long-term health effects due to SARS-CoV-2 infection.

Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of major adverse cardiovascular events: emulation of a randomised target trial using electronic health records.

BACKGROUND: Randomised clinical trials showed that compared with placebo, SGLT2 inhibitors and GLP-1 receptor agonists reduced risk of adverse cardiovascular events. The evidence base for the older antihyperglycaemic drug classes (DPP-4 inhibitors and sulfonylureas) is generally less well developed. Because most randomised trials evaluated one antihyperglycaemic medication versus placebo, a head-to-head comparative effectiveness analysis of the newer drug classes (SGLT2 inhibitors vs GLP-1 receptor agonists) or newer (SGLT2 inhibitors or GLP-1 receptor agonists) versus older (DPP-4 inhibitors or sulfonylureas) drug classes on risk of major adverse cardiovascular events (MACE) is not available. In this study, we aimed to evaluate the comparative effectiveness of incident use of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, or sulfonylureas on risk of MACE. METHODS: We first specified the protocol of a four-arm randomised pragmatic clinical trial and then emulated it using the health-care databases of the US Department of Veterans Affairs. We built a cohort of metformin users with incident use of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, or sulfonylureas between Oct 1, 2016 and Sept 30, 2021, and followed up until Dec 31, 2022. We used the overlap weighting approach to balance the treatment groups using a battery of predefined variables and a set of algorithmically selected variables from high-dimensional data domains. Both intention-to-treat and per-protocol analyses (the latter estimated the effect of maintained use of the antihyperglycaemic throughout follow-up) were conducted to estimate risk of MACE-defined as a composite endpoint of stroke, myocardial infarction, and all-cause mortality. FINDINGS: The final cohort consisted of 283 998 new users of SGLT2 inhibitors (n=46 516), GLP-1 receptor agonists (n=26 038), DPP-4 inhibitors (n=55 310), or sulfonylureas (n=156 134). In intention-to-treat analyses, compared with sulfonylureas, SGLT2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors were associated with lower risk of MACE (hazard ratio [HR] 0·77 [95% CI 0·74-0.80], 0·78 [0·74-0·81), and 0·90 [0·86-0.93], respectively). Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of MACE when compared with DPP-4 inhibitors (HR 0·86 [0·82-0·89] and 0·86 [0·82-0·90], respectively). The risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists yielded an HR of 0·99 (0·94-1·04). In per-protocol analyses, compared with sulfonylureas, SGLT2 inhibitors, GLP1 receptor agonists, and DPP-4 inhibitors were associated with reduced risk of MACE (HR 0·77 [95% CI 0·73-0·82], 0·77 [0·72-0·82], and 0·88 [0·83-0·93], respectively). Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of MACE when compared with DPP-4 inhibitors (HR 0·88 [0·83-0·93] and 0·88 [0·82-0·93], respectively). The risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists yielded an HR of 1·01 (0·94-1·07). INTERPRETATION: Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with reduced risk of MACE compared with DPP-4 inhibitors or sulfonylureas. DPP-4 inhibitors were associated with reduced risk of MACE compared with sulfonylureas. There was no statistically significant difference in risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists. The results provide evidence of the real-world comparative effectiveness of the four most commonly used second-line antihyperglycaemics and could guide choice of antihyperglycaemic therapy. FUNDING: US Department of Veterans Affairs and the American Society of Nephrology.

Molnupiravir and risk of post-acute sequelae of covid-19: cohort study.

OBJECTIVE: To examine whether treatment with the antiviral agent molnupiravir during the first five days of SARS-CoV-2 infection is associated with reduced risk of post-acute adverse health outcomes. DESIGN: Cohort study. SETTING: US Department of Veterans Affairs. PARTICIPANTS: 229 286 participants who tested positive for SARS-CoV-2 between 5 January 2022 and 15 January 2023, had at least one risk factor for progression to severe covid-19, and survived the first 30 days after testing positive were enrolled. 11 472 participants received a prescription for molnupiravir within five days of the positive test result and 217 814 received no covid-19 antiviral or antibody treatment (no treatment group). MAIN OUTCOME MEASURES: Risks of post-acute sequelae of SARS-CoV-2 (PASC, defined based on a prespecified set of 13 post-acute sequelae), post-acute death, post-acute hospital admission, and each individual post-acute sequela between the molnupiravir group and no treatment group were examined after application of inverse probability weighting to balance the treatment and no treatment groups. Post-acute outcomes were ascertained from 30 days after the first SARS-CoV-2 positive test result until end of follow-up. Risks on the relative scale (relative risk or hazard ratio) and absolute scale (absolute risk reduction at 180 days) were estimated. RESULTS: Compared with no treatment, molnupiravir use within five days of a positive SARS-CoV-2 test result was associated with reduced risk of PASC (relative risk 0.86 (95% confidence interval 0.83 to 0.89); absolute risk reduction at 180 days 2.97% (95% confidence interval 2.31% to 3.60%)), post-acute death (hazard ratio 0.62 (0.52 to 0.74); 0.87% (0.62% to 1.13%)), and post-acute hospital admission (0.86 (0.80 to 0.93); 1.32% (0.72% to 1.92%)). Molnupiravir was associated with reduced risk of eight of the 13 post-acute sequelae: dysrhythmia, pulmonary embolism, deep vein thrombosis, fatigue and malaise, liver disease, acute kidney injury, muscle pain, and neurocognitive impairment. Molnupiravir was also associated with reduced risk of PASC in people who had not received a covid-19 vaccine, had received at one or two vaccine doses, and had received a booster dose, and in people with primary SARS-CoV-2 infection and reinfection. CONCLUSIONS: In people with SARS-CoV-2 infection and at least one risk factor for progression to severe covid-19, compared with no treatment, molnupiravir use within five days of infection was associated with reduced risk of PASC in people who had not received a covid-19 vaccine, had received one or two vaccine doses, and had received a booster dose, and in those with primary SARS-CoV-2 infection and reinfection. Among people at high risk of progression to severe covid-19, molnupiravir use within five days of SARS-CoV-2 infection may be a viable approach to reduce the risk of PASC.

Air Pollution and Acute Kidney Injury in the U.S. Medicare Population: A Longitudinal Cohort Study.

BACKGROUND: Recent studies have reported the association between air pollution exposure and reduced kidney function. However, it is unclear whether air pollution is associated with an increased risk of acute kidney injury (AKI). OBJECTIVES: To address this gap in knowledge, we investigated the effect estimates of long-term exposures to fine particulate matter [PM ≤2.5µm in aerodynamic diameter (PM2.5)], nitrogen dioxide (NO2), and ozone (O3) on the risk of first hospital admission for AKI using nationwide Medicare data. METHODS: This nationwide population-based longitudinal cohort study included 61,300,754 beneficiaries enrolled in Medicare Part A fee-for-service (FFS) who were ≥65 years of age and resided in the continental United States from the years 2000 through 2016. We applied Cox-equivalent Poisson models to estimate the association between air pollution and first hospital admission for AKI. RESULTS: Exposure to PM2.5, NO2, and O3 was associated with increased risk for first hospital admission for AKI, with hazard ratios (HRs) of 1.17 (95% CI: 1.16, 1.19) for a 5-µg/m3 increase in PM2.5, 1.12 (95% CI: 1.11, 1.13) for a 10-ppb increase in NO2, and 1.03 (95% CI: 1.02, 1.04) for a 10-ppb increase in summer-period O3 (June to September). The associations persisted at annual exposures lower than the current National Ambient Air Quality Standard. DISCUSSION: This study found an association between exposures to air pollution and the risk of the first hospital admission with AKI, and this association persisted even at low concentrations of air pollution. Our findings provide beneficial implications for public health policies and air pollution guidelines to alleviate health care expenditures and the disease burden attributable to AKI. https://doi.org/10.1289/EHP10729.

Nirmatrelvir and risk of hospital admission or death in adults with covid-19: emulation of a randomized target trial using electronic health records.

OBJECTIVE: To estimate the effectiveness of nirmatrelvir, compared with no treatment, in reducing admission to hospital or death at 30 days in people infected with the SARS-CoV-2 virus and at risk of developing severe disease, according to vaccination status and history of previous SARS-CoV-2 infection. DESIGN: Emulation of a randomized target trial with electronic health records. SETTING: Healthcare databases of the US Department of Veterans Affairs PARTICIPANTS: 256 288 participants with a SARS-CoV-2 positive test result and at least one risk factor for developing severe covid-19 disease, between 3 January and 30 November 2022. 31 524 were treated with nirmatrelvir within five days of testing positive for SARS-CoV-2 and 224 764 received no treatment. MAIN OUTCOME MEASURES: The effectiveness of starting nirmatrelvir within five days of a positive SARS-CoV-2 test result versus no treatment in reducing the risk of admission to hospital or death at 30 days was estimated in those who were not vaccinated, in those who received one or two doses of vaccine, and those who received a vaccine booster and, separately, in participants with a primary SARS-CoV-2 infection or reinfection. The inverse probability weighting method was used to balance personal and health characteristics between the groups. Relative risk and absolute risk reduction were computed from cumulative incidence at 30 days, estimated by weighted Kaplan-Meier estimator. RESULTS: Among people who were not vaccinated (n=76 763; 5338 nirmatrelvir and 71 425 no treatment), compared with no treatment, the relative risk of nirmatrelvir in reducing admission to hospital or death at 30 days was 0.60 (95% confidence interval 0.50 to 0.71); the absolute risk reduction was 1.83% (95% confidence interval 1.29% to 2.49%). The relative risk and absolute risk reduction, compared with no treatment, were 0.65 (0.57 to 0.74) and 1.27% (0.90% to 1.61%), respectively, in people who received one or two doses of vaccine (n=84 620; 7989 nirmatrelvir and 76 631 no treatment); 0.64 (0.58 to 0.71) and 1.05% (0.85% to 1.27%) in individuals who received a booster dose of vaccine (n=94 905; 18 197 nirmatrelvir and 76 708 no treatment); 0.61 (0.57 to 0.65) and 1.36% (1.19% to 1.53%) in participants with a primary SARS-CoV-2 infection (n=228 081; 26 350 nirmatrelvir and 201 731 no treatment); and 0.74 (0.63 to 0.87) and 0.79% (0.36% to 1.18%) in participants who were reinfected with the SARS-CoV-2 virus (n=28 207; 5174 nirmatrelvir and 23 033 no treatment). Nirmatrelvir was associated with a reduced risk of admission to hospital or death in those aged ≤65 years and > 65 years; in men and women; in black and white participants; in those with 1-2, 3-4, and ≥5 risk factors for progression to severe covid-19 illness; and in those infected during the omicron BA.1 or BA.2 predominant era, and the BA.5 predominant era. CONCLUSIONS: In people with SARS-CoV-2 infection who were at risk of developing severe disease, compared with no treatment, nirmatrelvir was associated with a reduced risk of admission to hospital or death at 30 days in people who were not vaccinated, vaccinated, and had received a booster vaccine, and in those with a primary SARS-CoV-2 infection and reinfection.

Risk of Death in Patients Hospitalized for COVID-19 vs Seasonal Influenza in Fall-Winter 2022-2023.

This study uses data from the US Department of Veterans Affairs to assess whether SARS-CoV-2 remains associated with higher risk of death compared with seasonal influenza in fall-winter 2022-2023.

Molnupiravir and risk of hospital admission or death in adults with covid-19: emulation of a randomized target trial using electronic health records.

OBJECTIVE: To emulate a randomized target trial to estimate the association between the antiviral drug molnupiravir and hospital admission or death in adults with SARS-CoV-2 infection in the community during the omicron predominant era who were at high risk of progression to severe covid-19. DESIGN: Emulation of a randomized target trial using electronic health records. SETTING: US Department of Veterans Affairs. PARTICIPANTS: 85 998 adults with SARS-CoV-2 infection between 5 January and 30 September 2022 and at least one risk factor for progression to severe covid-19: 7818 participants were eligible for and treated with molnupiravir and 78 180 received no treatment. MAIN OUTCOMES MEASURE: The primary outcome was a composite of hospital admission or death at 30 days. The clone method with inverse probability of censoring weighting was used to adjust for informative censoring and balance baseline characteristics between the groups. The cumulative incidence function was used to estimate the relative risk and the absolute risk reduction at 30 days. RESULTS: Molnupiravir was associated with a reduction in hospital admissions or death at 30 days (relative risk 0.72 (95% confidence interval 0.64 to 0.79)) compared with no treatment; the event rates for hospital admission or death at 30 days were 2.7% (95% confidence interval 2.5% to 3.0%) for molnupiravir and 3.8% (3.7% to 3.9%) for no treatment; the absolute risk reduction was 1.1% (95% confidence interval 0.8% to 1.4%). Molnupiravir appeared to be effective in those who had not been vaccinated against covid-19 (relative risk 0.83 (0.70 to 0.97) and absolute risk reduction 0.9% (0.2% to 1.9%)), had received one or two vaccine doses (0.69 (0.56 to 0.83) and 1.3% (0.7% to 1.9%)), and had received a booster dose (0.71 (0.58 to 0.83) and 1.0% (0.5% to 1.4%)); in those infected during the era when the omicron subvariant BA.1 or BA.2 was predominant (0.72 (0.62 to 0.83) and 1.2% (0.7% to 1.6%)) and when BA.5 was predominant (0.75 (0.66 to 0.86) and 0.9% (0.5% to 1.3%)); and in those with no history of SARS-CoV-2 infection (0.72 (0.64 to 0.81) and 1.1% (0.8% to 1.4%)) and with a history of SARS-CoV-2 infection (0.75 (0.58 to 0.97) and 1.1% (0.1% to 1.8%)). CONCLUSIONS: The findings of this emulation of a randomized target trial suggest that molnupiravir might have reduced hospital admission or death at 30 days in adults with SARS-CoV-2 infection in the community during the recent omicron predominant era who were at high risk of progression to severe covid-19 and eligible for treatment with molnupiravir.

Long-term gastrointestinal outcomes of COVID-19.

A comprehensive evaluation of the risks and 1-year burdens of gastrointestinal disorders in the post-acute phase of COVID-19 is needed but is not yet available. Here we use the US Department of Veterans Affairs national health care databases to build a cohort of 154,068 people with COVID-19, 5,638,795 contemporary controls, and 5,859,621 historical controls to estimate the risks and 1-year burdens of a set of pre-specified incident gastrointestinal outcomes. We show that beyond the first 30 days of infection, people with COVID-19 exhibited increased risks and 1-year burdens of incident gastrointestinal disorders spanning several disease categories including motility disorders, acid related disorders (dyspepsia, gastroesophageal reflux disease, peptic ulcer disease), functional intestinal disorders, acute pancreatitis, hepatic and biliary disease. The risks were evident in people who were not hospitalized during the acute phase of COVID-19 and increased in a graded fashion across the severity spectrum of the acute phase of COVID-19 (non-hospitalized, hospitalized, and admitted to intensive care). The risks were consistent in comparisons including the COVID-19 vs the contemporary control group and COVID-19 vs the historical control group as the referent category. Altogether, our results show that people with SARS-CoV-2 infection are at increased risk of gastrointestinal disorders in the post-acute phase of COVID-19. Post-covid care should involve attention to gastrointestinal health and disease.

Association of Treatment With Nirmatrelvir and the Risk of Post-COVID-19 Condition.

Importance: Post-COVID-19 condition (PCC), also known as long COVID, affects many individuals. Prevention of PCC is an urgent public health priority. Objective: To examine whether treatment with nirmatrelvir in the acute phase of COVID-19 is associated with reduced risk of PCC. Design, Setting, and Participants: This cohort study used the health care databases of the US Department of Veterans Affairs (VA) to identify patients who had a SARS-CoV-2 positive test result between January 3, 2022, and December 31, 2022, who were not hospitalized on the day of the positive test result, who had at least 1 risk factor for progression to severe COVID-19 illness, and who had survived the first 30 days after SARS-CoV-2 diagnosis. Those who were treated with oral nirmatrelvir within 5 days after the positive test (n = 35 717) and those who received no COVID-19 antiviral or antibody treatment during the acute phase of SARS-CoV-2 infection (control group, n = 246 076) were identified. Exposures: Treatment with nirmatrelvir or receipt of no COVID-19 antiviral or antibody treatment based on prescription records. Main Outcomes and Measures: Inverse probability weighted survival models were used to estimate the association of nirmatrelvir (vs control) with post-acute death, post-acute hospitalization, and a prespecified panel of 13 post-acute COVID-19 sequelae (components of PCC) and reported in relative scale as relative risk (RR) or hazard ratio (HR) and in absolute scale as absolute risk reduction in percentage at 180 days (ARR). Results: A total of 281 793 patients (mean [SD] age, 61.99 [14.96]; 242 383 [86.01%] male) who had a positive SARS-CoV-2 test result and had at least 1 risk factor for progression to severe COVID-19 illness were studied. Among them, 246 076 received no COVID-19 antiviral or antibody treatment during the acute phase of SARS-CoV-2 infection, and 35 717 received oral nirmatrelvir within 5 days after the positive SARS-CoV-2 test result. Compared with the control group, nirmatrelvir was associated with reduced risk of PCC (RR, 0.74; 95% CI, 0.72-0.77; ARR, 4.51%; 95% CI, 4.01-4.99), including reduced risk of 10 of 13 post-acute sequelae (components of PCC) in the cardiovascular system (dysrhythmia and ischemic heart disease), coagulation and hematologic disorders (pulmonary embolism and deep vein thrombosis), fatigue and malaise, acute kidney disease, muscle pain, neurologic system (neurocognitive impairment and dysautonomia), and shortness of breath. Nirmatrelvir was also associated with reduced risk of post-acute death (HR, 0.53; 95% CI, 0.46-0.61); ARR, 0.65%; 95% CI, 0.54-0.77), and post-acute hospitalization (HR, 0.76; 95% CI, 0.73-0.80; ARR, 1.72%; 95% CI, 1.42-2.01). Nirmatrelvir was associated with reduced risk of PCC in people who were unvaccinated, vaccinated, and boosted, and in people with primary SARS-CoV-2 infection and reinfection. Conclusions and Relevance: This cohort study found that in people with SARS-CoV-2 infection who had at least 1 risk factor for progression to severe disease, treatment with nirmatrelvir within 5 days of a positive SARS-CoV-2 test result was associated with reduced risk of PCC across the risk spectrum in this cohort and regardless of vaccination status and history of prior infection; the totality of findings suggests that treatment with nirmatrelvir during the acute phase of COVID-19 may reduce the risk of post-acute adverse health outcomes.

Risks and burdens of incident dyslipidaemia in long COVID: a cohort study.

BACKGROUND: Non-clinical evidence and a few human studies with short follow-ups suggest increased risk of dyslipidaemia in the post-acute phase of COVID-19 (ie, >30 days after SARS-CoV-2 infection). However, detailed large-scale controlled studies with longer follow-ups and in-depth assessment of the risks and burdens of incident dyslipidaemia in the post-acute phase of COVID-19 are not yet available. We, therefore, aimed to examine the risks and 1-year burdens of incident dyslipidaemia in the post-acute phase of COVID-19 among people who survive the first 30 days of SARS-CoV-2 infection. METHODS: In this cohort study, we used the national health-care databases of the US Department of Veterans Affairs to build a cohort of 51 919 participants who had a positive COVID-19 test and survived the first 30 days of infection between March 1, 2020, and Jan 15, 2021; a non-infected contemporary control group (n=2 647 654) that enrolled patients between March 1, 2020, and Jan 15, 2021; and a historical control group (n=2 539 941) that enrolled patients between March 1, 2018, and Jan 15, 2019. Control groups had no evidence of SARS-CoV-2 infection, and participants in all three cohorts were free of dyslipidaemia before cohort enrolment. We then used inverse probability weighting using predefined and algorithmically-selected high dimensional variables to estimate the risks and 1-year burdens of incident dyslipidaemia, lipid-lowering medications use, and a composite of these outcomes. We reported two measures of risk: hazard ratios (HRs) and burden per 1000 people at 12 months. Additionally, we estimated the risks and burdens of incident dyslipidaemia outcomes in mutually exclusive groups based on the care setting of the acute infection (ie, participants who were non-hospitalised, hospitalised, or admitted to intensive care during the acute phase of SARS-CoV-2 infection). FINDINGS: In the post-acute phase of the SARS-CoV-2 infection, compared with the non-infected contemporary control group, those in the COVID-19 group had higher risks and burdens of incident dyslipidaemia, including total cholesterol greater than 200 mg/dL (hazard ratio [HR] 1·26, 95% CI 1·22-1·29; burden 22·46, 95% CI 19·14-25·87 per 1000 people at 1 year), triglycerides greater than 150 mg/dL (1·27, 1·23-1·31; 22·03, 18·85-25·30), LDL cholesterol greater than 130 mg/dL (1·24, 1·20-1·29; 18·00, 14·98-21·11), and HDL cholesterol lower than 40 mg/dL (1·20, 1·16-1·25; 15·58, 12·52-18·73). The risk and burden of a composite of these abnormal lipid laboratory outcomes were 1·24 (95% CI 1·21-1·27) and 39·19 (95% CI 34·71-43·73), respectively. There was also increased risk and burden of incident lipid-lowering medications use (HR 1·54, 95% CI 1·48-1·61; burden 25·50, 95% CI 22·61-28·50). A composite of any dyslipidaemia outcome (laboratory abnormality or lipid-lowering medications use) yielded an HR of 1·31 (95% CI 1·28-1·34) and a burden of 54·03 (95% CI 49·21-58·92). The risks and burdens of these post-acute outcomes increased in a graded fashion corresponding to the severity of the acute phase of COVID-19 infection (ie, whether patients were non-hospitalised, hospitalised, or admitted to intensive care). The results were consistent in analyses comparing the COVID-19 group to the non-infected historical control group. INTERPRETATION: Our findings suggest increased risks and 1-year burdens of incident dyslipidaemia and incident lipid-lowering medications use in the post-acute phase of COVID-19 infection. Post-acute care for those with COVID-19 should involve attention to dyslipidaemia as a potential post-acute sequela of SARS-CoV-2 infection. FUNDING: US Department of Veterans Affairs.