Impact of age and comorbidities on SARS-CoV-2 vaccine-induced T cell immunity.

BACKGROUND: Older age and chronic disease are important risk factors for developing severe COVID-19. At population level, vaccine-induced immunity substantially reduces the risk of severe COVID-19 disease and hospitalization. However, the relative impact of humoral and cellular immunity on protection from breakthrough infection and severe disease is not fully understood. METHODS: In a study cohort of 655 primarily older study participants (median of 63 years (IQR: 51-72)), we determined serum levels of Spike IgG antibodies using a Multiantigen Serological Assay and quantified the frequency of SARS-CoV-2 Spike-specific CD4 + and CD8 + T cells using activation induced marker assay. This enabled characterization of suboptimal vaccine-induced cellular immunity. The risk factors of being a cellular hypo responder were assessed using logistic regression. Further follow-up of study participants allowed for an evaluation of the impact of T cell immunity on breakthrough infections. RESULTS: We show reduced serological immunity and frequency of CD4 + Spike-specific T cells in the oldest age group (≥75 years) and higher Charlson Comorbidity Index (CCI) categories. Male sex, age group ≥75 years, and CCI > 0 is associated with an increased likelihood of being a cellular hypo-responder while vaccine type is a significant risk factor. Assessing breakthrough infections, no protective effect of T cell immunity is identified. CONCLUSIONS: SARS-CoV-2 Spike-specific immune responses in both the cellular and serological compartment of the adaptive immune system increase with each vaccine dose and are progressively lower with older age and higher prevalence of comorbidities. The findings contribute to the understanding of the vaccine response in individuals with increased risk of severe COVID-19 disease and hospitalization.

Vaccination has proven very effective in protecting against severe disease and hospitalization of people with COVID-19, the disease caused by SARS-CoV-2. It is still unclear, however, how the different components of the immune system respond to SARS-CoV-2 vaccination and protect from infection and severe disease. Two of the most predominant components of the immune system are specialized proteins and cells. The proteins circulate in the blood and help clear the virus by binding to it, while the cells either kill the virus or help other cells to produce more antibodies. Here, we examined the response of these two components to the SARS-CoV-2 vaccine in 655 Danish citizens. The response of both components was lower in people over 75 years old and with other diseases. These findings help in understanding the immune responses following SARS-CoV-2 vaccination in people at increased risk of severe symptoms of COVID-19.

Treatment effect modifiers in hospitalised patients with COVID-19 receiving remdesivir and dexamethasone.

BACKGROUND: The combined effectiveness of remdesivir and dexamethasone in subgroups of hospitalised patients with COVID-19 is poorly investigated. METHODS: In this nationwide retrospective cohort study, we included 3826 patients with COVID-19 hospitalised between February 2020 and April 2021. The primary outcomes were use of invasive mechanical ventilation and 30-day mortality, comparing a cohort treated with remdesivir and dexamethasone with a previous cohort treated without remdesivir and dexamethasone. We used inverse probability of treatment weighting logistic regression to assess associations with progression to invasive mechanical ventilation and 30-day mortality between the two cohorts. The analyses were conducted overall and by subgroups based on patient characteristics. RESULTS: Odds ratio for progression to invasive mechanical ventilation and 30-day mortality in individuals treated with remdesivir and dexamethasone compared to treatment with standard of care alone was 0.46 (95% confidence interval, 0.37-0.57) and 0.47 (95% confidence interval, 0.39-0.56), respectively. The reduced risk of mortality was observed in elderly patients, overweight patients and in patients requiring supplemental oxygen at admission, regardless of sex, comorbidities and symptom duration. CONCLUSIONS: Patients treated with remdesivir and dexamethasone had significantly improved outcomes compared to patients treated with standard of care alone. These effects were observed in most patient subgroups.

Levels of SARS-CoV-2 antibodies among fully vaccinated individuals with Delta or Omicron variant breakthrough infections.

SARS-CoV-2 variants of concern have continuously evolved and may erode vaccine induced immunity. In this observational cohort study, we determine the risk of breakthrough infection in a fully vaccinated cohort. SARS-CoV-2 anti-spike IgG levels were measured before first SARS-CoV-2 vaccination and at day 21-28, 90 and 180, as well as after booster vaccination. Breakthrough infections were captured through the Danish National Microbiology database. incidence rate ratio (IRR) for breakthrough infection at time-updated anti-spike IgG levels was determined using Poisson regression. Among 6076 participants, 127 and 364 breakthrough infections due to Delta and Omicron variants were observed. IRR was 0.29 (95% CI 0.15-0.56) for breakthrough infection with the Delta variant, comparing the highest and lowest quintiles of anti-spike IgG. For Omicron, no significant differences in IRR were observed. These results suggest that quantitative level of anti-spike IgG have limited impact on the risk of breakthrough infection with Omicron.

Positive Predictive Value of the ICD-10 Diagnosis Code for Long-COVID.

PURPOSE: To examine the positive predictive value (PPV) of International Classification version 10 (ICD-10) diagnosis codes for long coronavirus disease 2019 (long-COVID) in a Danish Health registry. PATIENTS AND METHODS: This was a medical record review of all patients with a diagnosis code of long-COVID (DB948A) at all hospitals in the North Denmark Region from February 27, 2020 through June 30, 2021. Confirmed long-COVID was categorized as fulfillment of all three criteria: (1) a positive polymerase chain reaction (PCR) test for SARS-CoV-2 on a respiratory sample or a positive serum antibody test, (2) symptoms suggestive of long-COVID with no other diagnosis considered more likely, and (3) symptom duration >6 weeks. RESULTS: A total of 306 patients were assigned a hospital diagnosis code for long-COVID corresponding to 1.4% of all SARS-CoV-2 positive individuals during the study period (n=21,727). Next, 40 patients were excluded due to incomplete diagnostic evaluation at time of record review leaving 266 patients for analysis. The patients had a median age of 51 years (interquartile range 43-60) and 175/266 (66%) were females. Long-COVID was confirmed in 249/266 yielding an overall PPV of 94% (95%CI: 90-96) and did not differ substantially according to most age groups, sex, previous hospitalization for COVID-19, or by using 12 weeks of symptom duration as cut-off. The PPV was low for children and adolescents (n=5), the very elderly (n=9), and those included by secondary long-COVID diagnoses (n=10). CONCLUSION: The overall PPV of diagnosis codes for long-COVID in the North Denmark Region was high and was likely suitable for future registry-based studies of long-COVID. Caution is advised at the extremes of age and secondary diagnosis codes.

Prophylactic anticoagulation with low molecular weight heparin in COVID-19: cohort studies in Denmark and Sweden.

OBJECTIVES: To evaluate safety and effectiveness of prophylactic anticoagulation with low molecular weight heparin (LMWH) in individuals hospitalised for COVID-19. METHODS: Using healthcare records from the Capital Region of Denmark (March 2020-February 2021) and Karolinska University Hospital in Sweden (February 2020-September 2021), we conducted an observational cohort study comparing clinical outcomes 30 days after admission among individuals hospitalised for COVID-19 starting prophylactic LMWH during the first 48 hours of hospitalisation with outcomes among those not receiving prophylactic anticoagulation. We used inverse probability weighting to adjust for confounders and bias due to missing information. Risk ratios, risk differences and robust 95% confidence intervals (CI) were estimated using binomial regression. Country-specific risk ratios were pooled using random-effects meta-analysis. RESULTS: We included 1692 and 1868 individuals in the Danish and Swedish cohorts. Of these, 771 (46%) and 1167 (62%) received prophylactic LMWH up to 48 hours after admission. The combined mortality in Denmark and Sweden was 12% (N = 432) and the pooled risk ratio was 0.91 (CI 0.60-1.38) comparing individuals who received LMWH to those who did not. The relative risk of ICU admission was 1.12 (0.76-1.66), while we observed no increased risk of bleeding 0.63 (0.13-2.94). The relative risk of venous thromboembolism was 0.80 (0.43-1.47). CONCLUSION: We found no benefit on mortality with prophylactic LMWH and no increased risk of bleeding among COVID-19 patients receiving prophylactic LMWH.

Characteristics associated with serological COVID-19 vaccine response and durability in an older population with significant comorbidity: the Danish Nationwide ENFORCE Study.

OBJECTIVES: To identify individual characteristics associated with serological COVID-19 vaccine responsiveness and the durability of vaccine-induced antibodies. METHODS: Adults without history of SARS-CoV-2 infection from the Danish population scheduled for SARS-CoV-2 vaccination were enrolled in this parallel group, phase 4 study. SARS-CoV-2 Spike IgG and Spike-ACE2-receptor-blocking antibodies were measured at days 0, 21, 90, and 180. Vaccine responsiveness was categorized according to Spike IgG and Spike-ACE2-receptor-blocking levels at day 90 after first vaccination. Nondurable vaccine response was defined as day-90 responders who no longer had significant responses by day 180. RESULTS: Of 6544 participants completing two vaccine doses (median age 64 years; interquartile range: 54-75), 3654 (55.8%) received BTN162b2, 2472 (37.8%) mRNA-1273, and 418 (6.4%) ChAdOx1 followed by an mRNA vaccine. Levels of both types of antibodies increased from baseline to day 90 and then decreased to day 180. The decrease was more pronounced for levels of Spike-ACE2-receptor-blocking antibodies than for Spike IgG. Proportions with vaccine hyporesponsiveness and lack of durable response were 5.0% and 12.1% for Spike IgG and 12.7% and 39.6% for Spike-ACE2-receptor-blocking antibody levels, respectively. Male sex, vaccine type, and number of comorbidities were associated with all four outcomes. Additionally, age ≥75 years was associated with hyporesponsiveness for Spike-ACE2-receptor-blocking antibodies (adjusted odds ratio: 1.59; 95% confidence interval: 1.25-2.01) but not for Spike IgG. DISCUSSION: Comorbidity, male sex, and vaccine type were risk factors for hyporesponsiveness and nondurable response to COVID-19 vaccination. The functional activity of vaccine-induced antibodies declined with increasing age and had waned to pre-second-vaccination levels for most individuals after 6 months.

Venous Thromboembolism and Major Bleeding in Patients With Coronavirus Disease 2019 (COVID-19): A Nationwide, Population-Based Cohort Study.

BACKGROUND: Venous thromboembolism (VTE) is a potentially fatal complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and thromboprophylaxis should be balanced against risk of bleeding. This study examined risks of VTE and major bleeding in hospitalized and community-managed SARS-CoV-2 patients compared with control populations. METHODS: Using nationwide population-based registries, 30-day risks of VTE and major bleeding in SARS-CoV-2 positive patients were compared with those of SARS-CoV-2 test-negative patients and with an external cohort of influenza patients. Medical records of all COVID-19 patients at 6 departments of infectious diseases in Denmark were reviewed in detail. RESULTS: The overall 30-day risk of VTE was 0.4% (40/9460) among SARS-CoV-2 patients (16% hospitalized), 0.3% (649/226 510) among SARS-CoV-2 negative subjects (12% hospitalized), and 1.0% (158/16 281) among influenza patients (59% hospitalized). VTE risks were higher and comparable in hospitalized SARS-CoV-2 positive (1.5%), SARS-CoV-2 negative (1.8%), and influenza patients (1.5%). Diagnosis of major bleeding was registered in 0.5% (47/9460) of all SARS-CoV-2 positive individuals and in 2.3% of those hospitalized. Medical record review of 582 hospitalized SARS-CoV-2 patients observed VTE in 4% (19/450) and major bleeding in 0.4% (2/450) of ward patients, of whom 31% received thromboprophylaxis. Among intensive care patients (100% received thromboprophylaxis), risks were 7% (9/132) for VTE and 11% (15/132) for major bleeding. CONCLUSIONS: Among people with SARS-CoV-2 infection in a population-based setting, VTE risks were low to moderate and were not substantially increased compared with SARS-CoV-2 test-negative and influenza patients. Risk of severe bleeding was low for ward patients, but mirrored VTE risk in the intensive care setting.

Improved Survival Among Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) Treated With Remdesivir and Dexamethasone. A Nationwide Population-Based Cohort Study.

BACKGROUND: There are limited data on outcomes of moderate to severe coronavirus disease 2019 (COVID-19) among patients treated with remdesivir and dexamethasone in a real-world setting. We sought to compare the effectiveness of standard of care (SOC) alone versus SOC plus remdesivir and dexamethasone. METHODS: Two population-based nationwide cohorts of individuals hospitalized with COVID-19 during February through December 2020 were studied. Death within 30 days and need of mechanical ventilation (MV) were compared by inverse probability of treatment weighted (ITPW) logistic regression analysis and shown as odds ratio (OR) with 95% confidence interval (CI). RESULTS: The 30-days mortality rate of 1694 individuals treated with remdesivir and dexamethasone in addition to SOC was 12.6% compared to 19.7% for 1053 individuals receiving SOC alone. This corresponded to a weighted OR of 30-day mortality of 0.47 (95% CI: .38-.57) for patients treated with remdesivir and dexamethasone compared to patients receiving SOC alone. Similarly, progression to MV was reduced (OR 0.36; 95% CI: .29-.46). CONCLUSIONS: Treatment of moderate to severe COVID-19 during June through December that included remdesivir and dexamethasone was associated with reduced 30-day mortality and need of MV compared to treatment in February through May.

Partial oral antibiotic treatment for bacterial brain abscess: an open-label randomized non-inferiority trial (ORAL).

BACKGROUND: The advised standard treatment for bacterial brain abscess following surgery is 6 to 8 weeks of intravenous (IV) antibiotic treatment, but an early switch to oral antibiotic treatment has been suggested to be equally effective. METHODS: This investigator-initiated, international, multi-center, parallel group, open-label, randomized (1:1 allocation) controlled trial will examine if oral treatment after 2 weeks of IV antibiotic therapy is non-inferior to standard 6-8 weeks of IV antibiotics for bacterial brain abscess in adults (≥ 18 years of age). The study will be conducted at hospitals across Denmark, the Netherlands, France, Australia, and Sweden. Exclusion criteria are severe immunocompromise or impaired gastro-intestinal absorption, pregnancy, device-related brain abscesses, and brain abscess caused by nocardia, tuberculosis, or Pseudomonas spp. The primary objective is a composite endpoint at 6 months after randomization consisting of all-cause mortality, intraventricular rupture of brain abscess, unplanned re-aspiration or excision of brain abscess, relapse, or recurrence. The primary endpoint will be adjudicated by an independent blinded endpoint committee. Secondary outcomes include extended Glasgow Outcome Scale scores and all-cause mortality at end of treatment as well as 3, 6, and 12 months since randomization, completion of assigned treatment, IV catheter associated complications, durations of admission and antibiotic treatment, severe adverse events, quality of life scores, and cognitive evaluations. The planned sample size is 450 patients for a one-sided alpha of 0.025 and a power of 90% to exclude a difference in favor of standard treatment of more than 10%. Date of initiation of first study center was November 3, 2020, with active recruitment for 3 years and follow-up for 1 year of all patients. DISCUSSION: The results of this study may guide future recommendations for treatment of bacterial brain abscess. If early transition to oral antibiotics proves non-inferior to standard IV treatment, this will provide considerable health and costs benefits. TRIAL REGISTRATION: ClinicalTrials.gov NCT04140903, first registered 28.10.2019. EudraCT number: 2019-002845-39, first registered 03.07.2019.

SARS-CoV-2 infection and adverse outcomes in users of ACE inhibitors and angiotensin-receptor blockers: a nationwide case-control and cohort analysis.

OBJECTIVE: To examine the impact of ACE inhibitor (ACE-I)/angiotensin receptor blocker (ARB) use on rate of SARS-CoV-2 infection and adverse outcomes. METHODS: This nationwide case-control and cohort study included all individuals in Denmark tested for SARS-CoV-2 RNA with PCR from 27 February 2020 to 26 July 2020. We estimated confounder-adjusted ORs for a positive test among all SARS-CoV-2 tested, and inverse probability of treatment weighted 30-day risk and risk ratios (RRs) of hospitalisation, intensive care unit (ICU) admission and mortality comparing current ACE-I/ARB use with calcium channel blocker (CCB) use and with non-use. RESULTS: The study included 13 501 SARS-CoV-2 PCR-positive and 1 088 695 PCR-negative individuals. Users of ACE-I/ARB had a marginally increased rate of a positive PCR when compared with CCB users (aOR 1.17, 95% CI 1.00 to 1.37), but not when compared with non-users (aOR 1.00 95% CI 0.92 to 1.09).Among PCR-positive individuals, 1466 (11%) were ACE-I/ARB users. The weighted risk of hospitalisation was 36.5% in ACE-I/ARB users and 43.3% in CCB users (RR 0.84, 95% CI 0.70 to 1.02). The risk of ICU admission was 6.3% in ACE-I/ARB users and 5.4% in CCB users (RR 1.17, 95% CI 0.64 to 2.16), while the 30-day mortality was 12.3% in ACE-I/ARB users and 13.9% in CCB users (RR 0.89, 95% CI 0.61 to 1.30). The associations were similar when ACE-I/ARB users were compared with non-users. CONCLUSIONS: ACE-I/ARB use was associated neither with a consistently increased rate nor with adverse outcomes of SARS-CoV-2 infection. Our findings support the current recommendation of continuing use of ACE-Is/ARBs during the SARS-CoV-2 pandemic. TRIAL REGISTRATION NUMBER: EUPAS34887.

Positive Predictive Value of ICD-10 Diagnosis Codes for COVID-19.

PURPOSE: To examine the positive predictive value (PPV) of International Classification version 10 (ICD-10) diagnosis codes for Coronavirus disease 2019 (COVID-19). PATIENTS AND METHODS: Medical record review of all patients assigned a diagnosis code of COVID-19 (DB342A or DB972A) at six Danish departments of infectious diseases from February 27 through May 4, 2020. Confirmed COVID-19 diagnosis was defined as either: 1) definite, a positive polymerase chain reaction (PCR) for severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) on a respiratory sample combined with symptoms suggestive of COVID-19: 2) probable, clinical presentation of COVID-19 without detection of SARS-CoV-2 and no alternative diagnoses considered more likely; or 3) possible, clinical presentation of COVID-19 without detection of SARS-CoV-2, and the patient was discharged or deceased before further investigations were carried out. We computed the PPV with 95% confidence intervals (CI) as the number of patients with confirmed (i.e., definite, probable, and possible) COVID-19 divided by the number of patients assigned a diagnosis code for COVID-19. RESULTS: The study included 710 patients with a median age of 61 years (interquartile range [IQR] 47-74) and 285/710 (40%) were female. COVID-19 was confirmed in 706/710 (99%) with 705/710 (99%) categorized as definite, 1/710 (0.1%) as probable, and 0 patients as possible COVID-19. The diagnosis was disproven in 4/710 (0.6%) patients who were hospitalized due to bacterial pneumonia (n = 2), influenza (n = 1), and urinary tract infection (n = 1). The overall PPV for COVID-19 was 99% (95% CI 99-100) and remained consistently high among all subgroups including sex, age groups, calendar period, and stratified by diagnosis code and department of infectious diseases (range 97-100%). CONCLUSION: The overall PPV of diagnosis codes for COVID-19 in Denmark was high and may be suitable for future registry-based prognosis studies of COVID-19.

Hospital admission and mortality rates for non-covid diseases in Denmark during covid-19 pandemic: nationwide population based cohort study.

OBJECTIVE: To determine the incidence of hospital admissions and associated mortality rates for non-covid medical conditions during the covid-19 pandemic. DESIGN: Nationwide, population based cohort study. SETTING: Denmark from 13 March 2019 to 27 January 2021. PARTICIPANTS: All Danish residents >1 year of age. MAIN OUTCOMES MEASURES: Population based healthcare registries that encompass the entire Danish population were used to compare hospital admission and mortality rates during the covid-19 pandemic (from 11 March 2020 to 27 January 2021) with the prepandemic baseline data (from 13 March 2019 to 10 March 2020). Hospital admissions were categorised as covid-19 when patients were assigned a diagnosis code for covid-19 within five days of admission. All patients were followed until migration, death, or end of follow-up, whichever came first. Rate ratios for hospital admissions were computed using Poisson regression and were directly standardised using the Danish population on 1 January 2019 as reference. 30 day mortality rate ratios were examined by Cox regression, adjusted for age and sex, and covid-19 diagnosis was used as a competing risk. RESULTS: 5 753 179 residents were identified during 567.8 million person weeks of observation, with 1 113 705 hospital admissions among 675 447 people. Compared with the prepandemic baseline period (mean hospital admission rate 204.1 per 100 000/week), the overall hospital admission rate for non-covid-19 conditions decreased to 142.8 per 100 000/week (rate ratio 0.70, 95% confidence interval 0.66 to 0.74) after the first national lockdown, followed by a gradual return to baseline levels until the second national lockdown when it decreased to 158.3 per 100 000/week (0.78, 0.73 to 0.82). This pattern was mirrored for most major diagnosis groups except for non-covid-19 respiratory diseases, nervous system diseases, cancer, heart failure, sepsis, and non-covid-19 respiratory infections, which remained lower throughout the study period. Overall 30 day mortality rates were higher during the first national lockdown (mortality rate ratio 1.28, 95% confidence interval 1.23 to 1.32) and the second national lockdown (1.20, 1.16 to 1.24), and these results were similar across most major diagnosis groups. For non-covid-19 respiratory diseases, cancer, pneumonia, and sepsis, the 30 day mortality rate ratios were also higher between lockdown periods. CONCLUSIONS: Hospital admissions for all major non-covid-19 disease groups decreased during national lockdowns compared with the prepandemic baseline period. Additionally, mortality rates were higher overall and for patients admitted to hospital with conditions such as respiratory diseases, cancer, pneumonia, and sepsis. Increased attention towards management of serious non-covid-19 medical conditions is warranted.

Efficacy of the TMPRSS2 inhibitor camostat mesilate in patients hospitalized with Covid-19-a double-blind randomized controlled trial.

BACKGROUND: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials. METHODS: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load. FINDINGS: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group (P = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log10 copies/mL (p <0·05) and -0·82 log10 in the placebo group (P <0·05). INTERPRETATION: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001200-42.

Renin-Angiotensin System Blockers and Adverse Outcomes of Influenza and Pneumonia: A Danish Cohort Study.

Background Angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) may worsen the prognosis of coronavirus disease 2019, but any association could be confounded by the cardiometabolic conditions indicating ACE-I/ARB use. We therefore examined the impact of ACE-Is/ARBs on respiratory tract infection outcomes. Methods and Results This cohort study included all adult patients hospitalized with influenza or pneumonia from 2005 to 2018 in Denmark using population-based medical databases. Thirty-day mortality and risk of admission to the intensive care unit in ACE-Is/ARBs users was compared with nonusers and with users of calcium channel blockers. We used propensity scores to handle confounding and computed propensity score-weighted risks, risk differences (RDs), and risk ratios (RRs). Of 568 019 patients hospitalized with influenza or pneumonia, 100 278 were ACE-I/ARB users and 37 961 were users of calcium channel blockers. In propensity score-weighted analyses, ACE-I/ARB users had marginally lower 30-day mortality than users of calcium channel blockers (13.9% versus 14.5%; RD, -0.6%; 95% CI, -1.0 to -0.1; RR, 0.96; 95% CI, 0.93-0.99), and a lower risk of admission to the intensive care unit (8.0% versus 9.6%; RD, -1.6%; 95% CI, -2.0 to -1.2; RR, 0.83; 95% CI, 0.80-0.87). Compared with nonusers, current ACE-I/ARB users had lower mortality (RD, -2.4%; 95% CI, -2.8 to -2.0; RR, 0.85; 95% CI, 0.83-0.87), but similar risk of admission to the intensive care unit (RD, 0.4%; 95% CI, 0.0-0.7; RR, 1.04; 95% CI, 1.00-1.09). Conclusions Among patients with influenza or pneumonia, ACE-I/ARB users had no increased risk of admission to the intensive care unit and slightly reduced mortality after controlling for confounding.