Homologous and Heterologous Covid-19 Booster Vaccinations.

BACKGROUND: Although the three vaccines against coronavirus disease 2019 (Covid-19) that have received emergency use authorization in the United States are highly effective, breakthrough infections are occurring. Data are needed on the serial use of homologous boosters (same as the primary vaccine) and heterologous boosters (different from the primary vaccine) in fully vaccinated recipients. METHODS: In this phase 1-2, open-label clinical trial conducted at 10 sites in the United States, adults who had completed a Covid-19 vaccine regimen at least 12 weeks earlier and had no reported history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection received a booster injection with one of three vaccines: mRNA-1273 (Moderna) at a dose of 100 µg, Ad26.COV2.S (Johnson & Johnson-Janssen) at a dose of 5×1010 virus particles, or BNT162b2 (Pfizer-BioNTech) at a dose of 30 µg. The primary end points were safety, reactogenicity, and humoral immunogenicity on trial days 15 and 29. RESULTS: Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients. CONCLUSIONS: Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by the National Institute of Allergy and Infectious Diseases; DMID 21-0012 ClinicalTrials.gov number, NCT04889209.).

Residency in Long-Term Care Facilities: An Important Risk Factor for RSV Hospitalization.

Older age and comorbid conditions increase risk for severe RSV. Skilled nursing (SNF) and assisted living (AL) facilities represent an intersection of risk factors. In a 3-year prospective study (Rochester, NY) we compared population-based incidence of RSV-associated hospitalization for community-dwelling, SNF and AL adults ≥65 years. Median age was 76, 83 and 86 years, respectively, and dementia and CHF more prevalent among SNF and assisted living residents. Average annual incidence was 117 (95%CI:104-132), 440 (95%CI:307-629) and 740/100,000 persons (95%CI:523-1045) for community-dwelling, SNF and AL adults ≥65 years, respectively, demonstrating need for unequivocal RSV vaccine recommendations in SNF and AL residents.

Real-life Assessment of BioFire FilmArray Pneumonia Panel in Adults Hospitalized With Respiratory Illness.

BACKGROUND: Inability to identify the microbial etiology of lower respiratory tract infection leads to unnecessary antibiotic use. We evaluated the utility of the BioFire FilmArray Pneumonia Panel (BioFire PN) to inform microbiologic diagnosis. METHODS: Hospitalized adults with respiratory illness were recruited; sputa and clinical/laboratory data were collected. Sputa were cultured for bacteria and tested with BioFire PN. Microbial etiology was adjudicated by 4 physicians. Bacterial polymerase chain reaction (PCR) was compared with culture and clinical adjudication. RESULTS: Of 298 sputa tested, BioFire PN detected significantly more pathogens (350 bacteria, 16 atypicals, and 164 viruses) than sputum culture plus any standard-of-care testing (91% vs 60%, P < .0001). When compared with culture, the sensitivity of BioFire PN for individual bacteria was 46% to 100%; specificity, 61% to 100%; and negative predictive value, 92% to 100%. Cases were adjudicated as viral (n = 58) and bacterial (n = 100). PCR detected bacteria in 55% of viral cases and 95% of bacterial (P < .0001). High serum procalcitonin and bacterial adjudication were more often associated with sputa with 106 or 107 copies detected. CONCLUSIONS: Multiplex PCR testing of sputa for bacteria is useful to rule out bacterial infection with added value to detect viruses and atypical bacteria.

Neutralizing Antibody Immune Correlates for a Recombinant Protein Vaccine in the COVAIL Trial.

For COVAIL recipients of a COVID-19 Sanofi booster vaccine, neutralizing antibody titers were assessed as a correlate of risk (CoR) of COVID-19. Peak and exposure-proximal titers were inverse CoRs with covariate-adjusted hazard ratios (95% confidence intervals) 0.30 (0.11, 0.78) and 0.25 (0.07, 0.85) per 10-fold increase in weighted average titer.

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19.

BACKGROUND: Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known. METHODS: We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15. RESULTS: A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003). CONCLUSIONS: Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).

The Negative Effect of Preexisting Immunity on Influenza Vaccine Responses Transcends the Impact of Vaccine Formulation Type and Vaccination History.

The most effective measure to induce protection from influenza is vaccination. Thus, yearly vaccination is recommended, which, together with infections, establishes diverse repertoires of B cells, antibodies, and T cells. We examined the impact of this accumulated immunity on human responses in adults to split, subunit, and recombinant protein-based influenza vaccines. Enzyme-linked immunosorbent assay (ELISA) assays, to quantify serum antibodies, and peptide-stimulated CD4 T-cell cytokine ELISpots revealed that preexisting levels of hemagglutinin (HA)-specific antibodies were negatively associated with gains in antibody postvaccination, while preexisting levels of CD4 T cells were negatively correlated with vaccine-induced expansion of CD4 T cells. These patterns were seen independently of the vaccine formulation administered and the subjects' influenza vaccine history. Thus, although memory CD4 T cells and serum antibodies consist of components that can enhance vaccine responses, on balance, the accumulated immunity specific for influenza A H1 and H3 proteins is associated with diminished future responses.

Gene Expression Risk Scores for COVID-19 Illness Severity.

BACKGROUND: The correlates of coronavirus disease 2019 (COVID-19) illness severity following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are incompletely understood. METHODS: We assessed peripheral blood gene expression in 53 adults with confirmed SARS-CoV-2 infection clinically adjudicated as having mild, moderate, or severe disease. Supervised principal components analysis was used to build a weighted gene expression risk score (WGERS) to discriminate between severe and nonsevere COVID-19. RESULTS: Gene expression patterns in participants with mild and moderate illness were similar, but significantly different from severe illness. When comparing severe versus nonsevere illness, we identified >4000 genes differentially expressed (false discovery rate < 0.05). Biological pathways increased in severe COVID-19 were associated with platelet activation and coagulation, and those significantly decreased with T-cell signaling and differentiation. A WGERS based on 18 genes distinguished severe illness in our training cohort (cross-validated receiver operating characteristic-area under the curve [ROC-AUC] = 0.98), and need for intensive care in an independent cohort (ROC-AUC = 0.85). Dichotomizing the WGERS yielded 100% sensitivity and 85% specificity for classifying severe illness in our training cohort, and 84% sensitivity and 74% specificity for defining the need for intensive care in the validation cohort. CONCLUSIONS: These data suggest that gene expression classifiers may provide clinical utility as predictors of COVID-19 illness severity.

Immunogenicity of a 2-Dose Regimen of Moderna mRNA Beta/Omicron BA.1 Bivalent Variant Vaccine Boost in a Randomized Clinical Trial.

We compared the serologic responses of 1 dose versus 2 doses of a variant vaccine (Moderna mRNA-1273 Beta/Omicron BA.1 bivalent vaccine) in adults. A 2-dose boosting regimen with a variant vaccine did not increase the magnitude or the durability of the serological responses compared to a single variant vaccine boost.

Immunogenicity of the BA.1 and BA.4/BA.5 Severe Acute Respiratory Syndrome Coronavirus 2 Bivalent Boosts: Preliminary Results From the COVAIL Randomized Clinical Trial.

In a randomized clinical trial, we compare early neutralizing antibody responses after boosting with bivalent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines based on either BA.1 or BA.4/BA.5 Omicron spike protein combined with wild-type spike. Responses against SARS-CoV-2 variants exhibited the greatest reduction in titers against currently circulating Omicron subvariants for both bivalent vaccines.

Perturbations in Respiratory Syncytial Virus Activity During the SARS-CoV-2 Pandemic.

Respiratory syncytial virus (RSV) is a common cause of respiratory disease in all age groups, with young children and older adults experiencing the most severe illness. The coronavirus disease 2019 (COVID-19) pandemic resulted in striking changes in the activity of seasonal respiratory viruses, including RSV. After a period of suppression early in the pandemic, an interseasonal surge of RSV occurred in 2021. Viral activity was detected primarily in children and young adults after relaxation of public health measures, but without the usual proportional increases in infections and hospitalizations in older adults who were likely still adhering to stricter public health measures.

Effect of Oral Streptococci Expressing Pneumococcus-like Cross-Reactive Capsule Types on World Health Organization Recommended Pneumococcal Carriage Detection Procedure.

BACKGROUND: Carriage studies are fundamental to assessing the effects of pneumococcal vaccines. Because a large proportion of oral streptococci carry homologues of pneumococcal genes, non-culture-based detection and serotyping of upper respiratory tract (URT) samples can be problematic. In the current study, we investigated whether culture-free molecular methods could differentiate pneumococci from oral streptococci carried by adults in the URT. METHODS: Paired nasopharyngeal (NP) and oropharyngeal (OP) samples were collected from 100 older adults twice a month for 1 year. Extracts from the combined NP + OP samples (n = 2400) were subjected to lytA real-time polymerase chain reaction (PCR). Positive samples were subjected to pure culture isolation, followed by species confirmation using multiple approaches. Multibead assays and whole-genome sequencing were used for serotyping. RESULTS: In 20 of 301 combined NP + OP extracts with positive lytA PCR results, probable pneumococcus-like colonies grew, based on colony morphology and biochemical tests. Multiple approaches confirmed that 4 isolates were Streptococcus pneumoniae, 3 were Streptococcus pseudopneumoniae, 12 were Streptococcus mitis, and 1 were Streptococcus oralis. Eight nonpneumococcal strains carried pneumococcus-like cps loci (approximate size, 18-25 kb) that showed >70% nucleotide identity with their pneumococcal counterparts. While investigating the antigenic profile, we found that some S. mitis strains (P066 and P107) reacted with both serotype-specific polyclonal (type 39 and FS17b) and monoclonal (Hyp10AG1 and Hyp17FM1) antisera, whereas some strains (P063 and P074) reacted only with polyclonal antisera (type 5 and FS35a). CONCLUSION: The extensive capsular overlap suggests that pneumococcal vaccines could reduce carriage of oral streptococci expressing cross-reactive capsules. Furthermore, direct use of culture-free PCR-based methods in URT samples has limited usefulness for carriage studies.

Incidence of Respiratory Syncytial Virus Infection Among Hospitalized Adults, 2017-2020.

BACKGROUND: Respiratory syncytial virus (RSV) causes acute respiratory illness (ARI) and triggers exacerbations of cardiopulmonary disease. Estimates of incidence in hospitalized adults range widely, with few data on incidence in adults with comorbidities that increase the risk of severity. We conducted a prospective, population-based, surveillance study to estimate incidence of RSV hospitalization among adults overall and those with specific comorbidities. METHODS: Hospitalized adults aged ≥18 years residing in the surveillance area with ≥2 ARI symptoms or exacerbation of underlying cardiopulmonary disease were screened during the 2017-2018, 2018-2019, and 2019-2020 RSV seasons in 3 hospitals in Rochester, New York and New York City. Respiratory specimens were tested for RSV using polymerase chain reaction assays. RSV incidence per 100 000 was adjusted by market share. RESULTS: Active and passive surveillance identified 1099 adults hospitalized with RSV. Annual incidence during 3 seasons ranged from 44.2 to 58.9/100 000. Age-group-specific incidence ranged from 7.7 to 11.9/100 000, 33.5 to 57.5/100 000, and 136.9 to 255.6/100 000 in patients ages 18-49, 50-64, and ≥65 years, respectively. Incidence rates in patients with chronic obstructive pulmonary disease, coronary artery disease, and congestive heart failure were 3-13, 4-7, and 4-33 times, respectively, the incidence in patients without these conditions. CONCLUSIONS: We found a high burden of RSV hospitalization in this large prospective study. Notable was the high incidence among older patients and those with cardiac conditions. These data confirm the need for effective vaccines to prevent RSV infection in older and vulnerable adults.

Duration of antibiotic treatment using procalcitonin-guided treatment algorithms in older patients: a patient-level meta-analysis from randomized controlled trials.

BACKGROUND: Older patients have a less pronounced immune response to infection, which may also influence infection biomarkers. There is currently insufficient data regarding clinical effects of procalcitonin (PCT) to guide antibiotic treatment in older patients. OBJECTIVE AND DESIGN: We performed an individual patient data meta-analysis to investigate the association of age on effects of PCT-guided antibiotic stewardship regarding antibiotic use and outcome. SUBJECTS AND METHODS: We had access to 9,421 individual infection patients from 28 randomized controlled trials comparing PCT-guided antibiotic therapy (intervention group) or standard care. We stratified patients according to age in four groups (<75 years [n = 7,079], 75-80 years [n = 1,034], 81-85 years [n = 803] and >85 years [n = 505]). The primary endpoint was the duration of antibiotic treatment and the secondary endpoints were 30-day mortality and length of stay. RESULTS: Compared to control patients, mean duration of antibiotic therapy in PCT-guided patients was significantly reduced by 24, 22, 26 and 24% in the four age groups corresponding to adjusted differences in antibiotic days of -1.99 (95% confidence interval [CI] -2.36 to -1.62), -1.98 (95% CI -2.94 to -1.02), -2.20 (95% CI -3.15 to -1.25) and - 2.10 (95% CI -3.29 to -0.91) with no differences among age groups. There was no increase in the risk for mortality in any of the age groups. Effects were similar in subgroups by infection type, blood culture result and clinical setting (P interaction >0.05). CONCLUSIONS: This large individual patient data meta-analysis confirms that, similar to younger patients, PCT-guided antibiotic treatment in older patients is associated with significantly reduced antibiotic exposures and no increase in mortality.

Comparison of Human H3N2 Antibody Responses Elicited by Egg-Based, Cell-Based, and Recombinant Protein-Based Influenza Vaccines During the 2017-2018 Season.

BACKGROUND: The H3N2 component of egg-based 2017-2018 influenza vaccines possessed an adaptive substitution that alters antigenicity. Several influenza vaccines include antigens that are produced through alternative systems, but a systematic comparison of different vaccines used during the 2017-2018 season has not been completed. METHODS: We compared antibody responses in humans vaccinated with Fluzone (egg-based, n = 23), Fluzone High-Dose (egg-based, n = 16), Flublok (recombinant protein-based, n = 23), or Flucelvax (cell-based, n = 23) during the 2017-2018 season. We completed neutralization assays using an egg-adapted H3N2 virus, a cell-based H3N2 virus, wild-type 3c2.A and 3c2.A2 H3N2 viruses, and the H1N1 vaccine strain. We also performed enzyme-linked immunosorbent assays using a recombinant wild-type 3c2.A hemagglutinin. Antibody responses were compared in adjusted analysis. RESULTS: Postvaccination neutralizing antibody titers to 3c2.A and 3c2.A2 were higher in Flublok recipients compared with Flucelvax or Fluzone recipients (P < .01). Postvaccination titers to 3c2.A and 3c2.A2 were similar in Flublok and Fluzone High-Dose recipients, though seroconversion rates trended higher in Flublok recipients. Postvaccination titers in Flucelvax recipients were low to all H3N2 viruses tested, including the cell-based H3N2 strain. Postvaccination neutralizing antibody titers to H1N1 were similar among the different vaccine groups. CONCLUSIONS: These data suggest that influenza vaccine antigen match and dose are both important for eliciting optimal H3N2 antibody responses in humans. Future studies should be designed to determine if our findings directly impact vaccine effectiveness. CLINICAL TRIALS REGISTRATION: NCT03068949.

Procalcitonin-guided Antibiotic Treatment in Patients With Positive Blood Cultures: A Patient-level Meta-analysis of Randomized Trials.

BACKGROUND: Whether procalcitonin (PCT)-guided antibiotic management in patients with positive blood cultures is safe remains understudied. We performed a patient-level meta-analysis to investigate effects of PCT-guided antibiotic management in patients with bacteremia. METHODS: We extracted and analyzed individual data of 523 patients with positive blood cultures included in 13 trials, in which patients were randomly assigned to receive antibiotics based on PCT levels (PCT group) or a control group. The main efficacy endpoint was duration of antibiotic treatment. The main safety endpoint was mortality within 30 days. RESULTS: Mean duration of antibiotic therapy was significantly shorter for 253 patients who received PCT-guided treatment than for 270 control patients (-2.86 days [95% confidence interval [CI], -4.88 to -.84]; P = .006). Mortality was similar in both arms (16.6% vs 20.0%; P = .263). In subgroup analyses by type of pathogen, we noted a trend of shorter mean antibiotic durations in the PCT arm for patients infected with gram-positive organisms or Escherichia coli and significantly shorter treatment for subjects with pneumococcal bacteremia. In analysis by site of infection, antibiotic exposure was shortened in PCT subjects with Streptococcus pneumoniae respiratory infection and those with E. coli urogenital infections. CONCLUSIONS: This meta-analysis of patients with bacteremia receiving PCT-guided antibiotic management demonstrates lower antibiotic exposure without an apparent increase in mortality. Few differences were demonstrated in subgroup analysis stratified by type or site of infection but notable for decreased exposure in patients with pneumococcal pneumonia and E. coli urogenital infections.

Procalcitonin to guide antibiotic decision making.

PURPOSE OF REVIEW: There is convincing evidence linking antibiotic-stewardship efforts which include the infection marker procalcitonin (PCT) to more rational use of antibiotics with improvements in side-effects and clinical outcomes. This is particularly true in the setting of respiratory infection and sepsis. Yet, some recent trials have shown no benefit of PCT-guided care. Our aim was to discuss the benefits and limitations of using PCT for early infection recognition, severity assessment and therapeutic decisions in individual patients based on most the recent study data. RECENT FINDINGS: Current evidence from randomized trials, and meta-analyses of these trials, indicates that PCT-guided antibiotic stewardship results in a reduction in antibiotic use and antibiotic side-effects, which translates into improved survival of patients with respiratory infections and sepsis. Notably, initial PCT levels have been found to be helpful in defining the risk for bacterial infection in the context of a low pretest probability for bacterial infections (i.e., patients with bronchitis or chronic bastructive pulmonary disease exacerbation). Monitoring of repeated PCT measurements over time has also been found helpful for estimating recovery from bacterial infection and prognosis in higher risk situations (i.e., pneumonia or sepsis) and results in early and safe discontinuation of antibiotic therapy. Some trials, however, did not find a strong effect of PCT guidance which may be explained by low protocol adherence, assessment using only a single rather than repeat PCT levels and lower antibiotic exposure in control group patients. Using PCT in the right patient population, with high-sensitivity assays and with adequate training of physicians is important to increase protocol adherence and reduce antibiotic exposure. SUMMARY: Inclusion of PCT into antibiotic stewardship algorithms has the potential to improve the diagnostic and therapeutic management of patients presenting with respiratory illnesses and sepsis, and holds great promise to mitigate the global bacterial resistance crisis and move from a default position of standardized care to more personalized treatment decisions.

Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections.

BACKGROUND: Acute respiratory infections (ARIs) comprise of a large and heterogeneous group of infections including bacterial, viral, and other aetiologies. In recent years, procalcitonin (PCT), a blood marker for bacterial infections, has emerged as a promising tool to improve decisions about antibiotic therapy (PCT-guided antibiotic therapy). Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with ARIs and different settings ranging from primary care settings to emergency departments, hospital wards, and intensive care units. However, the effect of using procalcitonin on clinical outcomes is unclear. This is an update of a Cochrane review and individual participant data meta-analysis first published in 2012 designed to look at the safety of PCT-guided antibiotic stewardship. OBJECTIVES: The aim of this systematic review based on individual participant data was to assess the safety and efficacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from different clinical settings. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE, and Embase, in February 2017, to identify suitable trials. We also searched ClinicalTrials.gov to identify ongoing trials in April 2017. SELECTION CRITERIA: We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm (PCT-guided antibiotic stewardship algorithm) or usual care. We excluded trials if they focused exclusively on children or used procalcitonin for a purpose other than to guide initiation and duration of antibiotic treatment. DATA COLLECTION AND ANALYSIS: Two teams of review authors independently evaluated the methodology and extracted data from primary studies. The primary endpoints were all-cause mortality and treatment failure at 30 days, for which definitions were harmonised among trials. Secondary endpoints were antibiotic use, antibiotic-related side effects, and length of hospital stay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression adjusted for age, gender, and clinical diagnosis using a fixed-effect model. The different trials were added as random-effects into the model. We conducted sensitivity analyses stratified by clinical setting and type of ARI. We also performed an aggregate data meta-analysis. MAIN RESULTS: From 32 eligible RCTs including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which we included in the main individual participant data meta-analysis. We did not obtain individual participant data for four trials, and two trials did not include people with confirmed ARIs. According to GRADE, the quality of the evidence was high for the outcomes mortality and antibiotic exposure, and quality was moderate for the outcomes treatment failure and antibiotic-related side effects.Primary endpoints: there were 286 deaths in 3336 procalcitonin-guided participants (8.6%) compared to 336 in 3372 controls (10.0%), resulting in a significantly lower mortality associated with procalcitonin-guided therapy (adjusted OR 0.83, 95% CI 0.70 to 0.99, P = 0.037). We could not estimate mortality in primary care trials because only one death was reported in a control group participant. Treatment failure was not significantly lower in procalcitonin-guided participants (23.0% versus 24.9% in the control group, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). Results were similar among subgroups by clinical setting and type of respiratory infection, with no evidence for effect modification (P for interaction > 0.05). Secondary endpoints: procalcitonin guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 versus 8.1 days, 95% CI -2.71 to -2.15, P < 0.001) and lower risk of antibiotic-related side effects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). Length of hospital stay and intensive care unit stay were similar in both groups. A sensitivity aggregate-data analysis based on all 32 eligible trials showed similar results. AUTHORS' CONCLUSIONS: This updated meta-analysis of individual participant data from 12 countries shows that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic-related side effects. Results were similar for different clinical settings and types of ARIs, thus supporting the use of procalcitonin in the context of antibiotic stewardship in people with ARIs. Future high-quality research is needed to confirm the results in immunosuppressed patients and patients with non-respiratory infections.