Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

The COVID-19 pandemic has disproportionately impacted racial and ethnic minority communities, particularly African American and Latino communities. The impacts of social determinants of health, structural racism, misinformation, and mistrust have contributed to a decreased COVID-19 vaccine uptake. Effective methods of addressing and combatting these barriers are essential. Accurate and targeted messaging delivered by trusted voices from community-based organizations, government health systems and organizations, and healthcare and academic systems is imperative. Outreach and communication should be culturally sensitive, provided in the preferred language of the community, flexible, and tailored for in-person and virtual outlets. This communication must also increase trust, combat misinformation, and inspire COVID-19 vaccine confidence. In this manuscript, we outline a framework for inspiring COVID-19 vaccine confidence in African American and Latino communities. These methods of targeted outreach should be considered and implemented for urgent and nonurgent community public health efforts beyond the COVID-19 pandemic (e.g., monkeypox) and as a framework to inspire vaccine confidence in those living in racial and ethnic minority communities globally.

Urinary tract infections (UTIs) are clinically and economically burdensome. Gram positive causative uropathogens are rare, and Staphylococcus simulans has infrequently been isolated as a causative agent for UTIs. Here, we present two cases of S. simulans causing complicated urinary tract infections.

Infections due to Pseudomonas fulva remain a rare but emerging concern. A case of ventriculitis due to Enterobacter cloacae and Pseudomonas fulva following placement of an external ventricular drain is described. Similar to other reports, the organism was initially misidentified as Pseudomonas putida. The infection was successfully treated with levofloxacin.

Background: Implementing rigorous epidemiologic studies in low-resource settings involves challenges in participant recruitment and follow-up (e.g., mobile populations, distrust), biological sample collection (e.g., cold-chain, laboratory equipment scarcity) and data collection (e.g., literacy, staff training, and infrastructure). This article describes the use of a monitoring and evaluation (M & E) framework to improve study efficiency and quality during participant engagement, and biological sample and data collection in a longitudinal cohort study of Bolivian infants. Methods: The study occurred between 2013 and 2015 in El Alto, Bolivia, a high-altitude, urban, low-resource community. The study's M & E framework included indicators for participant engagement (e.g., recruitment, retention, safety), biological sample (e.g., stool and blood), and data (e.g., anthropometry, questionnaires) collection and quality. Monitoring indicators were measured regularly throughout the study and used for course correction, communication, and staff retraining. Results: Participant engagement indicators suggested that enrollment objectives were met (461 infants), but 15% loss-to-follow-up resulted in only 364 infants completing the study. Over the course of the study, there were four study-related adverse events (minor swelling and bruising related to a blood draw) and five severe adverse events (infant deaths) not related to study participation. Biological sample indicators demonstrated two blood samples collected from 95% (333 of 350 required) infants and stool collected for 61% of reported infant diarrhea episodes. Anthropometry data quality indicators were extremely high (median SDs for weight-for-length, length-for-age and weight-for-age z-scores 1.01, 0.98, and 1.03, respectively), likely due to extensive training, standardization, and monitoring efforts. Conclusions: Conducting human subjects research studies in low-resource settings often presents unique logistical difficulties, and collecting high-quality data is often a challenge. Investing in comprehensive M & E is important to improve participant recruitment, retention and safety, and sample and data quality. The M & E framework from this study can be applied to other longitudinal studies.

COVID-19 is disproportionally impacting racial and ethnic minority groups, namely Black, Latinx, and Native American communities, in both urban and rural areas in the United States (US).1 Latinx groups have 2 to 4 times higher rates of COVID-19 than expected for their population share in 43 out of the 44 jurisdictions in the US that reported ethnicity data. These ethnic disparities are also evident in terms of COVID-19 related deaths, which are 1.5 times higher for Latinx individuals compared to White counterparts. In California, despite representing 38% of the total population, Latinx persons account for 60% of all cases, and 48% of all deaths. In this issue of Clinical Infectious Diseases, Chamie et al aim to identify factors driving community spread of COVID-19 in San Francisco’s majority Latinx census tract 022901.

Globally, vitamin A deficiency (VAD) affects nearly 200 million children with negative health consequences. VAD can be measured by a retinol-binding protein (RBP) and serum retinol concentrations. Their concentrations are not always present in a 1:1 molar ratio and are affected by inflammation. This study sought to quantify VAD and its impact on infant mortality and infectious morbidity during the first 18 months of life in a cohort of mother-infant dyads in El Alto, Bolivia, while accounting for the previously mentioned measurement issues. Healthy mother-infant dyads (n = 461) were enrolled from two hospitals and followed for 12 to 18 months. Three serum samples were collected (at one to two, six to eight, and 12 to 18 months of infant age) and analyzed for RBP, and a random 10% subsample was analyzed for retinol. Linear regression of RBP on retinol was used to generate RBP cut-offs equivalent to retinol <0.7 µmol/L. All measures of RBP and retinol were adjusted for inflammation, which was measured by a C-reactive protein and alpha (1)-acid glycoprotein serum concentrations using linear regression. Infant mortality and morbidity rates were calculated and compared by early VAD status at two months of age. Retinol and RBP were weakly affected by inflammation. This association varied with infant age. Estimated VAD (RBP < 0.7 µmol/L) decreased from 71.0% to 14.8% to 7.7% at two, six to eight, and 12 to 18 months of age. VAD was almost nonexistent in mothers. Early VAD was not significantly associated with infant mortality or morbidity rates. This study confirmed a relationship between inflammation and vitamin A biomarkers for some subsets of the population and suggested that the vitamin A status in early infancy improves with age and may not have significantly affected morbidity in this population of healthy infants.

Background: The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. Methods: In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04351152, and is completed. Findings: Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41–137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79–89) participants in the lenzilumab group and in 190 (78%; 72–83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02–2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. Interpretation: Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown. Funding: Humanigen.

Background.  Mortality for cryptococcal meningitis remains significant, in spite of available treatment. Resistance to first-line maintenance therapy, particularly fluconazole, has been reported. Methods.  A retrospective chart review was performed on immunocompromised patients with cryptococcal meningitis, who had susceptibility testing performed between January 2001 and December 2011, at 3 hospitals in Atlanta, Georgia. Results.  A total of 35 immunocompromised patients with cryptococcal meningitis were identified, 13 (37.1%) of whom had an elevated minimum inhibitory concentration (MIC) to fluconazole (MIC ≥16 µg/mL). Eighty percent of patients were males with African American predominance, the median age was 37 years, and 80% of the patients were human immunodeficiency virus (HIV) positive. Subsequent recurrence of cryptococcal meningitis was more likely in HIV patients compared with solid organ transplant patients (P = .0366). Overall, there was a statistically significant increase in an elevated MIC to fluconazole in patients who had a history of prior azole use (odds ratio, 10.12; 95% confidence interval, 2.04-50.16). Patients with an elevated MIC to fluconazole and those with a high cerebrospinal fluid cryptococcal antigen load (≥1:512) were more likely to have central nervous system complications (P = .0358 and P = .023, respectively). Although no association was observed between an elevated MIC to fluconazole and mortality, those who received voriconazole or high-dose fluconazole (≥800 mg) for maintenance therapy were more likely to survive (P = .0288). Conclusions.  Additional studies are required to further investigate the morbidity and mortality associated with an elevated MIC to fluconazole in cryptococcal meningitis, to determine when it is appropriate to perform susceptibility testing, and to evaluate its cost effectiveness.

Background. Internal medicine physicians are often the first providers to encounter patients with a new diagnosis of tuberculosis. Given the public health risks of missed tuberculosis cases, assessing internal medicine residents' ability to diagnose tuberculosis is important. Methods. Internal medicine resident knowledge and practice patterns in pulmonary tuberculosis diagnosis at 7 academic hospitals were assessed utilizing (a) a 10-item validated pulmonary tuberculosis diagnosis assessment tool and (b) a retrospective chart review of 343 patients who underwent a pulmonary tuberculosis evaluation while admitted to a resident-staffed internal medicine or infectious disease service. Our primary outcomes were the mean score and percentage of correct responses per assessment tool question, and the percentage of patients who had Centers for Disease Control and Prevention-recommended tuberculosis diagnostic tests obtained. Results. Of the 886 residents who received the assessment, 541 responded, yielding a response rate of 61%. The mean score on the assessment tool (SD) was 4.4 (1.6), and the correct response rate was 57% (311/541) or less on 9 of 10 questions. On chart review, each recommended test was obtained for ≤ 43% (148/343) of patients, other than chest x-ray (328/343; 96%). A nucleic acid amplification test was obtained for 18% (62/343) of patients, whereas 24% (83/343) had only 1 respiratory sample obtained. Twenty patients were diagnosed with tuberculosis. Conclusions. Significant knowledge and practice gaps exist in internal medicine residents' abilities to diagnose tuberculosis. As residents represent the future providers who will be evaluating patients with possible tuberculosis, such deficiencies must be addressed.