Efficacy of infliximab, abatacept, and cenicriviroc for the treatment of adults hospitalized with COVID-19 pneumonia.

A randomized, double-blind, placebo-controlled clinical trial was conducted to investigate the efficacy of infliximab, abatacept, and cenicriviroc in treating patients hospitalized with COVID-19. The patient's clinical status was assessed daily on an 8-point ordinal scale. We evaluated the totality of evidence on the efficacy of the 3 immunomodulators by considering all possible changes in the clinical status of each patient over time. We demonstrated that infliximab accelerated improvement and reduced deterioration of clinical status when added to standard of care. There was also evidence for the benefit of abatacept. There was no evidence for the benefit of cenicriviroc.

Abatacept for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: We investigated whether abatacept, a selective costimulation modulator, provides additional benefit when added to standard-of-care for patients hospitalized with Covid-19. Methods: We conducted a master protocol to investigate immunomodulators for potential benefit treating patients hospitalized with Covid-19 and report results for abatacept. Intravenous abatacept (one-time dose 10 mg/kg, maximum dose 1000 mg) plus standard of care (SOC) was compared with shared placebo plus SOC. Primary outcome was time-to-recovery by day 28. Key secondary endpoints included 28-day mortality. Results: Between October 16, 2020 and December 31, 2021, a total of 1019 participants received study treatment (509 abatacept; 510 shared placebo), constituting the modified intention-to-treat cohort. Participants had a mean age 54.8 (SD 14.6) years, 60.5% were male, 44.2% Hispanic/Latino and 13.7% Black. No statistically significant difference for the primary endpoint of time-to-recovery was found with a recovery-rate-ratio of 1.14 (95% CI 1.00-1.29; p=0.057) compared with placebo. We observed a substantial improvement in 28-day all-cause mortality with abatacept versus placebo (11.0% vs. 15.1%; odds ratio [OR] 0.62 [95% CI 0.41- 0.94]), leading to 38% lower odds of dying. Improvement in mortality occurred for participants requiring oxygen/noninvasive ventilation at randomization. Subgroup analysis identified the strongest effect in those with baseline C-reactive protein >75mg/L. We found no statistically significant differences in adverse events, with safety composite index slightly favoring abatacept. Rates of secondary infections were similar (16.1% for abatacept; 14.3% for placebo). Conclusions: Addition of single-dose intravenous abatacept to standard-of-care demonstrated no statistically significant change in time-to-recovery, but improved 28-day mortality. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

Infliximab for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: Immune dysregulation contributes to poorer outcomes in severe Covid-19. Immunomodulators targeting various pathways have improved outcomes. We investigated whether infliximab provides benefit over standard of care. Methods: We conducted a master protocol investigating immunomodulators for potential benefit in treatment of participants hospitalized with Covid-19 pneumonia. We report results for infliximab (single dose infusion) versus shared placebo both with standard of care. Primary outcome was time to recovery by day 29 (28 days after randomization). Key secondary endpoints included 14-day clinical status and 28-day mortality. Results: A total of 1033 participants received study drug (517 infliximab, 516 placebo). Mean age was 54.8 years, 60.3% were male, 48.6% Hispanic or Latino, and 14% Black. No statistically significant difference in the primary endpoint was seen with infliximab compared with placebo (recovery rate ratio 1.13, 95% CI 0.99-1.29; p=0.063). Median (IQR) time to recovery was 8 days (7, 9) for infliximab and 9 days (8, 10) for placebo. Participants assigned to infliximab were more likely to have an improved clinical status at day 14 (OR 1.32, 95% CI 1.05-1.66). Twenty-eight-day mortality was 10.1% with infliximab versus 14.5% with placebo, with 41% lower odds of dying in those receiving infliximab (OR 0.59, 95% CI 0.39-0.90). No differences in risk of serious adverse events including secondary infections. Conclusions: Infliximab did not demonstrate statistically significant improvement in time to recovery. It was associated with improved 14-day clinical status and substantial reduction in 28- day mortality compared with standard of care. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

Economic analysis of rapid multiplex polymerase chain reaction testing for meningitis/encephalitis in adult patients.

PURPOSE: Many patients with suspected meningitis do not require hospitalization yet are admitted, often resulting in unnecessary care and additional cost. We assessed the possible economic impact of a rapid multiplex test for suspected adult community-acquired meningitis/encephalitis. METHODS: A model simulated diagnosis, clinical decisions, resource use/costs of standard of care (SOC) and two cerebrospinal fluid (CSF) testing strategies using the FDA-cleared BioFire® FilmArray® System (FA) which provides results in approximately one hour. RESULTS: Pathogens detected by FA caused approximately 74% of cases, 97% of which would be accurately diagnosed with FA. False positives and false negatives more often led to extended/unnecessary admission than inappropriate discharge/missed admission. Mean cost per case ranged from 16829 to 20791. A strategy of testing all suspected cases yielded greater savings (2213/case) than testing only those with abnormal CSF (812/case) and both were less expensive than SOC. CONCLUSION: This economic analysis demonstrates that FA can inform more appropriate clinician decisions resulting in cost savings with greater economic benefits achievable with syndromic testing of all cases, rather than SOC or targeted syndromic testing.

Cost of managing meningitis and encephalitis among infants and children in the United States.

A retrospective cohort study design was used to assess the use and costs of diagnostic tests, medication, and total hospitalization costs for pediatric patients with suspected meningitis/encephalitis who received a lumbar puncture (LP) procedure. Related costs were calculated by timing of LP performed and infectious etiology for infants (<1 year) and children (1-17 years). A total of 3030 infants and 3635 children with suspected ME diagnosed between 2011 and 2014 were included in the study. The mean hospitalization cost for infants and children was $12,759 and $11,119, respectively, with medication and laboratory test costs of $834 and $1771 for infants and $825 and $855 for children, respectively. Total visit cost increased with delayed LP procedure, ICU stay, and if the etiology was viral (other than enterovirus or arbovirus) or bacterial. Higher diagnostic and treatment costs were associated with delayed LP procedure, etiologic agent, and ICU stay.

Epidemiology of Meningitis and Encephalitis in Infants and Children in the United States, 2011-2014.

BACKGROUND: Large epidemiologic studies evaluating the etiologies, management decisions and outcomes of infants and children with meningitis and encephalitis in the United States are lacking. METHODS: Children 0-17 years of age with meningitis or encephalitis as assessed by International Classification of Diseases, Ninth Revision, codes available in the Premier Healthcare Database during 2011-2014 were analyzed. RESULTS: Six thousand six hundred sixty-five patients with meningitis or encephalitis were identified; 3030 (45.5%) were younger than 1 year of age, 295 (4.4%) were 1-2 years of age, 1460 (21.9%) were 3-9 years of age, and 1880 (28.2%) were 10-17 years of age. Etiologies included enterovirus (58.4%), unknown (23.7%), bacterial (13.0%), noninfectious (3.1%), herpes simplex virus (1.5%), other viruses (0.7%), arboviruses (0.5%) and fungal (0.04%). The majority of patients were male [3847 (57.7%)] and healthy [6094 (91.4%)] with no reported underlying conditions. Most underwent a lumbar puncture in the emergency department [5363 (80%)] and were admitted to the hospital [5363 (83.1%)]. Antibiotic therapy was frequent (92.2%) with children younger than 1 year of age with the highest rates (97.7%). Antiviral therapy was less common (31.1%). Only 539 (8.1%) of 6665 of patients received steroids. Early administration of adjunctive steroids was not associated with a reduction in mortality (P = 0.266). The overall median length of stay was 2 days. Overall mortality rate (0.5%) and readmission rates (<1%) was low for both groups. CONCLUSION: Meningitis and encephalitis in infants and children in the United States are more commonly caused by viruses and are treated empirically with antibiotic therapy and antiviral therapy in a significant proportion of cases. Adjunctive steroids are used infrequently and are not associated with a benefit in mortality.

Procalcitonin guidance in patients with lower respiratory tract infections: a systematic review and meta-analysis.

Although effective for bacterial lower respiratory tract infections (LRTIs), antibiotic treatment is often incorrectly prescribed for non-bacterial LRTIs. Procalcitonin has emerged as a promising biomarker to diagnose bacterial infections and guide antibiotic treatment decisions. As part of a regulatory submission to the U.S. Food and Drug Administration, this systematic review and meta-analysis summarizes the effects of procalcitonin-guided antibiotic stewardship on antibiotic use and clinical outcomes in adult LRTI patients. PubMed and the Cochrane Database of Systematic Reviews were searched for English-language randomized controlled trials published between January 2004 and May 2016. Random and fixed effects meta-analyses were performed to study efficacy (initiation of antibiotics, antibiotic use) and safety (mortality, length of hospital stay). Eleven trials were retained, comprising 4090 patients. Procalcitonin-guided patients had lower odds of antibiotic initiation (odds ratio: 0.26; 95% confidence interval [CI]: 0.13-0.52) and shorter mean antibiotic use (weighted mean difference: -2.15 days; 95% CI: -3.30 to -0.99) compared to patients treated with standard care. Procalcitonin use had no adverse impact on mortality (relative risk: 0.94; 95% CI: 0.69-1.28) and length of hospital stay (weighted mean difference: -0.15 days; 95% CI: -0.60 to 0.30). Procalcitonin guidance reduces antibiotic initiation and use among adults with LRTIs with no apparent adverse impact on length of hospital stay or mortality.

Cost of managing meningitis and encephalitis among adult patients in the United States of America.

OBJECTIVE: To determine the associated costs related to the diagnosis and treatment of meningitis and encephalitis (ME) in adult patients in the USA. METHODS: A retrospective observational study design was used to assess the use and costs of diagnostic tests and antimicrobial treatment and the total hospitalization costs for adult patients with suspected ME, who received a lumbar puncture procedure during an emergency department visit or during the first two service days of an inpatient stay. Related costs were calculated by timing of lumbar puncture performed and infectious etiology. RESULTS: A total 26429 adult patients with suspected ME diagnosed between 2011 and 2014 were included in the study. The mean hospitalization cost was $15 572±27168, with antimicrobial medication cost of $1144±4052 and laboratory test cost of $210±244. The total visit cost increased with delayed lumbar puncture procedure, intensive care unit stay, and if the etiology was fungi, arbovirus, or bacteria. CONCLUSIONS: Higher diagnostic and treatment costs are associated with a delayed lumbar puncture procedure, the etiological agent, and the requirement for an intensive care unit stay.

Economic analysis of rapid multiplex polymerase chain reaction testing for meningitis/encephalitis in pediatric patients.

AIM: We assessed the possible economic impact of a rapid test in pediatric patients with suspected community-acquired meningitis/encephalitis. MATERIALS & METHODS: Modeling simulated diagnosis, clinical decisions, resource use/costs of standard of care (SOC) and two cerebrospinal fluid testing strategies using FilmArray® (FA), a US FDA-cleared system that provides results in approximately 1 h. RESULTS: Pathogens detected by FA caused approximately 75% of cases, 97% of which would be accurately diagnosed with FA.  Mean cost/case ranged from $17,599 to $22,025.  Syndromic testing is less expensive than SOC. Testing all suspected cases yielded greater savings ($3481/case) than testing only those with abnormal cerebrospinal fluid ($2157/case). CONCLUSION: Greater economic benefits are achievable with syndromic testing of all cases, rather than SOC or targeted syndromic testing.

Efficacy and Safety of Procalcitonin Guidance in Patients With Suspected or Confirmed Sepsis: A Systematic Review and Meta-Analysis.

OBJECTIVE: Sepsis is a leading cause of mortality in noncoronary ICUs. Although immediate start of antibiotics reduces sepsis-related mortality, antibiotics are often administered for too long, leading to suboptimal treatment and, importantly, contributes to antimicrobial resistance. Prior literature suggests that procalcitonin correlates with infection and thus may help to guide the decision on when to stop antibiotic treatment. This study was conducted as part of a regulatory submission to the U.S. Food and Drug Administration and aimed to summarize the evidence of procalcitonin guidance on efficacy and safety outcomes in adult patients with sepsis. DATA SOURCES: PubMed and the Cochrane Database of Systematic Reviews. STUDY SELECTION: English-language randomized controlled trials evaluating procalcitonin use among adult patients with suspected or confirmed sepsis published between January 2004 and May 2016. DATA EXTRACTION: Inverse-variance weighting fixed and random effects meta-analyses were performed on the following efficacy and safety endpoints: antibiotic duration, all-cause mortality, and length of ICU stay. Two reviewers independently extracted data elements from identified studies and measured risk of bias with the Cochrane Risk of Bias Tool. DATA SYNTHESIS: From a total of 369 potentially eligible articles, 10 randomized controlled trials containing 3,489 patients were used for analysis. Procalcitonin-guided patients had shorter antibiotics duration compared with controls (7.35 vs. 8.85 d; weighted mean difference, -1.49 d; 95% CI, -2.27 to -0.71; p < 0.001). Procalcitonin use had no adverse impact on mortality (risk ratio, 0.90; 95% CI, 0.79-1.03; p = 0.114) and length of ICU stay (11.09 d vs. 11.91 d; weighted mean difference, -0.84 d; 95% CI, -2.52 to 0.84; p = 0.329). CONCLUSIONS: In adult patients with suspected or confirmed sepsis, procalcitonin guidance reduces antibiotics duration with no observed adverse effects on patient outcomes.

Epidemiology of Meningitis and Encephalitis in the United States, 2011-2014.

BACKGROUND: Large epidemiological studies evaluating the etiologies, management decisions, and outcomes of adults with meningitis or encephalitis in the United States (US) are lacking. METHODS: Adult patients (≥18 years) with meningitis or encephalitis by International Classification of Diseases, Ninth Revision codes available in the Premier Healthcare Database during 2011-2014 were analyzed. RESULTS: A total of 26429 patients with meningitis or encephalitis were identified. The median age was 43 years; 53% were female. The most common etiology was enterovirus (13463 [51.6%]), followed by unknown (4944 [21.4%]), bacterial meningitis (3692 [14.1%]), herpes simplex virus (2184 [8.3%]), noninfectious (921 [3.5%]), fungal (720 [2.7%]), arboviruses (291 [1.1%]), and other viruses (214 [0.8%]). Empiric antibiotics, antivirals, and antifungals were administered in 85.8%, 53.4%, and 7.8%, respectively, and varied by etiologies. Adjunctive steroids were utilized in 15.9% of all patients and in 39.3% of patients with pneumococcal meningitis, with an associated decrease in mortality (6.67% vs 12.5%, P = .0245). The median length of stay was 4 days, with the longest duration in those with fungal (13), arboviral (10), and bacterial meningitis (7). Overall inpatient mortality was 2.9% and was higher in those with bacterial (8.2%), fungal (8.2%), or arboviral (8.9%) disease. Overall readmission rate at 30 days was 3.2%; patients with arboviral (12.7%), bacterial (6.7%), and fungal (5.4%) etiologies had higher rates. CONCLUSIONS: Viruses are the most common cause of meningitis and encephalitis in the United States and are treated with antibiotic therapy in the majority of cases. Adjunctive steroid treatment is underutilized in pneumococcal meningitis, where it has shown to decrease mortality.

Effect of Procalcitonin Testing on Health-care Utilization and Costs in Critically Ill Patients in the United States.

BACKGROUND: There is a growing use of procalcitonin (PCT) to facilitate the diagnosis and management of severe sepsis. We investigated the impact of one to two PCT determinations on ICU day 1 on health-care utilization and cost in a large research database. METHODS: A retrospective, propensity score-matched multivariable analysis was performed on the Premier Healthcare Database for patients admitted to the ICU with one to two PCT evaluations on day 1 of ICU admission vs patients who did not have PCT testing. RESULTS: A total of 33,569 PCT-managed patients were compared with 98,543 propensity score-matched non-PCT patients. In multivariable regression analysis, PCT utilization was associated with significantly decreased total length of stay (11.6 days [95% CI, 11.4 to 11.7] vs 12.7 days [95% CI, 12.6 to 12.8]; 95% CI for difference, 1 to 1.3; P < .001) and ICU length of stay (5.1 days [95% CI, 5.1 to 5.2] vs 5.3 days [95% CI, 5.3 to 5.4]; 95% CI for difference, 0.1 to 0.3; P < .03), and lower hospital costs ($30,454 [95% CI, 29,968 to 31,033] vs $33,213 [95% CI, 32,964 to 33,556); 95% CI for difference, 2,159 to 3,321; P < .001). There was significantly less total antibiotic exposure (16.2 days [95% CI, 16.1 to 16.5] vs 16.9 days [95% CI, 16.8 to 17.1]; 95% CI for difference, -0.9 to 0.4; P = .006) in PCT-managed patients. Patients in the PCT group were more likely to be discharged to home (44.1% [95% CI, 43.7 to 44.6] vs 41.3% [95% CI, 41 to 41.6]; 95% CI for difference, 2.3 to 3.3; P = .006). Mortality was not different in an analysis including the 96% of patients who had an independent measure of mortality risk available (19.1% [95% CI, 18.7 to 19.4] vs 19.1% [95% CI, 18.9 to 19.3]; 95% CI for difference, -0.5 to 0.4; P = .93). CONCLUSIONS: Use of PCT testing on the first day of ICU admission was associated with significantly lower hospital and ICU lengths of stay, as well as decreased total, ICU, and pharmacy cost of care. Further elucidation of clinical outcomes requires additional data.

Statin Use Is Associated With Incident Diabetes Mellitus Among Patients in the HIV Outpatient Study.

INTRODUCTION: Statin therapy is effective in the prevention of cardiovascular disease in the general population but has been shown to modestly increase the risk for incident diabetes mellitus (DM). METHODS: We analyzed incident DM in HIV Outpatient Study (HOPS) participants followed at 8 HIV clinic sites during 2002-2011, comparing rates among those who initiated statin therapy during that period with those who did not. Using Cox proportional hazards models, we examined the association between cumulative years of statin exposure and the risk of developing DM, after controlling for age, sex, race/ethnicity, antiretroviral history, prevalent hepatitis C, body mass index, and cumulative exposure to protease inhibitor therapy. We also adjusted for propensity scores to account for residual confounding by indication. RESULTS: Of 4692 patients analyzed, 590 (12.6%) initiated statin therapy and 355 (7.2%) developed DM. Incident DM was independently associated with statin therapy (adjusted hazard ratio, 1.14 per year of statin use), as well as older age, Hispanic/Latino ethnicity, non-Hispanic/Latino black race, antiretroviral-naive status, prevalent hepatitis C, and body mass index ≥30 kg/m² (P < 0.05 for all). The association of statin use with incident DM was similar in the model adjusted for propensity score. CONCLUSIONS: Statin use was associated with a modestly increased risk of incident DM in an HIV-infected population, similar to existing data for the general population. HIV-infected patients should be monitored for glucose intolerance, but statins should not be withheld if clinically indicated for cardiovascular disease risk reduction.

HIV laboratory monitoring reliably identifies persons engaged in care.

BACKGROUND: Attendance at biannual medical encounters has been proposed as a minimum national standard for adequate engagement in HIV care. Using data from the HIV Outpatient Study, we analyzed how well dates of HIV-related laboratory testing correlated with attendance at biannual medical encounters. METHODS: HIV Outpatient Study is an open prospective cohort study of HIV-infected patients receiving outpatient care in the United States. The data set included dates for laboratory measurements and medical encounters. We included patients with at least 1 HIV laboratory test (CD4 cell count or plasma HIV RNA viral load) during 2010-2011. An HIV laboratory test was defined as associated with a medical encounter if it occurred within 3 weeks of the encounter. We assessed the predictive value of HIV laboratory tests as a proxy for adequate engagement in clinical care, defined as having had ≥2 HIV laboratory tests within 1 year and performed >90 days apart. RESULTS: A total of 10,321 HIV laboratory tests were recorded from 2909 patients. Adequate engagement in clinical care based on medical encounters was 88.2% and 77.3% when based on laboratory tests. Using HIV laboratory tests to assess engagement had a sensitivity of 85.7%, specificity of 86.0%, and positive and negative predictive values of 97.9% and 44.5%, respectively. Of the 22.7% classified as not engaged in care by the proxy measure, over half (55.5%) were actually engaged. CONCLUSIONS: Using laboratory monitoring reliably classified persons as engaged in care. Of the 22.7% of patients classified as not engaged in care, most were actually engaged.

Outcomes associated with conventional versus lipid-based formulations of amphotericin B in propensity-matched groups.

BACKGROUND: Lipid-based formulations of amphotericin B (LF-AMB) are indicated for treatment of invasive fungal infections in patients intolerant to conventional amphotericin B (CAB) or with refractory infections. Physicians still may choose to administer CAB to such patients. We described the use of CAB and LF-AMB in this population and quantified differences in post-amphotericin B length of stay (LOS) among survivors and hospital mortality in matched patients. METHODS: Data were extracted from Health Facts (Cerner Corporation, Kansas City, MO, USA) for a retrospective cohort analysis. Inpatients aged ≥18 years with evidence of fungal infection and with orders for LF-AMB or CAB on ≥2 days from January 2001 to June 2010 were identified. Patients were required to have renal insufficiency or other relative contraindications to use of CAB, exposure to nephrotoxic agents, or evidence of a CAB-refractory infection. Multilevel (hierarchical) mixed-effects logistic regression was used to determine factors associated with initial exposure to LF-AMB versus CAB. Multivariate adjustment of outcomes was done using propensity score matching. RESULTS: 655 patients were identified: 322 patients initiated therapy with CAB and 333 initiated treatment with LF-AMB. Compared to those initiating CAB, patients initiating LF-AMB had greater acuity and underlying disease severity. In unadjusted analyses, hospital mortality was significantly higher in the LF-AMB group (32.2% versus 23.7%; P = 0.02). After propensity score matching and covariate adjustment, mortality equalized and observed differences in LOS after amphotericin B initiation decreased. CONCLUSION: Among patients at risk for amphotericin B toxicity, differences between CAB and LF-AMB seen in crude outcomes analyses relate to channeling of sicker patients to initiate treatment with LF-AMB. Failing to account for differences among patients that drive clinical decision-making will result in inaccurate conclusions about the real-world effectiveness of different amphotericin B formulations.

A probability sample for monitoring the HIV-infected population in care in the U.S. and in selected states.

Epidemiologic and clinical changes in the HIV epidemic over time have presented a challenge to public health surveillance to monitor behavioral and clinical factors that affect disease progression and HIV transmission. The Medical Monitoring Project (MMP) is a supplemental surveillance project designed to provide representative, population-based data on clinical status, care, outcomes, and behaviors of HIV-infected persons receiving care at the national level. We describe a three-stage probability sampling method that provides both nationally and state-level representative estimates.In stage-I, 20 states, which included 6 separately funded cities/counties, were selected using probability proportional to size (PPS) sampling. PPS sampling was also used in stage-II to select facilities for participation in each of the 26 funded areas. In stage-III, patients were randomly selected from sampled facilities in a manner that maximized the possibility of having overall equal selection probabilities for every patient in the state or city/county. The sampling methods for MMP could be adapted to other research projects at national or sub-national levels to monitor populations of interest or evaluate outcomes and care for a range of specific diseases or conditions.