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AbstractBackgroundCommunity-onset bacterial coinfection in adults hospitalized with coronavirus disease 2019 (COVID-19) is reportedly uncommon, though empiric antibiotic use has been high. However, data regarding empiric antibiotic use and bacterial coinfection in children with critical illness from COVID-19 are scarce.MethodsWe evaluated children and adolescents aged <19 years admitted to a pediatric intensive care or high-acuity unit for COVID-19 between March and December 2020. Based on qualifying microbiology results from the first 3 days of admission, we adjudicated whether patients had community-onset bacterial coinfection. We compared demographic and clinical characteristics of those who did and did not (1) receive antibiotics and (2) have bacterial coinfection early in admission. Using Poisson regression models, we assessed factors associated with these outcomes.ResultsOf the 532 patients, 63.3% received empiric antibiotics, but only 7.1% had bacterial coinfection, and only 3.0% had respiratory bacterial coinfection. In multivariable analyses, empiric antibiotics were more likely to be prescribed for immunocompromised patients (adjusted relative risk [aRR], 1.34 [95% confidence interval {CI}, 1.01–1.79]), those requiring any respiratory support except mechanical ventilation (aRR, 1.41 [95% CI, 1.05–1.90]), or those requiring invasive mechanical ventilation (aRR, 1.83 [95% CI, 1.36–2.47]) (compared with no respiratory support). The presence of a pulmonary comorbidity other than asthma (aRR, 2.31 [95% CI, 1.15–4.62]) was associated with bacterial coinfection.ConclusionsCommunity-onset bacterial coinfection in children with critical COVID-19 is infrequent, but empiric antibiotics are commonly prescribed. These findings inform antimicrobial use and support rapid de-escalation when evaluation shows coinfection is unlikely.

AbstractWaldenström macroglobulinemia (WM) is a rare, indolent lymphoma, that predominately affects the elderly. We report the outcomes of young WM patients, evaluated over five decades, compared to their older counterparts, matched for the time of diagnosis. Between January 1, 1960 and October 31, 2013, 140 (11.8%) WM patients were ≤50 years of age at diagnosis in our database, and their estimated 10‐year overall survival (OS) was 74%, with death attributable to WM in a higher proportion of patients compared to their older (≥65 years) counterparts (91% vs. 58%, p = .0001). Young patients were grouped into three cohorts based on the timing of the initiation of therapy: Group 1 (1960–1977, n = 12), Group 2 (1978–1995, n = 48), and Group 3 (1996–2013, n = 74). Among young patients, there was no disease‐specific survival (DSS) difference across the three periods, [median DSS at 13 years (95% CI 5–23), 16 years (95% CI 14–22), and 15 years (95% CI 10‐NR; p = .41), respectively]. However, DSS for the older cohort incrementally improved (Group 1, median 5.2 years, Group 2: 9.6 years, Group 3: 12 years; p = .05) over these periods. The estimated average years‐of‐life lost for the young cohort was 11.2 years from diagnosis, based on the expected survival for a normal age‐ and sex‐matched population. Despite a protracted disease course, nearly all young patients succumb to their disease. In contrast to the improved survival of the elderly patient population, the evolving treatment strategies in WM have not impacted the outcome of young patients; however, the impact of Bruton tyrosine kinase inhibitors on this unique patient population remains to be determined.

Abstract Lenalidomide‐containing (R) triplet and quadruplet regimens are the standard of care for multiple myeloma (MM) and have been shown to increase the risk of thrombosis. The association between thromboembolism (TE) and survival in the novel multidrug era is not yet delineated. In this study, we evaluated the incidence of TE during the first year of MM diagnosis, its association with the type of induction regimen, and its impact on overall survival. We studied 672 newly diagnosed MM (NDMM) patients who received a triplet or quadruplet lenalidomide‐based induction at the Mayo Clinic, Rochester. TE was diagnosed in 83 patients (12.4%). Of these, 56 (8.3%) had a deep venous thrombosis (DVT), 23 (3.4%) had a pulmonary embolism (PE) with or without the DVT, and 4 (0.6%) patients had a stroke. Carfilzomib‐Rd (KRd) had the highest risk of TE (21.1%, 18/85), followed by quadruplets (11.1%, 5/45), bortezomib‐Rd (9.6%, 51/531), and 0/11 (0%), treated with other lenalidomide‐containing regimens. The difference in TE risk between KRd and the other regimens was statistically significant (OR = 2.6, p < .01). Nine patients developed a TE before being exposed to any treatment. Survival was significantly lower among patients that developed a TE (66 vs. 133 months, p < .01). The association of TE with reduced survival demonstrated in univariate analysis (HR = 2.2, 95% CI = 1.6–3.3) was maintained in the multivariable analysis adjusted for high‐risk interphase fluorescence in situ hybridization (FISH), sex, age, receipt of an upfront transplant, the response at induction, and the International Staging System (ISS) (HR = 2.61, CI = 1.74–3.9). We conclude that TE is an important aspect of MM management, and effective management is especially relevant in the novel treatment era.

Abstract Eosinophils comprise only 1-3% of circulating leukocytes but are often a diagnostic feature associated with a variety of inflammatory and disease states, including parasitic and fungal infections, allergic diseases (e.g., asthma, rhinitis and sensitivities to specific foods), cancer, and transplant rejection. The accurate evaluations of eosinophilia as well as the release of stored eosinophil granule proteins are important for the monitoring disease progression and/or assessing the effectiveness of a given treatment strategy(ies). Despite the availability of detection methods for each of the eosinophil granule proteins logistical difficulties limiting either the assays specificity and/or sensitivity have prevented their extensive use. We have generated unique eosinophil peroxidase specific monoclonal antibodies (EPX-mAb) and a high throughput sandwich ELISA assay as a means of overcoming these difficulties. Our EPX-mAb based ELISA is ~10 times more sensitive than traditional OPD based activity assays and allows detection of EPX in mouse BAL fluid after an acute OVA protocol as well as EPX release from mouse eosinophils stimulated ex vivo. The assay is highly specific and gives no signal in samples from EPX deficient mice even with massive eosinophilia (e.g., EPX deficient IL-5 transgenic mice). More significantly, this assay detects EPX in human tissue extracts and biological fluids and thus represents novel diagnostic assay previously unavailable in clinical settings.

Abstract POEMS syndrome is a rare paraneoplastic syndrome and therapies are directed against plasma cells that produce the proteins that cause this syndrome. Novel therapies are widely used in multiple myeloma aiming for plasma cell eradication. However, data on their use in POEMS syndrome are lacking. In this case series, we provide the Mayo Clinic experience in treating 16 patients with relapsed POEMS syndrome with novel agents (daratumumab, carfilzomib, pomalidomide, and elotuzumab). The patients were treated with a doublet including dexamethasone (N = 5) (31%) or in various combinations with other agents: DRd (N = 6), DC(V)d (N = 3), KRd (N = 3), KPd (N = 1), DP(V)d (N = 5), and EloRd (N = 1). The outcomes with novel agent therapies were favorable. Overall, twelve patients treated with daratumumab-based therapies (86%) and five patients treated with carfilzomib-based therapies (83%) responded to therapy. Among patients treated with daratumumab based therapies (N = 14), 9 patients achieved CR/VGPRH, 7 patients achieved CRV, and 5 patients achieved CRP. Among patients treated with carfilzomib-based therapies (N = 6), 3 patients achieved CR/VGPRH, and one achieved PRH. At a median follow-up of 38 months since starting of the novel agent (IQR 24–57), 15 of the patients (93%) are still alive, and the median TTNT was not reached. None of the patients discontinued therapy due to adverse events and no deaths occurred on therapy. Novel therapies were safe with 7 events of hospitalization due to pneumonia (4 in daratumumab-based therapies and 3 on carfilzomib-based therapies), and 4 patients were hospitalized due to volume overload. Three patients experienced infusion-related reactions (IRR) to the first dose of IV daratumumab. The response rate to novel agents was high, and the responses were deep. Novel agent therapies were safe, and no death case occurred on therapy. Future studies are needed to clarify the optimal sequence of novel agents and the best combination.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

ImportanceLate-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm.ObjectiveTo report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months’ corrected age.Design, Setting, and ParticipantsThis cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks’ gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers.ExposuresCulture-confirmed LOM.Main Outcomes and MeasuresIncidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021).ResultsAmong 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P &amp;lt; .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P &amp;lt; .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P &amp;lt; .001) and among those with culture-confirmed LOS (23%-79%, P &amp;lt; .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection.Conclusions and RelevanceIn this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.