Multicenter Prospective Study of Biomarkers for Diagnosis of Invasive Candidiasis in Children and Adolescents.

2022

2022 Jan 20

1537-6591

<p><strong>BACKGROUND: </strong>Diagnosis of invasive candidiasis (IC) relies on insensitive cultures; the relative utility of fungal biomarkers in children is unclear.</p>

<p><strong>METHODS: </strong>This multinational observational cohort study enrolled patients aged &gt;120 days and &lt;18 years with concern for IC from 1 January 2015 to 26 September 2019 at 25 centers. Blood collected at onset of symptoms was tested using T2Candida, Fungitell (1→3)-β-D-glucan, Platelia Candida Antigen (Ag) Plus, and Platelia Candida Antibody (Ab) Plus assays. Operating characteristics were determined for each biomarker, and assays meeting a defined threshold considered in combination. Sterile site cultures were the reference standard.</p>

<p><strong>RESULTS: </strong>Five hundred participants were enrolled at 22 centers in 3 countries, and IC was diagnosed in 13 (2.6%). Thirteen additional blood specimens were collected and successfully spiked with Candida species, to achieve a 5.0% event rate. Valid T2Candida, Fungitell, Platelia Candida Ag Plus, and Platelia Candida Ab Plus assay results were available for 438, 467, 473, and 473 specimens, respectively. Operating characteristics for T2Candida were most optimal for detecting IC due to any Candida species, with results as follows: sensitivity, 80.0% (95% confidence interval, 59.3%-93.2%), specificity 97.1% (95.0%-98.5%), positive predictive value, 62.5% (43.7%-78.9%), and negative predictive value, 98.8% (97.2%-99.6%). Only T2Candida and Platelia Candida Ag Plus assays met the threshold for combination testing. Positive result for either yielded the following results: sensitivity, 86.4% (95% confidence interval, 65.1%- 97.1%); specificity, 94.7% (92.0%-96.7%); positive predictive value, 47.5% (31.5%-63.9%); and negative predictive value, 99.2% (97.7%-99.8%).</p>

<p><strong>CONCLUSIONS: </strong>T2Candida alone or in combination with Platelia Candida Ag Plus may be beneficial for rapid detection of Candida species in children with concern for IC.</p>

<p><strong>CLINICAL TRIALS REGISTRATION: </strong>NCT02220790.</p>

10.1093/cid/ciab928

Clin Infect Dis

35134165

Return to School and COVID-19 Vaccination for Pediatric Solid Organ Transplant Recipients in the United States: Expert Opinion for 2021-2022.

2021

2021 Nov 03

2048-7207

<p>The COVID-19 pandemic continues to generate challenges for pediatric solid organ transplant (SOT) recipients and their families. As rates of COVID-19 fluctuate, new SARS-CoV-2 variants emerge, and adherence to and implementation of mitigation strategies vary from community to community, questions remain about the best and safest practices to prevent COVID-19 in vulnerable patients. Notably, decisions about returning to school remain difficult. We assembled a team of specialists in pediatric infectious diseases, transplant infectious diseases, public health, transplant psychology, and infection prevention and control to re-address concerns about school re-entry, as well as COVID-19 vaccines, for pediatric SOT recipients in the United States in 2021. Based on available literature and guidance from national organizations, we generated expert statements specific to pediatric SOT recipients focused on school attendance in 2021.</p>

10.1093/jpids/piab098

J Pediatric Infect Dis Soc

34734268

Early stool microbiome and metabolome signatures in pediatric patients undergoing allogeneic hematopoietic cell transplantation.

2021

e29384

2021 Oct 28

1545-5017

<p><strong>BACKGROUND: </strong>The contribution of the gastrointestinal tract microbiome to outcomes after allogeneic hematopoietic cell transplantation (HCT) is increasingly recognized. Investigations of larger pediatric cohorts aimed at defining the microbiome state and associated metabolic patterns pretransplant are needed.</p>

<p><strong>METHODS: </strong>We sought to describe the pretransplant stool microbiome in pediatric allogenic HCT patients at four centers. We performed shotgun metagenomic sequencing and untargeted metabolic profiling on pretransplant stool samples. Samples were compared with normal age-matched controls and by clinical characteristics. We then explored associations between stool microbiome measurements and metabolite concentrations.</p>

<p><strong>RESULTS: </strong>We profiled stool samples from 88 pediatric allogeneic HCT patients, a median of 4&nbsp;days before transplant. Pretransplant stool samples differed from healthy controls based on indices of alpha diversity and in the proportional abundance of specific taxa and bacterial genes. Relative to stool from healthy patients, samples from HCT patients had decreased proportion of Bacteroides, Ruminococcaeae, and genes involved in butyrate production, but were enriched for gammaproteobacterial species. No systematic differences in stool microbiome or metabolomic profiles by age, transplant indication, or hospital were noted. Stool metabolites demonstrated strong correlations with microbiome composition.</p>

<p><strong>DISCUSSION: </strong>Stool samples from pediatric allogeneic HCT patients demonstrate substantial dysbiosis early in the transplant course. As microbiome disruptions associate with adverse transplant outcomes, pediatric-specific analyses examining longitudinal microbiome and metabolome changes are imperative to identify causal associations and to inform rational design of interventions.</p>

10.1002/pbc.29384

Pediatr Blood Cancer

34709713

Comparative Effectiveness of Echinocandins vs Triazoles or Amphotericin B Formulations as Initial Directed Therapy for Invasive Candidiasis in Children and Adolescents.

2021

2021 Aug 10

2048-7207

<p><strong>BACKGROUND: </strong>Invasive candidiasis is the most common invasive fungal disease in children and adolescents, but there are limited pediatric-specific antifungal effectiveness data. We compared the effectiveness of echinocandins to triazoles or amphotericin B formulations (triazole/amphotericin B) as initial directed therapy for invasive candidiasis.</p>

<p><strong>METHODS: </strong>This multinational observational cohort study enrolled patients aged &gt;120 days and &lt;18 years with proven invasive candidiasis from January 1, 2014, to November 28, 2017, at 43 International Pediatric Fungal Network sites. Primary exposure was initial directed therapy administered at the time qualifying culture became positive for yeast. Exposure groups were categorized by receipt of an echinocandin vs receipt of triazole/amphotericin B. Primary outcome was global response at 14 days following invasive candidiasis onset, adjudicated by a centralized data review committee. Stratified Mantel-Haenszel analyses estimated risk difference between exposure groups.</p>

<p><strong>RESULTS: </strong>Seven-hundred and fifty invasive candidiasis episodes were identified. After exclusions, 541 participants (235 in the echinocandin group and 306 in the triazole/amphotericin B group) remained. Crude failure rates at 14 days for echinocandin and triazole/amphotericin B groups were 9.8% (95% confidence intervals [CI]: 6.0% to 13.6%) and 13.1% (95% CI: 9.3% to 16.8%), respectively. The adjusted 14-day risk difference between echinocandin and triazole/amphotericin B groups was -7.1% points (95% CI: -13.1% to -2.4%), favoring echinocandins. The risk difference was -0.4% (95% CI: -7.5% to 6.7%) at 30 days.</p>

<p><strong>CONCLUSIONS: </strong>In children with invasive candidiasis, initial directed therapy with an echinocandin was associated with reduced failure rate at 14 days but not 30 days. These results may support echinocandins as initial directed therapy for invasive candidiasis in children and adolescents.</p>

<p><strong>CLINICAL TRIALS REGISTRATION: </strong>NCT01869829.</p>

10.1093/jpids/piab024

J Pediatric Infect Dis Soc

34374424

Weighing the Risks of Perimyocarditis With the Benefits of SARS-CoV-2 mRNA Vaccination in Adolescents.

2021

2021 Jul 16

2048-7207

10.1093/jpids/piab061

J Pediatric Infect Dis Soc

34270752

Return to School for Pediatric Solid Organ Transplant Recipients in the United States During the COVID-19 Pandemic: Expert Opinion on Key Considerations and Best Practices.

2020

2020 Aug 04

2048-7207

<p>The COVID-19 pandemic has created many challenges for pediatric solid organ transplant (SOT) recipients and their families. As the pandemic persists, patients and their families struggle to identify the best and safest practices for resuming activities as areas re-open. In particular, decisions about returning to school remain difficult. We assembled a team of pediatric infectious diseases, transplant infectious diseases, public health, transplant psychology, and infection prevention and control specialists to address the primary concerns about school re-entry for pediatric SOT recipients in the United States. Based on available literature and guidance from national organizations, we generated consensus statements pertaining to school re-entry specific to pediatric SOT recipients. Although data are limited, and the COVID-19 pandemic highly dynamic, our goal was to create a framework from which providers and caregivers can identify the most important considerations for each pediatric SOT recipient to promote a safe return to school this fall.</p>

10.1093/jpids/piaa095

J Pediatric Infect Dis Soc

32750142

A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.

2020

2020 Feb 16

1600-6143

<p>Hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT) recipients are at increased risk for Clostridioides difficile infection (CDI). We conducted a multicenter retrospective study to describe the incidence of CDI in children transplanted between January 2010 and June 2013. Nested case-control substudies, matched 1:1 by transplant type, institution, patient age, and time of year (quartile) of transplant, identified CDI risk factors. Cohorts included 1496 HCT and 1090 SOT recipients. Among HCT recipients, 355 CDI episodes were diagnosed in 265 recipients (18.2%). Nested case-control study identified prior history of CDI (OR 2.6, 95% CI 1.5 - 4.7), proton-pump inhibitors (OR 2.1, 95% CI 1.3 - 3.4), and exposure to third (OR 2.4, 95% CI 1.4 - 4.2) or fourth generation (OR 2.1, 95% CI 1.2 - 3.7) cephalosporins as risk factors. Notably, fluoroquinolone exposure appeared protective (OR 0.6, 95% CI 0.3 - 0.9). Ninety-two episodes of CDI were diagnosed among 79 SOT recipients (7.3%) and exposure to PPIs (OR 2.4, 95% CI 1.1 - 5.4) and third generation cephalosporin therapy (OR 3.9, 95% CI 1.4 - 10.5) were identified as risk factors. Strategies to decrease PPI use and changes in the class of prophylactic antibiotics may impact CDI incidence and warrant further study.</p>

10.1111/ajt.15826

Am. J. Transplant.

32064754

Effect of Levofloxacin Prophylaxis on Bacteremia in Children With Acute Leukemia or Undergoing Hematopoietic Stem Cell Transplantation: A Randomized Clinical Trial.

2018

995-1004

2018 Sep 11

1538-3598

<p><strong>Importance: </strong>Bacteremia causes considerable morbidity among children with acute leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). There are limited data on the effect of antibiotic prophylaxis in children.</p>

<p><strong>Objective: </strong>To determine the efficacy and risks of levofloxacin prophylaxis in children receiving intensive chemotherapy for acute leukemia or undergoing HSCT.</p>

<p><strong>Design, Setting, and Participants: </strong>In this multicenter, open-label, randomized trial, patients (6 months-21 years) receiving intensive chemotherapy were enrolled (September 2011-April 2016) in 2 separate groups-acute leukemia, consisting of acute myeloid leukemia or relapsed acute lymphoblastic leukemia, and HSCT recipients-at 76 centers in the United States and Canada, with follow-up completed September 2017.</p>

<p><strong>Interventions: </strong>Patients with acute leukemia were randomized to receive levofloxacin prophylaxis for 2 consecutive cycles of chemotherapy (n = 100) or no prophylaxis (n = 100). Those undergoing HSCT were randomized to receive levofloxacin prophylaxis during 1 HSCT procedure (n = 210) or no prophylaxis (n = 214).</p>

<p><strong>Main Outcomes and Measures: </strong>The primary outcome was the occurrence of bacteremia during 2 chemotherapy cycles (acute leukemia) or 1 transplant procedure (HSCT). Secondary outcomes included fever and neutropenia, severe infection, invasive fungal disease, Clostridium difficile-associated diarrhea, and musculoskeletal toxic effects.</p>

<p><strong>Results: </strong>A total of 624 patients, 200 with acute leukemia (median [interquartile range {IQR}] age, 11 years [6-15 years]; 46% female) and 424 undergoing HSCT (median [IQR] age, 7 years [3-14]; 38% female), were enrolled. Among 195 patients with acute leukemia, the likelihood of bacteremia was significantly lower in the levofloxacin prophylaxis group than in the control group (21.9% vs 43.4%; risk difference, 21.6%; 95% CI, 8.8%-34.4%, P = .001), whereas among 418 patients undergoing HSCT, the risk of bacteremia was not significantly lower in the levofloxacin prophylaxis group (11.0% vs 17.3%; risk difference, 6.3%; 95% CI, 0.3%-13.0%; P = .06). Fever and neutropenia were less common in the levofloxacin group (71.2% vs 82.1%; risk difference, 10.8%; 95% CI, 4.2%-17.5%; P = .002). There were no significant differences in severe infection (3.6% vs 5.9%; risk difference, 2.3%; 95% CI, -1.1% to 5.6%; P = .20), invasive fungal disease (2.9% vs 2.0%; risk difference, -1.0%; 95% CI, -3.4% to 1.5%, P = .41), C difficile-associated diarrhea (2.3% vs 5.2%; risk difference, 2.9%; 95% CI, -0.1% to 5.9%; P = .07), or musculoskeletal toxic effects at 2 months (11.4% vs 16.3%; risk difference, 4.8%; 95% CI, -1.6% to 11.2%; P = .15) or at 12 months (10.1% vs 14.4%; risk difference, 4.3%; 95% CI, -3.4% to 12.0%; P = .28) between the levofloxacin and control groups.</p>

<p><strong>Conclusions and Relevance: </strong>Among children with acute leukemia receiving intensive chemotherapy, receipt of levofloxacin prophylaxis compared with no prophylaxis resulted in a significant reduction in bacteremia. However, there was no significant reduction in bacteremia for levofloxacin prophylaxis among children undergoing HSCT.</p>

10.1001/jama.2018.12512

JAMA

30208456

A Multicenter Consortium to Define the Epidemiology and Outcomes of Pediatric Solid Organ Transplant Recipients With Inpatient Respiratory Virus Infection.

2018

2018 Mar 10

2048-7207

<p><strong>Background: </strong>Respiratory virus infection (RVI) in pediatric solid organ transplant (SOT) recipients poses a significant risk; however, the epidemiology and effects of an RVI after pediatric SOT in the era of current molecular diagnostic assays are unclear.</p>

<p><strong>Methods: </strong>A retrospective observational cohort of pediatric SOT recipients (January 2010 to June 2013) was assembled from 9 US pediatric transplant centers. Charts were reviewed for RVI events associated with hospitalization within 1 year after the transplant. An RVI diagnosis required respiratory symptoms and detection of a virus (ie, human rhinovirus/enterovirus, human metapneumovirus, influenza virus, parainfluenza virus, coronavirus, and/or respiratory syncytial virus). The incidence of RVI was calculated, and the association of baseline SOT factors with subsequent pulmonary complications and death was assessed.</p>

<p><strong>Results: </strong>Of 1096 pediatric SOT recipients (448 liver, 289 kidney, 251 heart, 66 lung, 42 intestine/multivisceral), 159 (14.5%) developed RVI associated with hospitalization within 12 months after their transplant. RVI occurred at the highest rates in intestine/abdominal multivisceral (38%), thoracic (heart/lung) (18.6%), and liver (15.6%) transplant recipients and a lower rate in kidney (5.5%) transplant recipients. RVI was associated with younger median age at transplant (1.72 vs 7.89 years; P &lt; .001) and among liver or kidney transplant recipients with the receipt of a deceased-donor graft compared to a living donor (P = .01). The all-cause and attributable case-fatality rates within 3 months of RVI onset were 4% and 0%, respectively. Multivariable logistic regression models revealed that age was independently associated with increased risk for a pulmonary complication (odds ratio, 1.24 [95% confidence interval, 1.02-1.51]) and that receipt of an intestine/multivisceral transplant was associated with increased risk of all-cause death (odds ratio, 24.54 [95% confidence interval, 1.69-327.96]).</p>

<p><strong>Conclusions: </strong>In this study, hospital-associated RVI was common in the first year after pediatric SOT and associated with younger age at transplant. All-cause death after RVI was rare, and no definitive attributable death occurred.</p>

10.1093/jpids/piy024

J Pediatric Infect Dis Soc

29538674

A Multicenter Consortium to Define the Epidemiology and Outcomes of Inpatient Respiratory Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients.

2018

275-282

2018 Dec 3

2048-7207

<p><strong>Background: </strong>Respiratory virus infections (RVIs) pose a threat to children undergoing hematopoietic stem cell transplantation (HSCT). In this era of sensitive molecular diagnostics, the incidence and outcome of HSCT recipients who are hospitalized with RVI (H-RVI) are not well described.</p>

<p><strong>Methods: </strong>A retrospective observational cohort of pediatric HSCT recipients (between January 2010 and June 2013) was assembled from 9 US pediatric transplant centers. Their medical charts were reviewed for H-RVI events within 1 year after their transplant. An H-RVI diagnosis required respiratory signs or symptoms plus viral detection (human rhinovirus/enterovirus, human metapneumovirus, influenza, parainfluenza, coronaviruses, and/or respiratory syncytial virus). The incidence of H-RVI was calculated, and the association of baseline HSCT factors with subsequent pulmonary complications and death was assessed.</p>

<p><strong>Results: </strong>Among 1560 HSCT recipients, 259 (16.6%) acquired at least 1 H-RVI within 1 year after their transplant. The median age of the patients with an H-RVI was lower than that of patients without an H-RVI (4.8 vs 7.1 years; P &lt; .001). Among the patients with a first H-RVI, 48% required some respiratory support, and 14% suffered significant pulmonary sequelae. The all-cause and attributable case-fatality rates within 3 months of H-RVI onset were 11% and 5.4%, respectively. Multivariate logistic regression revealed that H-RVI onset within 60 days of HSCT, steroid use in the 7 days before H-RVI onset, and the need for respiratory support at H-RVI onset were associated with subsequent morbidity or death.</p>

<p><strong>Conclusion: </strong>Results of this multicenter cohort study suggest that H-RVIs are relatively common in pediatric HSCT recipients and contribute to significant morbidity and death. These data should help inform interventional studies specific to each viral pathogen.</p>

10.1093/jpids/pix051

J Pediatric Infect Dis Soc

29106589