Infections In Immunocompromised Children Research Articles

Posaconazole in paediatric malignancy and haematopoietic stem cell transplant: dosing to achieve therapeutic concentration.

Posaconazole is increasingly used for the treatment and prophylaxis of invasive fungal infections in immunocompromised children. We aimed to review evidence for paediatric posaconazole dosing regimens focusing on attainment of target concentrations and frequency of adverse effects. In May 2023, the Cochrane, Embase, MEDLINE and PubMed databases were searched for articles reporting posaconazole dosing in children with malignancy or post-haematopoietic stem cell transplantation. Studies reporting the attainment of target serum concentrations were included. Overall, 24 studies were included. Eighteen studies of the oral suspension consistently reported poor attainment of target concentrations for prophylaxis (≥0.7 µg/mL, 12%-78%) despite high daily doses of 14-23 mg/kg/day (max. 1200 mg/day). Target attainment was significantly affected by gastric pH and food intake. Six studies of the delayed-release tablet (DRT) reported 58%-94% achieved concentrations ≥0.7 µg/mL, with the majority using lower doses of 4-12 mg/kg/day (max. 300 mg/day). Similarly, one study of powder for oral suspension found 67%-100% achieved target concentrations with a dose of 6 mg/kg/day (max. 300 mg/day). As expected, the IV formulation had high attainment of prophylaxis targets (81%-90%) with 6-10 mg/kg/day (max. 400 mg/day). All formulations were well tolerated, and no relationship between adverse effects and posaconazole concentrations was identified. The required posaconazole dose in immunocompromised children varies depending on the formulation. The IV infusion had the highest attainment of therapeutic concentration followed by the DRT and powder for suspension. By contrast, the oral suspension had low attainment of target concentrations despite higher daily doses.

Risk Factors for Pneumocystis jirovecii Pneumonia in Children With Systemic Lupus Erythematosus Exposed to Prolonged High-Dose Glucocorticoids.

Pneumocystis jirovecii pneumonia (PJP) is a life-threatening opportunistic infection in immunocompromised children with systemic lupus erythematosus (SLE). Prophylaxis against PJP in high-risk children is crucial, but the risk factors for PJP in children with SLE are not adequately characterized. This study sought to identify the risk factors for PJP in long-term glucocorticoid-treated pediatric SLE patients. This study encompassed 71 treatment episodes involving 64 children with prolonged (≥4 weeks) high-dose (≥20 mg/d prednisone) steroid regimens. Fourteen treatment episodes involved the PJP, whereas others did not. Risk factors for PJP were assessed through Cox regression. The predictive value of these factors was evaluated using receiver operating characteristic curves. The incidence of PJP in different risk groups was compared using the Kaplan-Meier method. The creatinine (hazard ratio, 1.009; 95% confidence interval [CI], 1.001-1.017; p = 0.021) and the lowest lymphocyte count (hazard ratio, 0.007; 95% CI, 0.000-0.373; p = 0.014) were independent risk factors for PJP in children with SLE. The receiver operating characteristic curve showed that using creatinine greater than 72.5 μmol/L and the lowest lymphocyte count less than 0.6 × 109/L as risk predictors for PJP resulted in an area under the curve value of 0.934 (95% CI, 0.870-0.997; p < 0.001). The study revealed a significant increase in PJP prevalence (p < 0.001) in children with elevated creatinine levels and low lymphocyte count. Elevated levels of creatinine and decreased lymphocyte count are identified as distinct risk factors for PJP in children with SLE who receive prolonged high-dose steroid therapy.

Impact of a New Diagnostic Stewardship Team on Utilization and Interpretation of a Microbial Cell-Free DNA Detection Test

Abstract Background After commercial metagenomic next-generation sequencing of plasma microbial cell-free DNA (NGS-mcfDNA) became available at Children’s Healthcare of Atlanta (CHOA) in 2018 with an institutional requirement for Infectious Disease (ID) consultation and approval, we observed an initial period of test utilization without consistent ID involvement. Subsequently we assembled a Diagnostic Stewardship Team (DST) composed of a clinical microbiologist and 3 ID clinicians with expertise in diagnosis and management of infections in immunocompromised children and antimicrobial stewardship, to improve test utilization by clinicians and to optimally impact patient care. Methods We performed a retrospective medical record review as an IRB-deemed Quality Improvement project. NGS-mcfDNA results and their clinical impacts prior to the formation of the DST were assessed, using previously published standardized criteria as an initial framework (Hogan 2021)1. We shared our findings with Bone Marrow Transplant (BMT), Pediatric Intensive Care Unit (PICU), and ID clinicians, providing education on the potential benefits and limitations of NGS-mcfDNA testing. Stakeholder acceptability and engagement with the DST was prioritized, with emphasis on highlighting the benefits to clinicians of expertise in patient selection for testing and with interpretation of results which can be discordant with conventional microbiological tests. DST approval became required for all NGS-mcfDNA tests, with approval decision and discussion documented in the medical record, followed by documentation of test results, interpretation, and communications with treating and consulting clinicians. After one year of DST engagement, which began on June 1, 2021, we repeated our analysis of NGS-mcfDNA utilization and clinical impacts to evaluate the results of DST involvement. We classified time periods into pre-DST, February 28, 2018 - April 12, 2021, and post-DST, June 1, 2021 – May 31, 2022. Results The majority of NGS-mcfDNA tests sent in both the pre- and post-DST periods resulted in no or indeterminate clinical impact (65% pre-DST vs. 73% post-DST), while post-DST the percentage of positive clinical impacts increased (18% pre-DST vs. 25% post-DST), and the percentage of negative clinical impacts decreased (16% pre-DST vs. 2% post-DST), likely due to DST engagement. The number of tests per year increased by three-fold, while fewer patients had multiple NGS-mcfDNA tests sent. Awareness of the requirement for DST consultation and test approval lead to more selective NGS-mcfDNA test requests on the part of BMT clinicians, and the majority of positive clinical impacts from NGS-mcfDNA testing in BMT patients resulted from collaboration between BMT and ID in de-escalation of antimicrobials. An increased awareness of the potential benefits of NGS-mcfDNA testing for pre-treated and diagnostically challenging patients led to an increase in NGS-mcfDNA test requests from ID clinicians. Conclusion Implementation of a DST resulted in universal ID engagement with clinicians requesting NGS-mcfDNA tests and ID involvement in test interpretation. Discussion with experienced diagnostic stewards at the time of NGS-mcfDNA test consideration, with attention to the rationale for test request and consideration of potential test limitations prior to return of results, in addition to rigorous interpretation of results, can increase the positive clinical impacts and decrease the negative clinical impacts of NGS-mcfDNA tests. Reference 1. Hogan CA, Yang S, Garner OB, Green DA, Gomez CA, Dien Bard J, Pinsky BA, Banaei N. Clinical Impact of Metagenomic Next-Generation Sequencing of Plasma Cell-Free DNA for the Diagnosis of Infectious Diseases: A Multicenter Retrospective Cohort Study. Clin Infect Dis. 2021 Jan 27;72(2):239-245. doi: 10.1093/cid/ciaa035. PMID: 31942944. Characteristics of NGS-mcfDNA tests sent from CHOA NGS-mcfDNA tests in BMT patients post-DST (n=19 tests)

Lung infections in immunocompromised children.

Pulmonary infection is the leading cause of infectious morbidity and mortality in children with immune defects. We provide a comprehensive review of lung infections in immunocompromised children, with a focus on imaging findings and imaging-based management. We include an overview of the immune defences of the respiratory tract, the aetiologies of immune defects in children, the features of specific infections and important differential diagnoses and describe diagnostic strategies using imaging and non-imaging-based techniques.

Carbapenem-Resistant Enterobacteriaceae Infection in Immunocompromised Children with CRE Colonization: Incidence and Outcomes in an Antibiotic-Limited Setting

Objective: To determine the incidence of carbapenem-resistant Enterobacteriaceae (CRE) infection in patients with CRE colonization and compare the treatment outcomes between febrile patients with non-septic presentation who received empirical treatment with meropenem and those who did not. Material and Methods: The medical records of febrile patients with CRE colonization aged &lt;15 years who were hospitalized at Songklanagarind Hospital between January 2018 and December 2020 were reviewed. Results: Among the 61 patients with CRE colonization, CRE infection was identified during eight febrile episodes in six patients (9.8%). Hematologic malignancies, solid tumors, and other diseases were diagnosed in 21 (34.4%), 25 (41.0%), and 15 (24.6%) patients, respectively. The median (interquartile range [IQR]) duration from CRE colonization to the first episode of fever was 22 (1.8–60.8) days. Among the 82 febrile episodes without initial sepsis or central nervous system infection, 19 and 63 episodes, respectively, were initially treated with meropenem and non-carbapenems. Treatment outcomes—including the proportion of patients needing step-up antibiotics (21.1% vs. 36.5%), development of sepsis (5.3% vs. 15.9%), and death within 30 days (6.6% vs. 9.8%) - were not significantly different between the two groups.Patients who developed sepsis had significantly higher resistance to empirical antibiotics (75% vs. 26.3%) as well as a significantly higher incidence of severe neutropenia lasting more than one week (85.7% vs. 21.9%) than those without sepsis.Conclusion: Patients with CRE colonization who exhibit fever without clinical sepsis and have an absolute neutrophil count &gt;100 cells/mm3 can be empirically treated with non-carbapenems.

Cidofovir for Viral Infections in Immunocompromised Children: Guidance on Dosing, Safety, Efficacy, and a Review of the Literature.

To describe the use of cidofovir (CDV) for viral infections in immunocompromised children (IC) and provide guidance on dosing and supportive care. A PubMed search was conducted for literature published between 1997 and January 2022 using the following terms: cidofovir, plus children or pediatrics. Limits were set to include human subjects less than 24 years of age receiving intravenous (IV) or intrabladder CDV for treatment of infections due to adenovirus, polyomavirus-BK (BKV), herpesviruses, or cytomegalovirus. Data were heterogeneous, with largely uncontrolled studies. Conventional dosing (CDV 5 mg/kg/dose weekly) was commonly used in 60% (31/52) of studies and modified dosing (CDV 1 mg/kg/dose 3 times/week) was used in 17% (9/52) of studies, despite being off-label. Nephrotoxicity reported across studies totaled 16% (65/403 patients), which was higher for conventional dosing 29 of 196 patients (15%) than modified dosing 1 of 27 patients (4%). Saline hyperhydration and concomitant probenecid remain the cornerstones of supportive care, while some regimens omitting probenecid are emerging to target BKV. To our knowledge, this is the first comprehensive review of CDV use (indications, dosing, supportive care, response, and nephrotoxicity) in pediatric IC. Effective utilization of CDV in IC remains challenging. Further prospective studies are needed to determine the optimal CDV dosing; however, less aggressive dosing regimens such as modified thrice weekly dosing or low dosing once weekly omitting probenecid to enhance urinary penetration may be reasonable alternatives to conventional dosing in some IC.

1095. Retrospective Review of SARS-CoV-2 Infection in Immunocompromised Children at a Single Pediatric Institution

Abstract Background Immunocompromised individuals are considered higher risk for severe COVID-19 disease. Much of this data was collected from adults with limited pediatric reporting, although a recent study showed no worse outcome in immunocompromised children. In this study, we characterize our experience of immunocompromised children who were hospitalized with acute SARS-CoV-2 infection and aimed to identify a sub-group of patients who had worse outcomes. Methods We reviewed charts of all immunocompromised children hospitalized with SARS-CoV-2 RT-PCR positive results at our hospital from March 2020-April 2022. Disease severity was characterized according to the NIH COVID-19 guidelines. Clinical characteristics and outcomes were assessed. Individuals were grouped into solid organ transplant recipients, solid tumors, liquid tumors, and stem cell transplant recipients. Proportions were calculated per group in addition to the exact binomial confidence intervals (95%). Results We identified 39 pediatric aged patients ranging from 7 months to 20 years of age with a median age of 10. 35.9% (14/39) of individuals were solid organ transplant recipients, 25.6% (10/39) had solid tumors, 33% (13/39) had liquid tumors, and 5% (2/39) were stem cell transplant recipients. 17.9% were asymptomatic, 66.7% had mild disease, and 15.4% had severe/critical COVID-19 disease. The median time of positive SARS CoV-2 RT-PCR was 32 days. Six children had prolonged SARS-CoV-2 RT-PCR positive testing between 29-97 days with a mean of 49 days. Viral strand specific RNA testing for replicating virus was also persistently positive. Six experienced severe/critical disease resulting in death of three. Most of the patients were treated with predominantly T cell depleting agents (∼74%). However, four patients who had prolonged active critical infection were treated with B cell depleting agents or had known B cell dysfunction. Conclusion The majority of the immunocompromised children in our cohort had mild COVID-19 disease. A subset of individuals experienced ongoing prolonged RT-PCR positivity and testing indicating persistent viral replication, with three demonstrating an inability to control the virus and resulting in death. Worse outcomes may be related to their immune dysfunction and use of B cell depleting agents. Disclosures All Authors: No reported disclosures.

Hepatitis E Virus Infection in Pediatric Oncology.

In the 2016 ESPGHAN recommendations on how to deal with hepatitis E virus infection in immunocompromised children, patients treated with chemotherapy were not specifically mentioned. Two teenagers treated with chemotherapy for acute leukemia and medulloblastoma, respectively, were diagnosed with hepatic cytolysis. After numerous investigations hepatitis E was found, limiting the good progress of the chemotherapy treatment. In the case of liver cytolysis in immunocompromised children treated with chemotherapy, hepatitis E virus infection has to be promptly diagnosed.

Impact of Antibiotic Use for Febrile Neutropenia on Gut Microbiome Phyla in Children with Leukemia and Lymphoma

Introduction: Approximately 40% of children with leukemia/lymphoma experience one or more episodes of febrile neutropenia. These episodes are treated with empiric intravenous antibiotics that include broad spectrum β-lactams and vancomycin. Although studies suggest antibiotics change the gut microbiome, the effect is unclear. This study reports the impact of repeated courses and duration of antibiotic use on microbiome. Methods: We examined 39 pediatric patients diagnosed and treated at the IWK Health Centre, Nova Scotia Canada for acute lymphoblastic leukemia (28), acute myeloid leukemia (5), non-Hodgkin lymphoma (4) or Hodgkin lymphoma (2) after informed consent. DNA was extracted from 127 stool samples from timepoints before and during treatment were used for whole shotgun sequencing (Nextera XT). Sequences were cleaned of low quality, and human, and PhiX174 contaminate sequences (kneaddata pipeline). MetaPhlAn3 was used to profile the taxonomic composition of the microbial community. Samples were grouped by number of courses, none, 1-2, or ≥3, and by duration of courses, none, short (≤10 days), long/mixed (>10 days or mix of long and short) of β-lactams, vancomycin, or general antibiotic use. The abundance of phyla within these groups were compared using the Kruskal Wallis test (α<0.05) and post hoc Dunn test for pairwise comparison, corrected for multiple tests. This study was approved by the IWK ethics board. Results: The 39 patients include 22 males and 17 females, with 29 patients over the age of 3 and 10 patients under 3. Bacteroidetes phylum abundant in the gut were decreased when exposed to repeated courses of all antibiotic groups with none vs ≥3 courses (β-lactam p=0.0012; vancomycin p=0.0018; multiple antibiotic p=0.0021) and 1-2 courses vs ≥3 courses (β-lactam p=3.1E-6; vancomycin p=0.024; multiple antibiotic p=1.6E-8). We also noted an increase in Firmicutes in the children who received 1-2 courses vs ≥3 courses of β-lactam antibiotics (p=0.034). The phylum Proteobacteria was increased across those children who received 1-2 courses vs ≥3 courses (β-lactam p=8.1E-6; vancomycin p=0.0018; multiple antibiotic p=1.6E-5) and also increased in none vs ≥3 courses for vancomycin (p=3.8E-4). We noted differences in abundance based on duration of antibiotic treatment. For Bacteroidetes the abundance is higher in children who receive short course antibiotics vs those that receive longer course (>10 days) for β-lactam and multiple antibiotic (p=1.3E-6 and p=4.4E-7 respectively) and lower in children who receive short course vancomycin vs longer course (p=0.024). The Proteobacteria in the samples of children treated with β-lactam and multiple antibiotics showed higher abundance in those who received longer duration antibiotics (p=2.7E-5 and p=8.7E-6 respectively) whereas the children who received short courses of vancomycin showed higher counts (p=0.0018). No difference in Firmicute abundance was detected. Discussion: Concordant with the spectrum of β-lactam antibiotics, we saw a decrease in abundance of Bacteroidetes a predominately gram-negative gut bacterium. In contrast the Proteobacteria, a gram-negative phylum, was increased in children exposed to repeated courses of antibiotics. When we consider duration of antibiotic treatment, we see that the Bacteroidetes have higher prevalence in children who do not receive antibiotics or receive shorter course antibiotics indicating that this phylum is controlled by antibiotic treatment. In contrast, the Proteobacteria are more prevalent in children who receive longer duration of β-lactam. One limitation of this study was non-uniformity of stool sample collection due to logistical reasons in pediatric population. Conclusion: Repeated courses of antibiotics administered empirically to pediatric cancer patients with leukemia/lymphoma increases the relative abundance of certain gram-negative bacteria in the microbiome. Longer courses of the β-lactams and multi-antibiotic samples result in higher relative abundance of Proteobacteria potentially increasing infections in immunocompromised children. Further studies to determine optimum antibiotic duration and therapy are needed.

Viral infections in pediatric brain tumor patients treated with targeted therapies.

Brain tumors are the most common solid malignancies and the leading cause of cancer-related mortality in children. While numerous studies report on viral infections in children with hematologic malignancies and solid organ transplantation, epidemiologic data on the incidence and outcome of viral infections in pediatric patients with brain tumors treated with targeted therapies are still lacking. We retrospectively reviewed all children with brain tumors receiving targeted therapies in a primary or recurrent setting at the Medical University of Vienna from 2006 to 2021. Demographic variables, quantitative and qualitative parameters of possible infections, and treatment outcomes were recorded. In our cohort (n=117), 36% of the patients developed at least one PCR-proven viral infection. Respiratory and gastrointestinal tract infections were most common, with 31% and 25%, respectively. Central nervous system (CNS) infections occurred in approximately 10%, with an almost equal distribution of varicella-zoster virus, John Cunningham virus (JCV), and enterovirus. Two patients tested PCR-positive for SARS-CoV-2 infection, with one virus-related death caused by a SARS-CoV-2-related acute respiratory distress syndrome. Patients receiving bevacizumab or mTOR inhibitors seem to have a greater susceptibility to viral infections. Pediatric patients with brain tumors receiving targeted therapies have a higher risk of viral infections when compared to children receiving conventional chemotherapy or the general population, and life-threatening infections can occur. Fast detection and upfront treatment are paramount to prevent life-threatening infections in immunocompromised children suffering from brain tumors receiving targeted therapies.

P69 COVID vaccine uptake in young persons on immunosuppression under the care of tertiary paediatric rheumatology service

Introduction/BackgroundCOVID-19 disease, caused by SARS-CoV-2 virus, first emerged as a presentation of severe respiratory disease in 2019. Although children exhibit mild disease, concerns were raised about serious infection in immunocompromised children. The current national guidance recommends that immunocompromised children between 12 and 18 years of age should be offered three primary doses of the Pfizer BioNTech vaccine, 8 weeks apart, followed by a booster dose within 3 months. This audit looked at the awareness and uptake of this regime in young persons on immunosuppression. This information was disseminated to families during clinical contacts and automatic replies sent out from the team mailbox.Description/MethodTo collect the data for the audit, we used an anonymous questionnaire to capture the following information:• Diagnosis• Immunomodulatory/Immunosuppressive treatment• Their awareness of the regime for COVID vaccine (number of doses and interval)• Number of vaccines taken• If not taken, why?The questionnaires were handed out to 31 patients attending Paediatric Rheumatology day-care and outpatient clinics over a two-week period for their response. There were no non-responders. Patients who were not on any immunosuppressant medication were excluded.The split of their diagnoses and medications are summarised in tables 1 and 2:Patients with JIA (55%) unsurprisingly dominated the cohort, followed by JSLE, JDM and scleroderma. Only 3/31 patients (10%) were on any form of systemic steroid therapy (all on oral Prednisolone less than 0.5 mg/kg). Majority of the patients (21/31 – 68%) were on Methotrexate, either on its own, or in combination with one of the biologic agents (one scleroderma patient was on MTX + MMF). 14/21 (45%) patients were on one of the biologic agents, of which only one patient was on Rituximab.P69 Table 1:Patients' diagnosesDiagnosisNumber of respondentsJuvenile Idiopathic Arthritis (JIA)17 (2 – uveitis) – 55%Juvenile Systemic Lupus Erythematosus (JSLE)5 – 16%Juvenile Dermatomyositis (JDM)3 – 10%Localised scleroderma / Systemic Sclerosis3 – 10%ANCA Associated Vasculitis (AAV)1 – 3 %Systemic Autoinflammatory Disease2 (both Mevalonate Kinase deficiency) – 6%P69 Table 2:Patients' medicationsMedicationsNumber of respondentsSystemic steroids (on top of other medicines)3 (10%)Methotrexate (MTX)11 (35%)Methotrexate + Adalimumab6 (19%)Mycophenolate Mofetil (MMF)4 (13%)MTX + MMF1 (3%)Adalimumab3 (10%)MTX + Infliximab3 (10%)Canakinumab 2 (6%)Cyclophosphamide1 (3%)Discussion/ResultsThe results showed that only 6/31 (19%) of patients/their carers knew the correct number (3 + 1) of COVID vaccines recommended in this cohort. 18/31 (58%) patients had received the vaccine, of which 4 patients refused further doses due to side effects they had experienced following the first dose. Of the 13 young people who did not take the vaccine, 9 patients (29%) were unsure whether they need the vaccine. They did not know the benefits of the vaccine and were afraid it either could have a negative effect on immunocompromised children or just were not aware of the guidelines. The other 4 (13%) participants did not want to take the vaccine due to their own personal beliefs.Although concerns were raised about serious COVID-19 infection in immunocompromised children, there is currently very little evidence to suggest that the infection rate and severity of COVID-19 infection in children treated with Methotrexate or biologic agents is higher or the treatment needs to be discontinued or the doses adjusted. There is some emerging evidence to suggest that adults on Rituximab and to a lesser extend Mycophenolate may have increased risk of developing severe outcomes from COVID-19, which has not been replicated in children. The recommendation for third primary dose is based on preliminary results from UK studies of real-world vaccine effectiveness (VE) in persons who are immunosuppressed, suggesting a modest reduction in VE against symptomatic COVID-19. There is also emerging evidence that COVID vaccination significantly reduces the risk of Paediatric Inflammatory Multisystem Syndrome (PIMS-TS) in 12 – 18 year olds.Key learning points/ConclusionDespite the notion that the team had disseminated information on the vaccine regime to patients, only one fifth of the patients/carers knew the exact regime for COVID vaccine recommended in this group of young people.Just under 60% of the patients took the vaccine, with the rest choosing not to have it due to a mixture of lack of information and personal choice.The action plan was drawn up to:1. enquire about and document vaccination status, and provide advice and information during every clinical contact;2. include COVID vaccine in education sessions by nursing team;3. include the information as default in all clinic letters;4. reaudit in six months.

Antimicrobial Resistance in Staphylococcus Aureus and the Immunocompromised Child

Abstract: Staphylococcus aureus is a gram-positive bacterium. Many antibiotics are tried in opposition to S. aureus infection but in the end they all fail because of the multidrug resistance in this bacterium. Staphylococcus aureus are also responsible for many infections like skin and shock syndrome. From that point forward Methicillin-safe Staphylococcus aureus strains (MRSAMethicillin-resistant Staphylococcus aureus) were extremely normal which causes nosocomial diseases. Microorganisms for the need of the endurance goes through mutational changes either in their chromosomal DNA/RNA which gives the obstruction. One of the popular models is the obstruction against methicillin in Staphylococcus aureus. Due to high morbidness and death rate antimicrobial resistance becomes very challenging. Antimicrobial resistance (AMR) takes place when microscopic organisms like bacteria, virus, parasites swap over some period of time and they have no response to any medicines. This disease is difficult to treat and it causes the risk of death, different illnesses and also major infections. In this review paper, the difference between antimicrobial resistance and multidrug resistance, antibiotic resistance drugs, classification of multidrug resistance, mechanism of penicillin and methicillin in Staphylococcus aureus are going to be discussed. Due to their frequent contact with the healthcare system, requirement for empiric antimicrobials, and immunological dysfunction, children with immunocompromising diseases represent a special category for the acquisition of antimicrobial resistant infections. These infections are made more difficult by the relative dearth of information on the clinical characteristics and treatment of Staphylococcus aureus infections in children with impaired immune systems. Review of the literature that is currently accessible on the clinical characteristics, antimicrobial susceptibility, and treatment of S. aureus infections in immunocompromised children. Children with HIV are more likely to develop S. aureus infections, which are linked to higher HIV viral loads and more severe CD4 T-cell suppression. Additionally, children with HIV frequently develop staphylococcal infections that show a multidrug resistant phenotype.

Factors that predict severity of infection and seroconversion in immunocompromised children and adolescents with COVID-19 infection.

ObjectivesWe aimed to study the outcomes, severity, and seroconversion post SARS-CoV-2 infection in immunocompromised children and adolescents treated at our center.MethodFor this observational study, all pediatric patients who had COVID-19 infection from Sep-22-2020 to Nov-10-2021were identified by reviewing our laboratory records. Their charts were reviewed to determine clinical severity and outcome. Blood samples were drawn for anti-SARS-CoV-2 antibody assay. Serious COVID-19 infection (SVI) was defined if the patient had moderate, severe, or critical illness. A cutoff of 100 U/mL anti-SARS-CoV-2 antibodies was used to categorize low and high titer seroconversion.ResultsWe identified 263 pediatric patients with COVID-19; most (68%) were symptomatic: 5% had severe or critical infection, 25% were hospitalized, 12 required respiratory support, 12 were admitted to the ICU, and five patients (2%) died. Multivariable analysis revealed several factors that predict SVI: Age above 12 years (p=0.035), body mass index above 95th percentile (p=0.034), comorbid conditions (p=0.025), absolute neutrophil count ≤500(p=0.014) and absolute lymphocyte count ≤300 (p=0.022). Levels of anti-SARS-CoV-2 spike antibodies were obtained for 173 patients at a median of 94 days (range, 14–300) after PCR diagnosis; of them 142 (82%) patients seroconverted; the lowest seroconversion rate was observed in patients with hematological malignancies (79%). Our univariable model showed that the following factors were predictive of low titer: lower ANC, p=0.01; hematologic malignancy, p=0.023; receiving steroids in the last 14 days, p=0.032; time since last chemotherapy or immunosuppressive therapy less than 30 days, p=0.002; and being on active chemotherapy in the last 3 months prior to infection, p<0.001.ConclusionsSARS-CoV-2 antibodies developed in most immunocompromised patients with COVID-19 infection in our study. Mortality was relatively low in our patients. Our univariable and multivariable models showed multiple variables that predict severity of infections and antibody response post COVID-19 infection. These observations may guide choice of active therapy during infection and the best timing of vaccination in this high-risk population.

#14 Rapid, Non-Invasive Detection of Non-H. pylori Helicobacter Infections in Immunocompromised Children Using Microbial Cell-Free DNA Next Generation Sequencing in Plasma

Abstract Background Non-H. pylori Helicobacter (NHPH) infections are more common in immunocompromised hosts and are associated with chronic infection in patients with X-linked agammaglobulinemia. Enterohepatic Helicobacter spp. cause systemic disease including cellulitis, bacteremia, endocarditis, meningitis, arthritis, hepatobiliary disease, and enteritis. NHPH are fastidious gram-negative organisms and are rarely detected by culture or nucleic acid amplification tests in clinical laboratories, resulting in potentially poor clinical detection and treatment. We present data demonstrating the diagnostic advantage of using plasma microbial cell-free DNA Sequencing to rapidly identify NHPH to the species level. Method The Karius TestTM (KT) was developed and validated in Karius’s CLIA certified/CAP accredited lab (Redwood City, CA) and detects mcfDNA in plasma. Following DNA extraction, next-generation sequencing (NGS) is performed, and sequences are aligned to a curated database of &amp;gt; 1000 organisms. Microorganisms observed above background at statistically significant levels are reported and quantified in molecules per microliter (MPM). We conducted a retrospective review of KT detections of NHPH from December 2016-November 2021. A subset of pediatric patients (age &amp;lt;=21 years) was identified from this cohort. Available clinical information was extracted from the test requisition form. Results KT detected NHPH in 23 patients among 11 unique institutions in the span of 5 years, including 10 (43%) pediatric patients (Table 1). Nine of ten detections were quantified (Median 110 MPM; range 48-20932, MPM). The reference interval of mcfDNA abundance for all NHPH species (defined by the 97.5th %ile) in a cohort of 684 healthy subjects is 0 MPM (for comparison the reference interval for H. pylori is 42.2 MPM). The highest detection was H. magdeburgensis 20,932 MPM. Of the 10 patients, 8 were male and 2 were female and the mean age was 10.5 years (range 3-17). Nine of 10 patients had information regarding underlying diagnosis. There were 6 patients with primary immunodeficiency including 5 with X-linked agammaglobulinemia with a diverse manifestation of infections. Two patients had serial testing during the intercurrent infectious episode to monitor the response to treatment. Serial testing in one patient showed a dramatic decrease of NHPH mcfDNA from 27,907 MPM to 1,079 MPM over a 6-day span. Serial testing in a second patient showed a decrease of the NHPH mcfDNA from 124 MPM to an undetectable range 14 days later. Conclusion These cases highlight the potential use of rapid, non-invasive, plasma mcfDNA to diagnose and potentially monitor the response to treatment of infections caused by NHPH, especially in patients with primary immunodeficiency. NHPH are difficult to detect and identify using conventional microbiological methods and plasma mcfDNA NGS may play an important role in detecting these fastidious microorganisms and serial testing.

Combination of C-Reactive Protein and Procalcitonin in Distinguishing Fungal from Bacterial Infections Early in Immunocompromised Children.

Invasive fungal infection (IFI) is life-threatening in children with cancer and hematology disorders, especially when diagnosis and treatment are delayed. Conventional β-D-glucan and galactomannan tests have poor positive predictive values in the diagnosis of IFI in children with cancer. This study aims to access the diagnostic performance of C-reactive protein (CRP) and procalcitonin (PCT) in differentiating IFI from bacterial bloodstream infections in children with malignant and hematology disorders. CRP and PCT levels were measured in samples taken from patients between 12 and 24 h after fever onset, of which 24 and 102 were in the IFI and bacterial groups, respectively. We found that the CRP levels were much higher in the IFI group than the bacterial group (100.57 versus 40.04 mg/L, median, p < 0.001), while the PCT levels remained significantly lower (0.45 versus 1.29 μg/L, median, p = 0.007). Both CRP and PCT showed significant diagnostic utilities with an area under the curve (AUC) of 0.780 (95% CI, 0.664–0.896, p < 0.001) and 0.731 (95% CI, 0.634–0.828, p < 0.001) when using the cut-off values of 94.93 mg/L and 2.00 μg/L, respectively. However, the combined biomarker of CRP and PCT yielded a better diagnostic performance with an AUC of 0.934 (95% confidential interval (CI), 0.881–0.987, p < 0.001), which was significantly higher than that of CRP or PCT (both p < 0.001), with a sensitivity of 87.5% and a specificity of 87.3%. Our study demonstrates high levels of CRP combined with low PCT could differentiate IFI from bacterial bloodstream infections in immunocompromised children.

Integration of Interleukin-6 Improves the Diagnostic Precision of Metagenomic Next-Generation Sequencing for Infection in Immunocompromised Children.

The performance of metagenomic next-generation sequencing (mNGS) in identifying pathogens in immunocompromised children was not very clear. The purpose of this study is to assess the performance of mNGS in this population and to investigate whether the integration of serum cytokines and mNGS assay could improve diagnostic accuracy. We retrospectively collected the clinical data of pediatric patients who suffered febrile diseases and underwent mNGS determination simultaneously in the department of hematology/oncology between January 2019 and March 2021. Specimens were sent for conventional microbiological test (CMT), mNGS, and serum cytokine measurement in parallel. A total of 258 episodes of febrile diseases were enrolled, mNGS was positive in 224 cases, while CMT was positive in 78 cases. mNGS and CMT were both positive in 70 (27.1%) cases and were both negative in 26 (10.1%) cases. There were 154 (59.7%) cases positive by mNGS only while 8 (3.1%) were positive by CMT only. It was common that two or more pathogens were simultaneously detected by mNGS in a single specimen, with only 61 tests identified a single organism. Whether the organisms reported by mNGS were the microbiological etiology of infection was evaluated. Of the 224 cases with positive mNGS results, 135 (58.4%), 30 (13.0%), and 59 (28.6%) were considered as “probable,” “possible,” and “unlikely,” respectively. Patients with high IL-6 (≥ 390 pg/ml) were likely to be bacterial infection. Although mNGS reported mixed pathogens, 84.6% (33/39) and 83.3% (10/12) of patients presenting high IL-6 were confirmed as bacterial infection in the training and validation cohort, respectively. In conclusion, mNGS analysis demonstrates promising diagnostic potential in rapidly identifying clinically relevant pathogens. Given the detection of many clinically irrelevant organisms, the integration of IL-6 improves the precision of mNGS results interpretation.

185. Trends in Clinical Presentation and Antibiotic Resistance of Viridans Group Streptococci Bloodstream Infections in Immunocompromised Children

BackgroundLevofloxacin prophylaxis (LVXp) is recommended in children with severe neutropenia from underlying malignancy or hematopoietic cell transplantation (HCT). The impact of LVXp on the epidemiology of viridans group streptococcus bloodstream infections (VGS-BSI) is unknown. At our center, LVXp was prescribed to high-risk children with expected prolonged neutropenia (ANC < 100, > 7 days) as part of a clinical trial (2013-17) and routinely since November 2018. We aim to describe our local epidemiology, antibiotic susceptibilities, and clinical outcomes of VGS-BSI over time.MethodsVGS-BSI from 1/1/10-1/31/21 were identified via the laboratory database. Clinical data of patients followed at NCH with underlying malignancy, severe neutropenia, or HCT were extracted from the electronic health record. Available VGS isolates were subcultured, species identification confirmed by MALDI-ToF or 16s rDNA sequencing and susceptibility to penicillin (PCN), cefepime (CEF), vancomycin (VAN), and LVX performed via Etest per CLSI M100 guidelines. Non-parametric descriptive statistics were applied.ResultsOver a 10-yr period, 111 VGS-BSI occurred in 93 patients (Table 1); 15 (16%) patients had ≥ 2 VGS-BSI. 80 (86%) patients had fever and neutropenia (F&N); 26 (28%) required ICU care for vasopressors (N=17, 18%) or mechanical ventilation (N=10, 11%). Most VGS isolates were S. mitis/oralis group. In total, 15 (16%) patients received LVXp ≤ 6 months before VGS-BSI; 9 (10%) had breakthrough VGS-BSI while receiving LVXp and all isolates were LVX resistant. Figure 1 shows susceptibilities: overall, 24% of isolates had frank resistance to PCN, 19% CEF, 13% LVX; all were VAN susceptible. When evaluating for changes in susceptibilities over time, there was a significant difference in the proportion of LVX-resistant isolates (p=0.009, Cochran-Armitage χ 2), but not CEF (p=0.08) or PCN (p=0.86).Table 1. Demographic and Clinical Characteristics of Immunocompromised Children with Viridans Group Streptococci Bloodstream Infections (VGS-BSI) Figure 1. Antimicrobial Susceptibility Profile of Viridans Group Streptococci Bloodstream Isolates from Immunocompromised children, 2010-2021. Of 111 VGS-BSI reported during the study period from immunocompromised children, 83 (75%) were available for further testing. Antimicrobial susceptibility testing was performed by Etest and interpreted per CLSI M100. Susceptibility profiles to penicillin (PCN), cefepime (CEP) and, levofloxacin (LVX) are shown. Abbreviations: S—susceptible, I—intermediate, R—resistant. ConclusionBreakthrough, LVX-resistant VGS-BSI occurred in 10% of patients, most frequently in children with AML or HCT. Over time, there was a trend towards increased LVX resistance in the cohort. Routine antimicrobial testing and ongoing monitoring for emergence of resistance are warranted to inform local prophylaxis and empirical antibiotic strategies for high-risk children with F&N.Disclosures Monica I. Ardura, DO, MSCS, Shire (Grant/Research Support)

Management of episodes of febrile neutropenia in children with cancer. Consensus of the Latin American Society of Pediatric Infectious Diseases 2021

The Committee for Infections in Immunocompromised Children of Sociedad Latinoamericana de Infectología Pediátrica, presents this Consensus document, titled "Management of episodes of febrile neutropenia in children with cancer. Consensus of the Sociedad Latinoamericana de Infectología Pediátrica 2021". The document includes recommendations on prevention, prediction, diagnosis, treatment and prognosis of episodes of fever and neutropenia, including specific recommendations on: Analysis at admission; evaluation, adjustments and duration of antimicrobial therapies; diagnosis and management of invasive fungal infection; analysis of the main clinical source of infections; environmental conditions necessary for hospitals caring for children with cancer and chemoprophylaxis. Special emphasis has been placed on providing the best recommendations to optimize the management of episodes of fever and neutropenia in children with cancer, with equity and excellence through all the centers that treat these patients in Latin America.

Epidemiology, Diagnosis, and Treatment of Clostridioides difficile Infection in Immunocompromised Children.

Clostridioides difficile infection is very common in immunocompromised children. Management is confounded by frequent asymptomatic colonization, multiple alternative etiologies for gastrointestinal symptoms, and high rates of relapse. Important considerations include indications for testing, appropriate choice of diagnostic tests, antibiotic therapy for initial and subsequent episodes, and primary and secondary prevention.

Multiplex Real-Time Polymerase Chain Reaction on Sputum for the Diagnosis of Pneumocystis jirovecii Pneumonia in Children: A Retrospective Study.

BackgroundPneumocystis jirovecii pneumonia (PCP) is a serious opportunistic infection in immunocompromised children. Real-time polymerase chain reaction (PCR) is widely used for the diagnosis of PCP due to its good accuracy. However, the diagnostic performance of multiplex real-time PCR on sputum in children with PCP has never been explored.MethodsMedical records of 63 consecutive pediatric patients were analyzed retrospectively, including 13 cases with PCP and 50 with non-PCP pneumonia. Pneumocystis jirovecii (P. jirovecii) and other co-pathogens detected by multiplex real-time PCR in sputum samples were summarized. Using clinical composite diagnosis as the reference standard, we further compared the diagnostic performance of multiplex real-time PCR to combined serological markers (1,3)-β-D-glucan plus lactate dehydrogenase. Additionally, modifications of antimicrobial treatment for pediatric PCP patients after the report of multiplex real-time PCR results were reviewed.ResultsIn children with PCP, nonproductive cough and shortness of breath were more common, lymphocyte count in peripheral blood was markedly lower, and serum levels of (1,3)-β-D-glucan and lactate dehydrogenase were much higher than non-PCP group. Multiplex real-time PCR reached a sensitivity of 100% in diagnosing PCP, which was better than serum (1,3)-β-D-glucan plus lactate dehydrogenase (76.9%). Its specificity (98.0%) significantly surpassed serum (1,3)-β-D-glucan plus lactate dehydrogenase (84.4%). Furthermore, multiplex real-time PCR showed a good performance in identifying co-pathogens in sputum of pediatric PCP patients. Cytomegalovirus, Epstein–Barr virus and Streptococcus pneumoniae were the most common co-pathogens in these patients. Initial antimicrobial treatment was modified in 76.9% of children with PCP after the report of PCR results.ConclusionMultiplex real-time PCR on sputum is a diagnostic tool with good performance for the identification of P. jirovecii as well as co-pathogens in children with PCP. Sputum may be an alternative to bronchoalveolar lavage fluid for PCR assay in children when bronchoscopic examination is not feasible.