Recurrent Serratia marcescens osteomyelitis eight years after a contaminated open fracture: a case report and review of the literature.

Background: Serratia marcescens (S. marcescens) is an unusual cause of osteomyelitis. Infection may develop following open trauma, intravenous drug abuse, or in the presence of hardware, but osteoarticular infections outside of this context are atypical in the absence of immunodeficiency. Rarely, a chronic indolent infection may develop after open trauma with disease recurrence years after the initial injury. Case Description: We present the case of a 16-year-old male with extensive left lower extremity osteomyelitis secondary to S. marcescens eight years after an open fracture to this leg was complicated by an infection with the same organism. Suboptimal therapy of his initial infection may have contributed to persistent, latent disease before recurrence years later. Evaluation for immunodeficiency was negative and he responded well to ciprofloxacin antibiotic therapy. Conclusions: S. marcescens infection may complicate open fractures, and, if not adequately treated, a chronic, indolent infection may result, with disease recurrence years later. We stress the importance of adequate therapy for infectious complications following open fractures and discuss virulence factors of S. marcescens that may allow this organism to evade the immune system and survive subclinically within a host. The optimal therapy of S. marcescens osteomyelitis is not established and further studies are needed to best guide the therapeutic approach.

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

OBJECTIVE: To describe the use of cidofovir (CDV) for viral infections in immunocompromised children (IC) and provide guidance on dosing and supportive care. DATA SOURCES: A PubMed search was conducted for literature published between 1997 and January 2022 using the following terms: cidofovir, plus children or pediatrics. STUDY SELECTION AND DATA EXTRACTION: 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 SYNTHESIS: 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. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: To our knowledge, this is the first comprehensive review of CDV use (indications, dosing, supportive care, response, and nephrotoxicity) in pediatric IC. CONCLUSIONS: 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.

Unusual presentation of disseminated cryptococcal infection complicated by myocarditis in a heart transplant recipient.

BACKGROUND: Cryptococcus neoformans is the third most common cause of invasive fungal infection in solid organ transplant (SOT) recipients. While cryptococcal infection can involve any organ, cases of myocarditis are exceedingly rare. METHODS: A retrospective chart review was completed for this case report. RESULTS: We present the case of a 21-year-old heart transplant recipient who developed disseminated cryptococcal infection with biopsy-proven cryptococcal myocarditis. CONCLUSIONS: Cryptococcal disease in SOT recipients poses diagnostic and therapeutic challenges. There are no current guidelines for the duration of cryptococcal myocarditis treatment. Repeat myocardial biopsy may play a role in guiding length of therapy.

The Yield, Safety, and Cost-effectiveness of Decreasing Repeat Blood Cultures Beyond 48 Hours in a Pediatric Hematology-Oncology Unit.

Clear recommendations are needed on when repeat blood cultures (BCxs) in hospitalized children with cancer should be obtained. We reviewed all BCx obtained on the Hematology-Oncology Unit at Riley Hospital for Children, regardless of reason for patient admission or neutropenia status, between January 2015 and February 2021. Patients with positive BCx within 48 hours of initial cultures, history of stem cell transplant, or admitted to the intensive care unit were excluded. Medical records of patients with new positive BCx drawn >48 hours after initial BCx were reviewed. Seven (1.2%) hospitalization episodes grew new pathogens, or commensals treated as pathogens, on cultures beyond 48 hours. All patients with new, true pathogens were hemodynamically unstable or had recurrent fever when the new positive BCx was obtained. Twenty-three (4.0%) hospitalization episodes had contaminant cultures beyond 48 hours, with 74 (5.4%) of 1362 BCx collected beyond 48 hours being contaminated, resulting in an additional cost of $210,519 from increased length of stay. In conclusion, repeat BCx beyond 48 hours in pediatric hematology-oncology patients with negative initial cultures are low yield and costly. Repeat BCx can be safely and cost-effectively ceased after 48 hours of negative cultures in hemodynamically and clinically stable patients.

Absolute Monocyte Count as Early and Safe Marker for Antibiotic Cessation in Febrile Neutropenia Without Etiology in Pediatric Oncology Patients.

BACKGROUND: There is no practice standard regarding antibiotic duration in children with cancer and unexplained febrile neutropenia (FN). We hypothesized that absolute monocyte count (AMC) and absolute phagocyte count (APC= ANC + AMC + bands) are more sensitive, earlier, and safe markers of antibiotic cessation compared with absolute neutrophil count (ANC). METHODS: A retrospective review of FN episodes (FNEs) in pediatric oncology patients was conducted between 2009 and 2016. Included patients were afebrile for 24 hours and without an identified infectious source at antibiotic cessation. Primary endpoints, including recurrent fever, readmission, bloodstream infection, microbiologically documented infection, and adverse outcomes, were assessed 10 days after antibiotic cessation and compared among different bone marrow recovery parameters (ANC, AMC, APC). Secondary endpoints included length of FN stay, antibiotic-free days, and cost. RESULTS: Three hundred ninety-one FNEs in 235 patients were included. Three groups were compared based on ANC (cells/µL) at the time of antibiotic cessation: < 200 in 102 (26%), 200 to 500 in 111 (28%), and >500 in 178 (46%). No statistically significant differences in primary endpoints were identified among the 3 ANC groups; however, a trend toward unfavorable outcomes in the ANC ≤200 cells/µL group compared with the ANC >200 cells/µL was observed. Primary endpoints based on AMC >100 cells/µL at the time of antibiotic cessation showed statistically significant favorable outcomes compared AMC ≤100 cells/µL (80%, 88%, 90%, 89%, and 93% risk reduction in recurrent fever, readmission, new bloodstream infection, new microbiologically documented infection, and adverse events, respectively). Similar favorable results were seen when APC >300 cells/µL was used as a threshold for antibiotic cessation. The median length of stay for FN if discharged when AMC >100 cells/µL was 3 days shorter and associated with fewer unfavorable outcomes, thus resulting in fewer hospital days, fewer antibiotic days, and decreased cost. CONCLUSION: Our results suggest that AMC >100 cells/µL (regardless of ANC) or APC >300 cells/µL may be safe thresholds for empiric antibiotic cessation and result in reduced unfavorable clinical outcomes within 10 days postdischarge, reduced antibiotic days of therapy and reduced health care costs. Further prospective studies are needed to validate AMC as an accurate surrogate marker for antibiotic cessation in FNEs in children with cancer.

High frequency of viridians group streptococci bacteremia in pediatric neuroblastoma high-risk patients during induction chemotherapy.

Existing literature on febrile neutropenia (FN) has categorized patients with acute leukemia or those undergoing allogeneic stem cell transplantation (SCT) as being high risk for severe infection, bacteremia, and poor outcomes. Comprehensive studies of infection risk in pediatric high-risk neuroblastoma (NB-HR) during induction chemotherapy are limited, and mostly merged within the solid tumor (ST) group. Therefore, it is unclear whether infectious complications and outcomes for NB-HR are the same as in other ST groups. We conducted a retrospective medical record review of pediatric FN patients in a single center from March 2009 to December 2016. FN episodes were categorized into five groups based on underlying diagnosis (acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), NB-HR during induction chemotherapy, other solid tumors, and SCT). Comparative analyses of infectious complications between patients with NB-HR and those with other types of cancer diagnoses were performed. A total of 667 FN episodes (FNEs) were identified in 230 patients. FNEs occurred in 82 episodes with NB-HR. Bloodstream infection (BSI) occurred in 145 (21.7%) of total FN episodes. The most isolated organisms were the viridians group streptococci (VGS) (25%). NB-HR patients have higher rates of VGS bacteremia (OR 0.15, 95% [CI 0.04, 0.56]) and are more likely to be admitted to the Pediatric Intensive Care Unit (PICU) compared to patients with other solid tumors (OR 0.36, 95% [CI 0.15, 0.84]). Interestingly, there is no difference in VGS rates between patients with NB-HR and those with AML despite the fact that NB-HR patients do not receive a cytosine arabinoside (AraC)-based regimen. This large neuroblastoma cohort showed that patients with NB-HR during induction chemotherapy are at higher risk for VGS bacteremia and PICU admissions compared with patients with other solid tumors. Further prospective studies are needed to investigate infection-related complications in this high-risk group and to improve morbidity and mortality.

A prediction model for bacteremia and transfer to intensive care in pediatric and adolescent cancer patients with febrile neutropenia.

Febrile neutropenia (FN) is a common condition in children receiving chemotherapy. Our goal in this study was to develop a model for predicting blood stream infection (BSI) and transfer to intensive care (TIC) at time of presentation in pediatric cancer patients with FN. We conducted an observational cohort analysis of pediatric and adolescent cancer patients younger than 24 years admitted for fever and chemotherapy-induced neutropenia over a 7-year period. We excluded stem cell transplant recipients who developed FN after transplant and febrile non-neutropenic episodes. The primary outcome was onset of BSI, as determined by positive blood culture within 7 days of onset of FN. The secondary outcome was transfer to intensive care (TIC) within 14 days of FN onset. Predictor variables include demographics, clinical, and laboratory measures on initial presentation for FN. Data were divided into independent derivation (2009-2014) and prospective validation (2015-2016) cohorts. Prediction models were built for both outcomes using logistic regression and random forest and compared with Hakim model. Performance was assessed using area under the receiver operating characteristic curve (AUC) metrics. A total of 505 FN episodes (FNEs) were identified in 230 patients. BSI was diagnosed in 106 (21%) and TIC occurred in 56 (10.6%) episodes. The most common oncologic diagnosis with FN was acute lymphoblastic leukemia (ALL), and the highest rate of BSI was in patients with AML. Patients who had BSI had higher maximum temperature, higher rates of prior BSI and higher incidence of hypotension at time of presentation compared with patients who did not have BSI. FN patients who were transferred to the intensive care (TIC) had higher temperature and higher incidence of hypotension at presentation compared to FN patients who didn't have TIC. We compared 3 models: (1) random forest (2) logistic regression and (3) Hakim model. The areas under the curve for BSI prediction were (0.79, 0.65, and 0.64, P < 0.05) for models 1, 2, and 3, respectively. And for TIC prediction were (0.88, 0.76, and 0.65, P < 0.05) respectively. The random forest model demonstrated higher accuracy in predicting BSI and TIC and showed a negative predictive value (NPV) of 0.91 and 0.97 for BSI and TIC respectively at the best cutoff point as determined by Youden's Index. Likelihood ratios (LRs) (post-test probability) for RF model have potential utility of identifying low risk for BSI and TIC (0.24 and 0.12) and high-risk patients (3.5 and 6.8) respectively. Our prediction model has a very good diagnostic performance in clinical practices for both BSI and TIC in FN patients at the time of presentation. The model can be used to identify a group of individuals at low risk for BSI who may benefit from early discharge and reduced length of stay, also it can identify FN patients at high risk of complications who might benefit from more intensive therapies at presentation.

Case Series of False-Positive HIV Test Results in Pediatric Acute Lymphoblastic Leukemia Patients Following Chimeric Antigen Receptor T-Cell Therapy: Guidance on How to Avoid and Resolve Diagnostic Dilemmas.

Chimeric antigen receptor T-cell (CAR-T) Cell Therapy is approved for the treatment of pediatric patients with relapsed/refractory acute lymphoblastic leukemia B-ALL. Lentiviral vector technology, highly modified from HIV-1, is used to induce stable, long-term transgene expression by integration into the host genome. This integration may interfere with HIV-1 NAAT producing false-positive results. Guidance for HIV diagnostic testing in pediatric B-ALL undergoing this type of therapy is lacking. Herein, we report case series with presented scenarios in which HIV-1 NAAT testing among CAR-T cell patients produced false-positive results, highlighting the importance careful assay selection and performance among this patient population.

Pediatric Invasive Fungal Risk Score in Cancer and Hematopoietic Stem Cell Transplantation Patients With Febrile Neutropenia.

BACKGROUND: Invasive fungal diseases (IFDs) are opportunistic infections that result in significant morbidity and mortality in pediatric oncology patients. Predictive risk tools for IFD in pediatric cancer are not available. METHODS: We conducted a 7-year retrospective study of pediatric oncology patients with a diagnosis of febrile neutropenia at UCM Comer Children's Hospitals. Fourteen clinical, laboratory, and treatment-related risk factors for IFD were analyzed. Stepwise variable selection for multiple logistic regression was used to develop a risk prediction model for IFD. Two comparative analyses have been conducted: (i) all suspected IFD cases and (ii) all proven and probable IFD cases. RESULTS: A total of 667 febrile neutropenia episodes were identified in 265 patients. IFD was diagnosed in 62 episodes: 13 proven, 27 probable, and 22 possible. In the final multiple logistic regression models, 5 variables were independently significant for both analyses: fever days, neutropenia days, hypotension, and absolute lymphocyte count <250 at the time of diagnosis. The odds ratio and a relative weight for each factor were then calculated and summed to calculate a predictive score. A risk score of ≤4 and ≤5 (10/11 maximum) for each model signifies low risk, respectively (<1.2% incidence). Model discrimination was evaluated by the area under the receiver operator characteristics curve with an area under the curve of 0.95/0.94 for each model. CONCLUSION: Our prediction IFD risk models perform well, are easy-to-use, and are based on readily available clinical data. Profound lymphopenia absolute lymphocyte count <250 mm3 could serve as a new important prognostic marker for the development of IFD in pediatric cancer and hematopoietic stem cell transplant patients.

Febrile Neutropenia Syndromes in Children: Risk Factors and Outcomes of Primary, Prolonged, and Recurrent Fever.

BACKGROUND: The approach to recurrent febrile neutropenia (FN) in children with cancer has not been sufficiently addressed and was cited as a research gap in the International Pediatric Fever and Neutropenia (IPFNP) Guideline 2017. METHODS: Retrospective medical record review for all pediatric cancer patients with a diagnosis of FN was performed. Variables were collected at 2 different time sets (at day 1 and day 4 of presentation). Three FN syndromes have been defined based on the duration and time course of the fever: (1) primary: fever resolved before 96 hours and did not follow with recurrent fever; (2) prolonged fever: episodes failing to defervesce after at least 96 hours of antibacterial therapy; (3) recurrent fever: a new episode of fever >72 hours after resolution of the initial fever when a patient remained neutropenic and on antibiotics or if a fever developed within 1 week after antibiotic discontinuation. These entities were compared with define risk factors and adverse outcomes associated with recurrent fever. RESULTS: A total of 633 FN episodes (FNEs) were identified in 268 patients. Each FNE was classified as primary (n=453, 71.5%), prolonged (n=119, 18.7%), or recurrent (n=61, 9.7%). In multivariable analysis, acute myelogenous leukemia (odds ratio [OR]=4.6, 95% confidence interval [CI]: 2.95-7.24), allogeneic stem cell transplant (SCT) (OR=4.9, 95% CI: 2.61-7.35), absolute lymphocyte count <300/mm3 (OR=3.8, 95% CI: 1.30-5.02), prior neutropenia of ≥10 days, (OR=3.95, 95% CI: 1.70-5.93) and hypotension (OR=3.65, 95% CI: 1.30-5.86) on day 1 of presentation were all associated with an increased risk of recurrent fever when compared with primary fever. In subset analysis for only the high-risk FN group, hypotension (OR=3.2, 95% CI: 1.80-4.96), prior neutropenia ≥10 days (OR=2.55, 95% CI: 1.40-6.22), and absolute lymphocyte count <300/mm3 at presentation (OR=2.6, P=0.03, 95% CI: 2.65-7.12) were associated with an increased risk of recurrent fever when compared with high-risk FN not developing recurrent fever. Allogeneic SCT (OR=5.9, 95% CI: 2.65-7.12) and prior neutropenia ≥10 days (OR=2.11, 95% CI: 1.25-9.32) were significantly associated with recurrent fever when compared with prolonged fever. Invasive fungal disease was a more common etiology with recurrent fever compared with primary and prolonged fever (P=0.001 and 0.01, respectively). Recurrent fever episodes were more likely to be admitted to the pediatric intensive care unit (OR=3, 95% CI: 1.27-6.23) and had a higher 30-day mortality (OR=8, 95% CI: 1.87-71.85) when compared with primary fever. CONCLUSIONS: Knowledge of risk factors for recurrent fever may enable the early detection infection-related complications of this high-risk group, and possible improved approaches to treatment resulting in decreased morbidity and mortality.

Pediatric Febrile Neutropenia: Change in Etiology of Bacteremia, Empiric Choice of Therapy and Clinical Outcomes.

BACKGROUND: The optimal choice of initial antibiotic therapy for patients with high-risk febrile neutropenia (FN) in children is unclear and varies by the institution on the basis of local antibiograms and epidemiology of specific pathogens. The authors evaluated the appropriateness of antibiotics for the empiric treatment of FN in pediatric patients with cancer in our institution on the basis of changes in the epidemiology of organisms isolated from blood cultures (BCx). METHODS: The authors conducted a retrospective medical record review of pediatric patients who received any oncology care (including patients with cancer and patients who had stem cell transplant) at University of Chicago Medicine Comer Children's Hospitals (March 2009 to December 2016) with a diagnosis of FN who had at least 1 BCx obtained. They reviewed pathogens isolated from BCx and determined whether they were pathogens or contaminants using the Infectious Diseases Society of America (IDSA) guidelines and the team's decision to treat. They investigated the microbiologic spectrum and susceptibility patterns of pathogens causing bacteremia in pediatric FN and whether the empiric therapy chosen may have affected clinical outcomes. RESULTS: A total of 667 FN episodes were identified in 268 patients. BCx were negative in 497 (74.5%) and were determined to be contaminants in 27 (4%). In 143 episodes (21.5%), the BCx were positive for a pathogenic species. Polymicrobial bacteremia was identified in 25 episodes; a total of 176 pathogens were isolated. The majority of pathogens (95/176, 54%) were Gram-positive (GP), whereas 64 of 162 (36%) were Gram-negative (GN), 5 were fungal, and 4 were mycobacterial. The most common GP pathogens were viridans group streptococci (VGS) (n=34, 19.3%), coagulase-negative staphylococci (n=25, 14%), and methicillin-susceptible Staphylococcus aureus (n=12, 6.8%). Of aerobic GN bacilli, 15 (8.5%) were AmpC producers and 3 (1.7%) carried extended-spectrum beta-lactamases. There was no increase in the prevalence of multidrug-resistant GN isolates during the study period. Patients with VGS and multidrug-resistant GN bacteremia were more likely to be admitted to the pediatric intensive care unit [odds ratio (OR), 3.24; P=0.017; and OR, 2.8; P=0.07, respectively]. There were trends toward a higher prevalence of GP pathogens causing bacteremia and the emergence of VGS with decreased penicillin sensitivity. The prevalence of bacteremia with VGS was higher in acute myelogenous leukemia and neuroblastoma (OR, 2.3; P<0.01) than in patients with other solid tumors. CONCLUSIONS: Empiric antibiotic treatment should be tailored to patients' risk for VGS and multidrug-resistant organisms. Individual hospitals should monitor the pathogens causing FN among patients with cancer to guide choice of empiric therapy.

Association Between Depth of Neutropenia and Clinical Outcomes in Febrile Pediatric Cancer and/or Patients Undergoing Hematopoietic Stem-cell Transplantation.

BACKGROUND: Infectious Diseases Society of America guidelines defines febrile neutropenia (FN) patients as high risk, if they have an absolute neutrophil count (ANC) ≤100 cells/µL anticipated to last >7 days. However, data evaluating the clinical significance of the depth and duration of neutropenia are limited. METHODS: We conducted a retrospective cohort study of pediatric oncology patients presenting with FN to examine whether the effects of the depth and duration of neutropenia prior to presentation were predictive of blood stream infection (BSI), invasive fungal disease (IFD), pediatric intensive care unit (PICU) admission or length of stay. RESULTS: A total of 585 FN episodes (FNEs) were identified in 265 patients. ANC at the time of presentation was <100 in 411 (70%), 100-500 in 119 (20%), and >500 cells/µL with subsequent decline to <500 cells/µL in the next 48 hours in 55 (10%) of FNEs. In the group with ANC > 500 with subsequent decline in 48 hours, rates of IFD and BSI were higher when compared with ANC < 100 cells/µL [odds ratio (OR) = 5.9, 95% confidence interval (CI): 0.7-29.6] and (OR = 2.35, 95% CI: 01.02-5.4), and patients in this group were more likely to be admitted to the PICU (OR= 5.1, 95% CI: 1.134-19.46). No difference in outcomes was identified when the groups of ANC < 100 and ANC of 100-500 cells/µL were compared. Neutropenia >7 days prior to FNE was an independent risk factor for BSI (OR = 2.88, 95% CI: 1.55-5.35 and increased length of stay. CONCLUSIONS: Clinicians should not be reassured when patients present with FN and initial ANC >500 cells/mL after recent chemotherapy if continued decline is expected as patients in this group are at high risk of IFD, BSI and PICU admission.

Cerebellar swelling due to familial hemophagocytic lymphohistiocytosis: An unusual presentation.

BACKGROUND: Cerebellar swelling with obstructive hydrocephalus is a rare but life threatening condition, associated with different etiologies, familial hemophagocytic lymphohistiocytosis (HLH) being rarely one of them. PATIENT: 2-year-7-month old boy presented with irritability, cerebellar dysfunction, and somnolence. Brain MRI showed marked diffuse cerebellar swelling and obstructive hydrocephalus with mild tonsillar herniation. Laboratory testing revealed pancytopenia, elevated liver enzymes, elevated ferritin and triglycerides levels and decreased fibrinogen. The diagnosis of familial HLH was confirmed by the presence of homozygous missense mutation of Syntaxin 11 gene. The child was treated with HLH-2004 protocol of chemotherapy followed by allogenic stem cell transplantation. His neurological condition improved significantly after treating the underlying disease. CONCLUSION: Cerebellar swelling is a rare manifestation of familial HLH. High degree of clinical suspicion may allow a timely diagnosis and appropriate therapy.