The Durability of Antibody Responses of Two Doses of High-Dose Relative to Two Doses of Standard-Dose Inactivated Influenza Vaccine in Pediatric Hematopoietic Cell Transplant Recipients: A Multi-Center Randomized Controlled Trial.

BACKGROUND: Our previous study established a 2-dose regimen of high-dose trivalent influenza vaccine (HD-TIV) to be immunogenically superior compared to a 2-dose regimen of standard-dose quadrivalent influenza vaccine (SD-QIV) in pediatric allogeneic hematopoietic cell transplant (HCT) recipients. However, the durability of immunogenicity and the role of time post-HCT at immunization as an effect modifier are unknown. METHODS: This phase II, multi-center, double-blinded, randomized controlled trial compared HD-TIV to SD-QIV in children 3-17 years old who were 3-35 months post-allogeneic HCT, with each formulation administered twice, 28-42 days apart. Hemagglutination inhibition (HAI) titers were measured at baseline, 28-42 days following each dose, and 138-222 days after the second dose. Using linear mixed effects models, we estimated adjusted geometric mean HAI titer ratios (aGMR: HD-TIV/SD-QIV) to influenza antigens. Early and late periods were defined as 3-5 and 6-35 months post-HCT, respectively. RESULTS: During 3 influenza seasons (2016-2019), 170 participants were randomized to receive HD-TIV (n = 85) or SD-QIV (n = 85). HAI titers maintained significant elevations above baseline for both vaccine formulations, although the relative immunogenic benefit of HD-TIV to SD-QIV waned during the study. A 2-dose series of HD-TIV administered late post-HCT was associated with higher GMTs compared to the early post-HCT period (late group: A/H1N1 aGMR = 2.16, 95% confidence interval [CI] = [1.14-4.08]; A/H3N2 aGMR = 3.20, 95% CI = [1.60-6.39]; B/Victoria aGMR = 1.91, 95% CI = [1.01-3.60]; early group: A/H1N1 aGMR = 1.03, 95% CI = [0.59-1.80]; A/H3N2 aGMR = 1.23, 95% CI = [0.68-2.25]; B/Victoria aGMR = 1.06, 95% CI = [0.56-2.03]). CONCLUSIONS: Two doses of HD-TIV were more immunogenic than SD-QIV, especially when administered ≥6 months post-HCT. Both groups maintained higher titers compared to baseline throughout the season. CLINICAL TRIALS REGISTRATION: NCT02860039.

Strategic infection prevention after genetically modified hematopoietic stem cell therapies: recommendations from the International Society for Cell & Gene Therapy Stem Cell Engineering Committee.

There is lack of guidance for immune monitoring and infection prevention after administration of ex vivo genetically modified hematopoietic stem cell therapies (GMHSCT). We reviewed current infection prevention practices as reported by providers experienced with GMHSCTs across North America and Europe, and assessed potential immunologic compromise associated with the therapeutic process of GMHSCTs described to date. Based on these assessments, and with consensus from members of the International Society for Cell & Gene Therapy (ISCT) Stem Cell Engineering Committee, we propose risk-adapted recommendations for immune monitoring, infection surveillance and prophylaxis, and revaccination after receipt of GMHSCTs. Disease-specific and GMHSCT-specific considerations should guide decision making for each therapy.

Description of a national, multi-center registry of patients with sickle cell disease and SARS-CoV-2 infection: Data from the Pediatric COVID-19 United States Registry.

Children with sickle cell disease (SCD) are at risk of complications from viral infections, including SARS-CoV-2. We present the clinical characteristics and outcomes of pediatric patients with SCD from the Pediatric COVID-19 United States Registry who developed acute COVID-19 due to SARS-CoV-2 infection (n = 259) or multisystem inflammatory syndrome in children (MIS-C; n = 4). Nearly half of hospitalized children with SCD and SARS-CoV-2 infection required supplemental oxygen, though children with SCD had fewer intensive care (ICU) admissions compared to the general pediatric and immunocompromised populations. All registry patients with both SCD and MIS-C required ICU admission. Children with SCD are at risk of severe disease with SARS-CoV-2 infection, highlighting the importance of vaccination in this vulnerable population.

Body surface area compared to body weight dosing of valganciclovir is associated with increased toxicity in pediatric solid organ transplantation recipients.

Optimal dosing of valganciclovir (VGCV) for cytomegalovirus (CMV) prevention in pediatric solid organ transplantation recipients (SOTR) is controversial. Dosing calculated based on body surface area (BSA) and creatinine clearance is recommended but simplified body weight (BW) dosing is often prescribed. We conducted a retrospective 6-center study to compare safety and efficacy of these strategies in the first-year posttransplant There were 100 (24.2%) pediatric SOTR treated with BSA and 312 (75.7%) with BW dosing. CMV DNAemia was documented in 31.0% vs 23.4% (P = .1) at any time during the first year and breakthrough DNAemia in 16% vs 12.2% (P = .3) of pediatric SOTR receiving BSA vs BW dosing, respectively. However, neutropenia (50% vs 29.3%, P <.001), lymphopenia (51% vs 15.0%, P <.001), and acute kidney injury causing treatment modification (8.0% vs 1.8%, P <.001) were documented more frequently during prophylaxis in pediatric SOTR receiving BSA vs BW dosing. The adjusted odds ratio of VGCV-attributed toxicities comparing BSA and BW dosing was 2.3 (95% confidence interval [CI], 1.4-3.7] for neutropenia, 7.0 (95% CI, 3.9-12.4) for lymphopenia, and 4.6 (95% CI, 2.2-9.3) for premature discontinuation or dose reduction of VGCV, respectively. Results demonstrate that BW dosing is associated with significantly less toxicity without any increase in CMV DNAemia.

Allogeneic CD34+ selected hematopoietic stem cell boost following CAR T-cell therapy in a patient with prolonged cytopenia and active infection.

Hematological toxicity (hematotoxicity) leading to peripheral cytopenias is a common long-term adverse effect following the use of CD19-chimeric antigen receptor (CD19-CAR) T-cell therapies. However, management remains unclear for patients whose cytopenias persist beyond 1 month after CAR T-cell infusion. We present the case of a 21-year old who received CD19-CAR T-cell therapy for relapse following a haploidentical transplant. He developed hematotoxicity and consequently multiple life-threatening infections. We administered a CD34+ hematopoietic stem cell boost (HSCB) from his transplant donor, which led to hematopoietic recovery and resolution of his infections without any effect on the activity of CD19-CAR T cells. CD34+ HSCB can be a safe and effective option to treat hematotoxicity following CD19-CAR T-cell therapy.

Fluoroquinolone prophylaxis in patients with neutropenia at high risk of serious infections: Exploring pros and cons.

BACKGROUND: The use of fluoroquinolones to prevent infections in neutropenic patients with cancer or undergoing hematopoietic stem cell transplantation (HSCT) is a controversial issue, with international guidelines providing conflicting recommendations. Although potential benefits are clear, concerns revolve around efficacy, potential harms, and antimicrobial resistance (AMR) implications. DISCUSSION: Fluoroquinolone prophylaxis reduces neutropenic fever (NF) bloodstream infections and other serious bacterial infections, based on evidence from systematic reviews, randomized controlled trials, and observational studies in adults and children. Fluoroquinolone prophylaxis may also reduce infection-related morbidity and healthcare costs; however, evidence is conflicting. Adverse effects of fluoroquinolones are well recognized in the general population; however, studies in the cancer cohort where it is used for a defined period of neutropenia have not reflected this. The largest concern for routine use of fluoroquinolone prophylaxis remains AMR, as many, but not all, observational studies have found that fluoroquinolone prophylaxis might increase the risk of AMR, and some studies have suggested negative impacts on patient outcomes as a result. CONCLUSIONS: The debate surrounding fluoroquinolone prophylaxis calls for individualized risk assessment based on patient characteristics and local AMR patterns, and prophylaxis should be restricted to patients at the highest risk of serious infection during the highest risk periods to ensure that the risk-benefit analysis is in favor of individual and community benefit. More research is needed to address important unanswered questions about fluoroquinolone prophylaxis in neutropenic patients with cancer or receiving HSCT.

Evolution of vancomycin-resistant Enterococcus faecium during colonization and infection in immunocompromised pediatric patients.

Patients with hematological malignancies or undergoing hematopoietic stem cell transplantation are vulnerable to colonization and infection with multidrug-resistant organisms, including vancomycin-resistant Enterococcus faecium (VREfm). Over a 10-y period, we collected and sequenced the genomes of 110 VREfm isolates from gastrointestinal and blood cultures of 24 pediatric patients undergoing chemotherapy or hematopoietic stem cell transplantation for hematological malignancy at St. Jude Children's Research Hospital. We used patient-specific reference genomes to identify variants that arose over time in subsequent gastrointestinal and blood isolates from each patient and analyzed these variants for insight into how VREfm adapted during colonization and bloodstream infection within each patient. Variants were enriched in genes involved in carbohydrate metabolism, and phenotypic analysis identified associated differences in carbohydrate utilization among isolates. In particular, a Y585C mutation in the sorbitol operon transcriptional regulator gutR was associated with increased bacterial growth in the presence of sorbitol. We also found differences in biofilm-formation capability between isolates and observed that increased biofilm formation correlated with mutations in the putative E. faecium capsular polysaccharide (cps) biosynthetic locus, with different mutations arising independently in distinct genetic backgrounds. Isolates with cps mutations showed improved survival following exposure to lysozyme, suggesting a possible reason for the selection of capsule-lacking bacteria. Finally, we observed mutations conferring increased tolerance of linezolid and daptomycin in patients who were treated with these antibiotics. Overall, this study documents known and previously undescribed ways that VREfm evolve during intestinal colonization and subsequent bloodstream infection in immunocompromised pediatric patients.

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

BACKGROUND: Diagnosis of invasive candidiasis (IC) relies on insensitive cultures; the relative utility of fungal biomarkers in children is unclear. METHODS: This multinational observational cohort study enrolled patients aged >120 days and <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)-ß-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. RESULTS: 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%). CONCLUSIONS: 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. CLINICAL TRIALS REGISTRATION: NCT02220790.

A consensus conference to define the utility of advanced infectious disease diagnostics in solid organ transplant recipients.

The last decade has seen an explosion of advanced assays for the diagnosis of infectious diseases, yet evidence-based recommendations to inform their optimal use in the care of transplant recipients are lacking. A consensus conference sponsored by the American Society of Transplantation (AST) was convened on December 7, 2021, to define the utility of novel infectious disease diagnostics in organ transplant recipients. The conference represented a collaborative effort by experts in transplant infectious diseases, diagnostic stewardship, and clinical microbiology from centers across North America to evaluate current uses, unmet needs, and future directions for assays in 5 categories including (1) multiplex molecular assays, (2) rapid antimicrobial resistance detection methods, (3) pathogen-specific T-cell reactivity assays, (4) next-generation sequencing assays, and (5) mass spectrometry-based assays. Participants reviewed and appraised available literature, determined assay advantages and limitations, developed best practice guidance largely based on expert opinion for clinical use, and identified areas of future investigation in the setting of transplantation. In addition, attendees emphasized the need for well-designed studies to generate high-quality evidence needed to guide care, identified regulatory and financial barriers, and discussed the role of regulatory agencies in facilitating research and implementation of these assays. Findings and consensus statements are presented.

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1.

BACKGROUND: Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia. METHODS: We performed a dual-center, phase 1-2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1. RESULTS: Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven. CONCLUSIONS: Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, NCT01512888.).

Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis.

BACKGROUND: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. METHODS: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review. RESULTS: We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment. CONCLUSIONS: Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).

Early pulmonary complications related to cancer treatment in children.

In this review, we summarize early pulmonary complications related to cancer therapy in children and highlight characteristic findings on imaging that should be familiar to a radiologist reviewing imaging from pediatric cancer patients.

Nasal Wash Cytokines during Respiratory Viral Infection in Pediatric Allogeneic Hematopoietic Cell-Transplant Recipients.

Allogeneic hematopoietic cell-transplant (alloHCT) recipients are at increased risk of complications from viral respiratory-tract infections (vRTIs). We measured cytokine concentrations in nasal washes (NWs) from pediatric alloHCT recipients to better understand their local response to vRTI. Forty-one immunologic analytes were measured in 70 NWs, collected during and after vRTI, from 15 alloHCT recipients (median age, 11 yr) with 19 episodes of vRTI. These were compared with NW cytokine concentrations from an independent group of otherwise healthy patients. AlloHCT recipients are able to produce a local response to vRTI and produce IFN-α2 and IL-12p40 in significant quantities above an uninfected baseline early in infection. Compared with otherwise healthy comparator-group patients, alloHCT recipients have higher NW concentrations of IL-4 when challenged with vRTI. Further study of these immunologic analytes as well as of type 1 versus type 2 balance in the respiratory mucosa in the context of vRTI during immune reconstitution may be of future research interest in this vulnerable patient population.

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

Hematopoietic cell transplant (HCT) and solid organ transplant (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 (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.5-4.7), proton pump inhibitors (PPIs; 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.

Experience using intravenous posaconazole in paediatric and young adult oncology patients.

BACKGROUND: Posaconazole exhibits broad-spectrum antifungal activity. An IV formulation became available in 2014. Few studies describing the use of this formulation exist in patients under the age of 18 years. This study describes our experience using IV posaconazole in paediatric and young adult cancer patients. METHODS: This single-centre retrospective chart review evaluated patients who received IV posaconazole and had at least one posaconazole plasma concentration obtained after five or more days with a consistent dosage. Relationships between doses required to achieve a plasma concentration of ≥1 µg/mL and patient age, weight and body surface area (BSA) were evaluated. The clinical record was reviewed to identify descriptions of any adverse events. RESULTS: Twenty-five patients were analysed, with a median age of 10.5 years (range 1.9-22.9 years; 92% were <18 years). All patients were able to achieve a posaconazole plasma concentration ≥1 µg/mL during their treatment course. The daily mg/kg/day dose required to achieve the target concentration decreased significantly with increasing age of the patient (P = 0.018). Assessment of dosage based on BSA suggested a requirement of 225 mg/m2/day across all age groups <18 years. Adverse events documented in the clinical record were consistent with those described with the oral formulations. No CNS toxicities were observed with use of IV posaconazole. CONCLUSIONS: Concentrations ≥1 µg/mL are achievable and a BSA-based dosing approach may allow a consistent empirical dose for patients <18 years of age. Therapeutic drug monitoring is recommended to ensure patients achieve therapeutic concentrations.

The use of imaging to identify immunocompromised children requiring biopsy for invasive fungal rhinosinusitis.

BACKGROUND AND PURPOSE: Children with severe immunocompromise due to cancer therapy or hematopoietic cell transplant are at risk both for potentially lethal invasive fungal rhinosinusitis (IFRS), and for complications associated with gold-standard biopsy diagnosis. We investigated whether early imaging could reliably identify or exclude IFRS in this population, thereby reducing unnecessary biopsy. METHODS: We reviewed clinical/laboratory data and cross-sectional imaging from 31 pediatric patients evaluated for suspicion of IFRS, 19 without (age 11.8 ± 5.4 years) and 12 with proven IFRS (age 11.9 ± 4.6 years). Imaging examinations were graded for mucosal thickening (Lund score), for fungal-specific signs (FSS) of bone destruction, extra-sinus inflammation, and nasal mucosal ulceration. Loss of contrast enhancement (LoCE) was assessed separately where possible. Clinical and imaging findings were compared with parametric or nonparametric tests as appropriate. Diagnostic accuracy was assessed by receiver operating characteristic (ROC) analysis. Positive (+LR) and negative likelihood ratios (-LR) and probabilities were calculated. RESULTS: Ten of 12 patients with IFRS and one of 19 without IFRS had at least one FSS on early imaging (83% sensitive, 95% specific, +LR = 15.83, -LR = 0.18; P < .001). Absolute neutrophil count (ANC) ≤ 200/mm3 was 100% sensitive and 58% specific for IFRS (+LR = 2.38, -LR = 0; P = .001). Facial pain was the only discriminating symptom of IFRS (P < .001). In a symptomatic child with ANC ≤ 200/m3 , the presence of at least one FSS indicated high (79%) probability of IFRS; absence of FSS suggested low (<4%) probability. CONCLUSION: In symptomatic, severely immunocompromised children, the presence or absence of fungal-specific imaging findings may effectively rule in or rule out early IFRS, potentially sparing some patients the risks associated with biopsy.

Practice patterns and incidence of adenovirus infection in allogeneic hematopoietic cell transplant recipients: Multicenter survey of transplant centers in the United States.

BACKGROUND: Adenovirus (AdV) is increasingly recognized as a threat to successful outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Guidelines have been developed to inform AdV screening and treatment practices, but the extent to which they are followed in clinical practice in the United States is still unknown. The incidence of AdV in the United States is also not well documented. The main objectives of the AdVance US study were thus to characterize current AdV screening and treatment practices in the United States and to estimate the incidence of AdV infection in allo-HCT recipients across multiple pediatric and adult transplant centers. METHODS: Fifteen pediatric centers and 6 adult centers completed a practice patterns survey, and 15 pediatric centers and four adult centers completed an incidence survey. RESULTS: The practice patterns survey results confirm that pediatric transplant centers are more likely than adult centers to routinely screen for AdV, and are also more likely to have a preemptive AdV treatment approach compared to adult centers. Perceived risk of AdV infection is a determining factor for whether routine screening and preemptive treatment are implemented. Most pediatric centers screen higher-risk patients for AdV weekly, in blood, and have a preemptive AdV treatment approach. The incidence survey results show that from 2015 to 2017, a total of 1230 patients underwent an allo-HCT at the 15 pediatric transplant centers, and 1815 patients underwent an allo-HCT at the 4 adult transplant centers. The incidences of AdV infection, AdV viremia, and AdV viremia ≥ 1000 copies/mL within 6 months after the first allo-HCT were 23%, 16%, and 9%, respectively, for patients at pediatric centers, and 5%, 3%, and 2%, respectively, for patients at adult centers. CONCLUSIONS: These findings provide a more recent estimate of the incidence of AdV infection in the United States, as well as a multicenter view of practice patterns around AdV infection screening and intervention criteria, in pediatric and adult allo-HCT recipients.

Pentamidine for Prophylaxis against Pneumocystis jirovecii Pneumonia in Pediatric Oncology Patients Receiving Immunosuppressive Chemotherapy.

Pneumocystis jirovecii pneumonia is a life-threatening opportunistic infection in children receiving immunosuppressive chemotherapy. Without prophylaxis, up to 25% of pediatric oncology patients receiving chemotherapy will develop Pneumocystis jirovecii pneumonia. Trimethoprim-sulfamethoxazole is the preferred agent for prophylaxis against Pneumocystis jirovecii pneumonia. Pentamidine may be an acceptable alternative for pediatric patients unable to tolerate trimethoprim-sulfamethoxazole. A retrospective review was conducted of pediatric oncology patients who received ≥1 dose of pentamidine for Pneumocystis jirovecii pneumonia prophylaxis between January 2007 and August 2014. Electronic medical records were reviewed to determine the incidence of breakthrough Pneumocystis jirovecii pneumonia or discontinuation of pentamidine associated with adverse events. A total of 754 patients received pentamidine prophylaxis during the period. There were no cases of probable or proven Pneumocystis pneumonia, and 4 cases (0.5%) of possible Pneumocystis pneumonia. The incidence of possible breakthrough Pneumocystis pneumonia was not significantly different between subgroups based on age (<12 months [1.7%] versus ≥12 months [0.4%], P = 0.3), route of administration (aerosolized [0%] versus intravenous [1.0%], P = 0.2), or hematopoietic stem cell transplant status (transplant [0.4%] versus no transplant [0.8%], P = 0.6). Pentamidine was discontinued due to an adverse drug event in 23 children (3.1%), more frequently for aerosolized than for intravenous administration (7.6% versus 2.2%, respectively, P = 0.004). Intravenous or inhaled pentamidine may be a safe and effective second-line alternative for prophylaxis against Pneumocystis jirovecii pneumonia in children with cancer receiving immunosuppressive chemotherapy or hematopoietic stem cell transplantation.

Mucormycosis in children with cancer and hematopoietic cell transplant-A single center cohort study.

Although mucormycosis is an important cause of morbidity and mortality in children with cancer, our understanding of the typical characteristics of these infections is incomplete. We reviewed all cases of mucormycosis diagnosed at a single pediatric cancer center over 5 decades to identify the clinical features of mucormycosis in pediatric oncology patients and to identify risk factors for mortality. There were 44 cases of mucormycosis diagnosed between 1970-2019. Most patients (89%) had hematological malignancies and a history of prolonged and severe neutropenia (91%). In this series, hyperglycemia and exposure to corticosteroids were common. Pulmonary (36%) and disseminated infections (32%) were most common; rhino-orbital-cerebral infections were relatively infrequent (11%). Rhizopus spp. was the most common etiological agent (40%) followed by Mucor spp. (31%), and Cunninghamella spp. (19%). Overall mortality was 44% and 51% and attributable mortality was 39% and 41% at the end of antifungal therapy and end of follow up, respectively. Attributable mortality fell to 18% in 2010-2019, from 58-60% in previous decades; adjunctive surgery was associated with decreased mortality. Mortality remains unacceptably high despite aggressive antifungal therapy and adjunctive surgery, suggesting novel therapeutic strategies are needed.