How I approach: the transplant recipient with fever and pulmonary infiltrates.

Recipients of hematopoietic stem cell transplants and solid organ transplants frequently develop pulmonary infiltrates from both infectious and non-infectious etiologies. Differentiation and further characterization of microbiologic etiologies-viral, bacterial, and fungal-can be exceedingly challenging. Pediatric patients face unique challenges as confirmatory evaluations with bronchoscopy or lung biopsy may be limited. A generalizable approach to diagnosing and managing these conditions has not been well established. This paper aims to summarize our initial clinical approach while discussing the relative evidence informing our practices. A pediatric patient with characteristic infiltrates who has undergone HSCT is presented to facilitate the discussion. Generalizable approaches to similar patients are highlighted as appropriate while highlighting considerations based on clinical course and key risk factors.

Pipeline of Novel Antifungals for Invasive Fungal Disease in Transplant Recipients: A Pediatric Perspective.

Invasive fungal disease (IFD) remains a significant cause of morbidity and mortality in children undergoing transplantation. There is a growing armamentarium of novel antifungal agents recently approved for use or in late stages of clinical development. The overarching goal of this review is to discuss the mechanisms of action, spectrum of activity, stage of development, and pediatric-specific data for the following agents: encochleated amphotericin B deoxycholate, fosmanogepix, ibrexafungerp, isavuconazole, olorofim, opelconazole, oteseconazole, and rezafungin. Additionally, key drug attributes of these novel agents and their potential future therapeutic roles in pediatric transplant recipients are discussed.

Safety and Tolerability of Monoclonal Antibody Therapies for Treatment of COVID-19 in Pediatric Patients.

There is a little data regarding safety or efficacy of monoclonal antibody treatment for mild-to-moderate COVID-19 in pediatric patients despite it being frequently used in adults. This retrospective study of 17 patients with mild-to-moderate COVID-19 who received monoclonal antibody therapy found that the treatment was well tolerated, safe, and may be effective in halting progression to severe disease.

Impact of hospital acquired infections on post-transplant one year mortality in pediatric bone marrow transplant patients.

OBJECTIVE: Children undergoing hematopoietic stem cell transplant (HSCT) are prone to infections, especially when hospitalized for the transplant or additional medical care. These infections are perceived to increase patient's mortality risk, but data are lacking. We conducted this study to assess the burden and the impact of hospital acquired infections (HAI) on mortality risk among pediatric HSCT patients. METHODS: This retrospective study included 169 patients that received allogeneic HSCT between January 1 2011 and July 6 2017 at Children's National Hospital, a tertiary referral center. Clinical and laboratory data were reviewed for 1 year after transplant to determine HAI and survival status. The HAI incident rates stratified by bloodstream, respiratory, and gastrointestinal infections were then compared between deceased patients and survivors. RESULTS: Including transplant, 169 patients sustained 499 hospital admissions for total of 10,523 patient days and 112 HAI episodes, resulting in a HAI rate of 10.6 per 1,000 patient-days. Within 1-year after transplant, 38 (22%) patient died, 30 (17.5%) with nonrelapse-related causes. Unadjusted univariate analysis revealed mortality correlated with cell source (p=0.035), donor type (p = 0.002), respiratory viral infections (P = .015), and central line associated blood stream infection (CLABSIs; P < .001). Adjusted analysis revealed CLABSI and respiratory adenovirus infection independently increased mortality risk by 3-fold (hazard ratio: 3.22, 95% confidence interval:1.30-8.00) and (hazard ratio: 3.32, 95% confidence interval: 1.22-9.06), respectively. CONCLUSIONS: In light of the high frequency of multiple factors contributing to mortality we are unable to determine the degree HAI contributed mortality. However, our findings suggest preventing CLABSIs and respiratory adenovirus infections are crucial to improve the 1-year survival among pediatric HSCT patients.

Characteristics and outcomes of osteomyelitis in children with sickle cell disease: A 10-year single-center experience.

BACKGROUND: Patients with sickle cell disease (SCD) are at increased risk for osteomyelitis (OM). Diagnosis of OM in SCD is challenging as the clinical presentation is similar to a vasoocclusive crisis (VOC) with no diagnostic gold standard. We report characteristics and outcomes of OM in SCD patients treated at our center over 10-year period. DESIGN/METHOD: We conducted a retrospective analysis of patients with SCD who were treated for OM at our center over a 10-year period (2006-2016). Cases were identified utilizing radiology data mining software. Radiology reports and medical charts of potential OM cases were reviewed. RESULTS: Twenty-eight children with SCD were treated for OM at our institution. Patients treated for OM were largely similar to patients treated for a VOC. However, patients treated for OM had significantly higher C-reactive protein (10 mg/dL vs 5.58 mg/dL, P = 0.03) and erythrocyte sedimentation rate (60 mm/h vs 47 mm/h, P = 0.02). Magnetic resonance imaging (MRI) findings were consistent with OM in 18 (64%) patients and indeterminate in the remaining. Based on clinical, laboratory, and radiological findings, the diagnosis of OM was considered confirmed in 3 patients, probable in 6 patients, and presumed in 19 patients. Nontyphoidal Salmonella was isolated from cultures in 9 (32%) patients, while no organism was identified in 19 (67%) patients. All patients were treated with antibiotics. Six patients (21%) required surgical interventions. CONCLUSIONS: OM continues to pose diagnostic challenges. Most patients are treated for OM without definitive confirmation. Nontyphoidal Salmonella was the only organism identified in our cohort.

Tap water: A possible source of nontuberculous mycobacterial infection in patients with T cell deficiency.

Five patients, all with severe T cell dysfunction, had invasive non-tuberculous mycobacteria (NTM) infections diagnosed over a 16 month period, with four meeting Centers for Disease Control and Prevention criteria for hospital-acquired infections. Testing of the hospitals tap water confirmed the presence of NTM. NTM are naturally present in water systems and present a threat to patients with lymphopenia; steps should be taken to avoid NTM exposure when caring for this patient population.

High Rates of Community and Hospital Acquired Infections in Patients with Cellular Immunodeficiencies.

PURPOSE: Patients with primary immunodeficiency diseases (PID) are perceived to be at high risk for acquiring as well as developing complications from infections. There is little data describing the infection type and frequency these patients may acquire in the community or during hospital admissions. Data is critically needed in order to inform best practices on how to protect these vulnerable patients. METHODS: This is a retrospective study which included PID patients who were discharged from Children's National Health System (CNHS) from January 1, 2011, through August 31, 2017, and were assigned a discharge diagnosis code indicating PID. Hospitalizations that occurred in the study period were reviewed to extract information on the type of infections upon admission and during hospitalization. The rate of hospital acquired infections (HAIs) was calculated by the number of HAIs divided by the total number of days between date of admission and date of discharge or receiving the first bone marrow transplant, whichever the one came first. The rates were then compared to the HAI rate among oncology patients receiving treatment at CNHS during the same study period. RESULTS: During this study period, 33 PID patients were admitted 80 times for a total of 1855 patient days. Of these 80 admissions, 31 were due to an infection. Ten of the 31 admissions with severe combined immunodeficiency disease (SCID) were infection related, 4/4 in ectodermal dysplasia with immunodeficiency due to gain of function mutation (IkappaBalpha) patients, 8/10 in Wiskott-Aldrich patients, 1/2 in STAT3 mutation patients, 1/1 in Hyper IGM patient, 1/5 in severe chronic active EBV (SCAEBV) patients, 1/1 NK defect, 2/21 in primary hemophagocytic lymphohistiocytosis patients, 3/4 chronic granulomatous disease, and 0/1 congenital neutropenia. HAI occurred in 11 out of 80 admissions (13.75%). Patients with SCID had the highest HAI rate of 13.09 per 1000 patient days, followed by SCAEBV (11.10), IkappaBalpha (6.58), and Wiskott-Aldrich (4.91). Comparing to oncology patients in which the HAI rate was 0.92 per 1000 patient days. SCID patients had 11.7 (95% confidence interval 3.7-29; p < 0.001) and T cell defects excluding SCID had 4.8 (95% CI 1.0-14.8; p = 0.03) times greater risk of acquiring an infection during a hospitalization. CONCLUSIONS: Patients with severe T cell defects such as SCID are at greater risk for infections in the community and in hospital settings. Additional infection prevention measures are likely needed when caring for these patients in a clinic or as an inpatient. Further studies are urgently needed to determine the most appropriate measures for these patients.

Thrombocytopenia May Mediate Disease Severity in Plasmodium falciparum Malaria Through Reduced Transforming Growth Factor Beta-1 Regulation of Proinflammatory and Anti-inflammatory Cytokines.

BACKGROUND: Transforming growth factor beta-1 (TGF-ß1) is an important regulator of inflammation. Platelets are a major source of TGF-ß1 and are reduced in severe malaria. However, the relationships between TGF-ß1 concentrations and platelet counts, proinflammatory and anti-inflammatory cytokine and chemokine concentrations and disease severity in malaria have not been characterized. METHODS: Platelet counts and serum concentrations of TGF-ß1, interleukin-1beta (IL-1ß), IL-6, IL-10, interferon (IFN)-γ, tumor necrosis factor (TNF)-α and RANTES were measured at the time of presentation in Ugandan children with cerebral malaria (CM, n = 75), uncomplicated malaria (UM, n = 67) and healthy community children (CC, n = 62). RESULTS: TGF-ß1 concentrations decreased with increasing severity of disease [median concentrations (25th, 75th percentile) in ng/mL in CC, 41.4 (31.6, 57.4); UM, 22.7 (14.1, 36.4); CM, 11.8 (8, 21); P for trend < 0.0001]. In children with CM or UM, TGF-ß1 concentrations correlated positively with platelet count (CM, P < 0.0001; UM, P = 0.0015). In children with CM, TGF-ß1 concentration correlated negatively with IFN-γ, IL-6 and IL-10 and positively with RANTES concentrations (all P < 0.01). TGF-ß1 concentration was not associated with death or adverse neurologic or cognitive outcomes in children with CM. CONCLUSIONS: TGF-ß1 concentrations decrease with increasing Plasmodium falciparum disease severity. In CM, thrombocytopenia correlates with decreased TGF-ß1, and decreased TGF-ß1 correlates with cytokine/chemokine changes associated with increased disease severity and death. Thrombocytopenia may mediate disease severity in malaria through reduced TGF-ß1-mediated regulation of cytokines associated with severe disease.