Bivalirudin Monitoring in Pediatric Ventricular Assist Device and Extracorporeal Membrane Oxygenation: Analysis of Single-Center Retrospective Cohort Data 2018-2022.

OBJECTIVES: The activated partial thromboplastin time (aPTT) is the most frequently used monitoring assay for bivalirudin in children and young adults on mechanical circulatory support including ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO). However, intrinsic variability of the aPTT complicates management and risks bleeding or thrombotic complications. We evaluated the utility and reliability of a bivalirudin-calibrated dilute thrombin time (Bival dTT) assay for bivalirudin monitoring in this population. DESIGN: Retrospective analysis of clinical data (including aPTT, dilute thrombin time [dTT]) and results of residual plasma samples from VAD patients were assessed in two drug-calibrated experimental assays. One assay (Bival dTT) was validated for clinical use in VAD patients, and subsequently used by clinicians in ECMO patients. Pearson correlation and simple linear regression were used to determine R2 correlation coefficients between the different laboratory parameters using Statistical Package for Social Sciences (Armonk, NY). SETTING: ICUs at Cincinnati Children's Hospital Medical Center. SUBJECTS: Children on VAD or ECMO support anticoagulated with bivalirudin. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred fifteen plasma samples from 11 VAD patients were analyzed. Both drug-calibrated experimental assays (anti-IIa and Bival dTT) showed excellent correlation with each other (R2 = 0.94) and with the dTT (R2 = 0.87), but poor correlation with aPTT (R2 = 0.1). Bival dTT was selected for validation in VAD patients. Subsequently, clinically ordered results (105) from 11 ECMO patients demonstrated excellent correlation between the Bival dTT and the standard dTT (R2 = 0.86) but very poor correlation with aPTT (R2 = 0.004). CONCLUSIONS: APTT is unreliable and correlates poorly with bivalirudin's anticoagulant effect in ECMO and VAD patients. A drug-calibrated Bival dTT offers superior reliability and opportunity to standardize results across institutions. Additional studies are needed to determine an appropriate therapeutic range and correlation with clinical outcomes.

How we use angiopoietin-2 in the diagnosis and management of vascular anomalies.

The diagnosis of vascular anomalies remains challenging due to significant clinical heterogeneity and uncertain etiology. Evaluation using biopsy and/or genetic testing for somatic variants is invasive, expensive, and prone to sampling error. There is great need for noninvasive and easily measured blood laboratory biomarkers that can aid not only in diagnosis, but also management of treatments for vascular anomalies. Angiopoietin-2, a circulating blood angiogenic factor, is highly elevated in patients with kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon and kaposiform lymphangiomatosis. Here, we describe our clinical experience using serum angiopoietin-2 as a biomarker for diagnosis and monitoring response to treatment.

Treatment practices and response in kaposiform hemangioendothelioma: A multicenter cohort study.

BACKGROUND AND OBJECTIVES: Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare vascular tumors in children historically associated with significant morbidity and mortality. This study was conducted to determine first-line therapy in the absence of available prospective clinical trials. METHODS: Patients from 17 institutions diagnosed with KHE/TA between 2005 and 2020 with more than 6 months of follow-up were included. Response rates to sirolimus and vincristine were compared at 3 and 6 months. Durability of response and response to other treatment modalities were also evaluated. RESULTS: Of 159 unique KHE/TA subjects, Kasabach-Merritt phenomenon (KMP) was present in 64 (40.3%), and only two patients were deceased (1.3%). Over 60% (n = 96) demonstrated treatment response at 3 months, and more than 70% (n = 114) by 6 months (no significant difference across groups). The vincristine group had higher radiologic response at 3 months compared to sirolimus (72.7% vs. 20%, p = .03), but there were no differences between these groups at 6 months. There were no differences in rates of recurrent or progressive disease between vincristine and sirolimus. CONCLUSIONS: In this large, multicenter cohort of 159 patients with KHE/TA, rates of KMP were consistent with historical literature, but the mortality rate (1.3%) was much lower. Overall treatment response rates were high (>70%), and there was no significant difference in treatment response or durability of disease comparing sirolimus to vincristine. Our results support individualized treatment decision plans depending on clinical scenario and patient/physician preferences. Response criteria and response rates reported here will be useful for guiding future treatment protocols for vascular tumors.

Prevalence and Predictors of Hereditary Hemorrhagic Telangiectasia and Capillary-Malformation Arteriovenous Malformation Syndrome Among Children with Neurovascular Malformations.

OBJECTIVE: To investigate the prevalence and predictors of hereditary hemorrhagic telangiectasia (HHT) and capillary-malformation arteriovenous malformation (CM-AVM) syndrome among children with no prior personal or family history of these diseases who presented with an arteriovenous shunt lesion. STUDY DESIGN: A retrospective chart review was completed on patients aged 0 through 21 years with arteriovenous shunt lesions evaluated at our Cerebrovascular Center. Diagnosis of definite or suspected HHT or CM-AVM was based on clinical features and genetic testing. Associations between final diagnosis and type and number of lesions, epistaxis, telangiectasias, CM, and pulmonary AVMs were assessed. RESULTS: Eighty-nine patients were included. Thirteen (14.6%) had definite HHT, 11 (12.4%) suspected HHT, and 4 (4.5%) definite CM-AVM. Having ≥2 episodes of epistaxis/year and ≥ 2 sites with telangiectasias were each associated with definite HHT (P < .001). Having ≥ 2 CM was associated with definite CM-AVM (P < .001). Pulmonary AVM was associated with increased odds of having definite HHT (OR = 6.3, 95% CI: 1.2-33.4). Multiple lesions (OR = 24.5, 95% CI: 4.5-134.8) and arteriovenous fistulas (OR = 6.2, 95% CI: 1.9-20.3) each increased the likelihood of having definite HHT or CM-AVM. Genetic testing was positive in 31% of patients tested. CONCLUSIONS: We recommend that children with neurovascular shunt lesions be offered genetic testing and undergo further evaluation for HHT and CM-AVM. Awareness and early diagnosis of these conditions is a critical step toward improving long-term outcomes and preventing disease-associated complications.

Response to sirolimus in capillary lymphatic venous malformations and associated syndromes: Impact on symptomatology, quality of life, and radiographic response.

BACKGROUND: Capillary lymphatic venous malformations (CLVM) and associated syndromes, including Klippel-Trenaunay syndrome (KTS) and congenital lipomatous overgrowth, vascular malformation, epidermal nevi, skeletal, and spinal syndrome (CLOVES), are underrecognized disorders associated with high morbidity from chronic pain, recurrent infections, bleeding, and clotting complications. The rarity of these disorders and heterogeneity of clinical presentations make large-scale randomized clinical drug trials challenging. Identification of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [gene]) mutations in CLVM has made targeted medications, such as sirolimus, attractive treatment options. The aim of this study was to investigate the safety and efficacy of sirolimus therapy in CLVM. PROCEDURE: A combined prospective and retrospective cohort of pediatric and young adult patients with CLVM treated with sirolimus was evaluated for disease response, including symptom improvement, quality of life (QOL), and radiologic response. Sirolimus dosing regimens and toxicities were also assessed. RESULTS: Twenty-nine patients with CLVM, including KTS and CLOVES, were included. Ninety-three percent of patients reported improved QOL, and 86% had improvement in at least one symptom. Most significantly, improvement was noted in 100% of patients with bleeding and 89% with thrombotic complications with corresponding decreases in mean D-dimer (p = .008) and increases in mean fibrinogen (p = .016). No patients had progressive disease on sirolimus. Most common side effects included neutropenia, lymphopenia, infection, and aphthous ulcers/stomatitis. No toxicities were life-threatening, and none required long-term discontinuation of sirolimus. CONCLUSION: Sirolimus appears to be effective at reducing complications and improving QOL in patients with CLVM and associated syndromes. In this patient cohort, sirolimus was well tolerated and resulted in few treatment-related toxicities.

Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees.

Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody loss. Clarification regarding whether the hypogammaglobulinemia is secondary or primary is important because this has implications for evaluation and management. Prior receipt of immunosuppressive medications and/or presence of conditions associated with SHG development, including protein loss syndromes, are histories that raise suspicion for SHG. In patients with these histories, a thorough investigation of potential etiologies of SHG reviewed in this report is needed to devise an effective treatment plan focused on removal of iatrogenic causes (eg, discontinuation of an offending drug) or treatment of the underlying condition (eg, management of nephrotic syndrome). When iatrogenic causes cannot be removed or underlying conditions cannot be reversed, therapeutic options are not clearly delineated but include heightened monitoring for clinical infections, supportive antimicrobials, and in some cases, immunoglobulin replacement therapy. This report serves to summarize the existing literature regarding immunosuppressive medications and populations (autoimmune, neurologic, hematologic/oncologic, pulmonary, posttransplant, protein-losing) associated with SHG and highlights key areas for future investigation.

Streptococcal pneumonia meningitis as an initial presentation of X-linked agammaglobulinemia: A case report and discussion.

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in the gene for Bruton's tyrosine kinase (Btk), with affected males most commonly presenting with recurrent bacterial infections during the first few years of life. Here we present a 17-month-old male with a chief complaint of worsening rash and fever, whose history of streptococcal pneumonia meningitis at 5 months of age prompted suspicion for an underlying immunodeficiency and subsequent diagnosis of XLA. Bacterial meningitis is a rare initial presentation of XLA, and therefore physicians may easily overlook any underlying immunodeficiency. Prompt workup for immunodeficiency should be initiated in any vaccinated patient with a history of pneumococcal meningitis outside of the newborn period. Further discussion surrounding the various presentations of XLA, their related clinical manifestations and laboratory findings, and the importance of thorough chart review may encourage earlier diagnosis and initiation of treatment of this disease.

Rituximab and eculizumab when treating nonmalignant hematologic disorders: infection risk, immunization recommendations, and antimicrobial prophylaxis needs.

Rituximab and eculizumab, monoclonal antibodies that deplete most B cells and activate the terminal complement, respectively, are used to treat nonmalignant hematologic disorders (NMHDs), sometimes with unfavorable effects on the immune system. Hypogammaglobulinemia and neutropenia have been reported with variable prevalence in patients treated with rituximab. Neutropenia is mild and transient, and serious infectious complications are uncommon, so treatment is not indicated. Hypogammaglobulinemia is of greater concern. There is a lack of agreement on a standardized definition, and pre- and posttreatment immunoglobulin (Ig) levels are not routinely obtained. The association among low Ig levels, infectious risk, and mortality and morbidity in this population is unclear. There are also no formal guidelines on indication, risk factors, and threshold level of IgG to prompt Ig replacement therapy (IgRT). Among patients with NMHD, preexisting or persistent hypogammaglobulinemia (PH) after treatment with rituximab has been linked to underlying primary immunodeficiency disorders; therefore, a high index of suspicion should be maintained, and immunologic and genetic evaluation should be considered. Overall, important strategies in managing patients who are receiving rituximab include routine monitoring of pre- and posttreatment IgG levels, immune reconstitution (eg, B-cell subsets), assessment of vaccination status and optimization before treatment, and individualized consideration for IgRT. Accordingly, we discuss immunizations. Eculizumab, most commonly used in the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome, poses increased risk of meningococcal infections. To decrease the risk of infection, a meningococcal vaccination series is recommended before initiating therapy, and prophylactic antibiotics are preferred during the course of treatment.

Predictors of postthrombotic syndrome in pediatric thrombosis: A systematic review and meta-analysis of the literature.

BACKGROUND: Postthrombotic syndrome (PTS) is a significant complication of pediatric deep venous thrombosis (DVT). There is a gap in the understanding of the risk factors associated with the development of pediatric PTS preventing the early identification of those patients at greatest risk, and the development of risk-stratified interventions. OBJECTIVES: To conduct a systematic review and meta-analysis of the literature on prognostic factors for PTS development in pediatric patients. METHODS: A systematic search of MEDLINE, EMBASE, and the Cochrane Library from 1960 to December 2018 was performed. Eligible studies reported at least one prognostic factor for PTS development in patients < 21 years of age with a radiographically confirmed DVT. To be included in the meta-analysis, prognostic factors had to be reported in at least three published studies. RESULTS AND CONCLUSIONS: Twelve studies (n = 1160 patients) met criteria for inclusion. Ninety-three percent of patients with an extremity DVT (n = 1076) were assessed for PTS. PTS developed in 40% (n = 434) of these patients. Central venous catheter-associated DVT (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.08-2.98), complete veno-occlusion (OR, 1.89; 95% CI, 1.04-3.46), and incomplete DVT resolution (OR, 2.07; 95% CI, 1.4-3.07) were identified as candidate prognostic factors for pediatric PTS. These findings should be interpreted in the context of the heterogeneity of the included studies and the limitations of current pediatric PTS assessment tools. Further, the predictive value of these prognostic factors will need to be validated in future collaborative prospective multicenter studies that maximize the homogeneity of pediatric DVT patients.

Clinical characterization and long-term outcomes in pediatric epithelioid hemangioendothelioma.

There is a paucity of information about the clinical characteristics and long-term outcomes of pediatric epithelioid hemangioendothelioma (EHE), a rare vascular neoplasm commonly presenting in adulthood. In our case series of 24 patients with EHE aged 2-26 years, the majority presented with multi-organ disease. Progression was seen in 63% of patients with a mean time to progression of 18.4 months (range: 0-72). Three patients treated with sirolimus achieved stable disease or partial response for >2.5 years. Longitudinal prospective pediatric studies are needed to develop standardized approaches to surgical and medical management.

A Retrospective Review of the Use of Sirolimus for Pediatric Patients With Epithelioid Hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor with no standardized treatment. The mammalian target of rapamycin inhibitor, sirolimus, has been used successfully in adult EHE and other vascular tumors in children but has not been studied in pediatric EHE. The aim of this retrospective case series is to discuss the results of sirolimus for treatment in 6 pediatric patients with EHE. Four of 6 patients demonstrated partial response or disease stabilization with sirolimus treatment. No treatment dosing, trough goals, or duration of treatment recommendations can be made. Prospective studies are warranted to further investigate the use of sirolimus in treatment of EHE.

Successful Use of Eltrombopag in a Pediatric Patient With Human Immunodeficiency Virus (HIV)-Associated Thrombocytopenia.

Thrombocytopenia and other hematologic manifestations related to HIV are not uncommon. Treatment of HIV-related thrombocytopenia is challenging: treatment options are not effective in all patients, or less well studied, particularly in the pediatric population. We aim to present and discuss the case of a 13-year-old with HIV and persistent thrombocytopenia who, after failing monthly IVIG infusions, showed normalization of platelet count on the novel thrombopoietin receptor agonist, eltrombopag. A retrospective chart review of the case patient's medical record was conducted. Additionally, a thorough literature review was performed on this topic, including the pathophysiology of underlying HIV-related thrombocytopenia and its treatment modalities. The patient was treated initially with monthly IVIG infusions for about 1 year but did not show a sustained response, particularly in between infusions. After initiation with eltrombopag 50 mg daily, the patient showed a sustained increase in his platelet count. During a brief lapse in eltrombopag treatment, his platelet count dropped, which then increased upon his reinitiation of therapy. He has continued to show a sustained platelet response and has not been symptomatic or required IVIG for more than 1 year. To our knowledge, this is the first report of a pediatric patient with HIV-related thrombocytopenia who has benefited from the use of eltrombopag.