Perioperative Transgender Hormone Management: Avoiding Venous Thromboembolism and Other Complications.

SUMMARY: This review discusses the current evidence regarding perioperative hormone therapy for transgender individuals, with an emphasis on strategies to reduce the risk of perioperative venous thromboembolism. Historically, surgeons routinely discontinued estrogen therapy in the perioperative period with the goal of reducing the risk of venous thromboembolism. However, abrupt estrogen cessation may also lead to adverse emotional and physiologic effects, including an exacerbation of one's gender dysphoria. The data on the relationship of feminizing hormones and venous thromboembolism in the perioperative setting are largely based on extrapolation of hormone regimens that are no longer in use and may not accurately reflect the actual risk of venous thromboembolism. Future studies will allow surgeons to engage in evidence-based, patient-centered, informed consent while also minimizing the risk of complications, such as venous thromboembolism.

Characteristics of Hospitalized Children With SARS-CoV-2 in the New York City Metropolitan Area.

OBJECTIVES: To describe the characteristics of hospitalized children with severe acute respiratory syndrome coronavirus 2 in New York City metropolitan area. PATIENTS AND METHODS: This was a multicenter, retrospective cohort study at 4 hospitals comprising 82 hospitalized children (0-21 years) who tested positive for severe acute respiratory syndrome coronavirus 2 after symptoms and risk screening between March 1 and May 10, 2020. We subdivided patients on the basis of their admission to acute or critical care units and by age groups. Further subanalyses were performed between patients requiring respiratory support or no respiratory support. RESULTS: Twenty-three (28%) patients required critical care. Twenty-nine (35%) patients requiring respiratory support, with 9% needing mechanical ventilation, and 1 required extracorporeal support. All patients survived to discharge. Children with any comorbidity were more likely to require critical care (70% vs 37%, P = .008), with obesity as the most common risk factor for critical care (63% vs 28%, P = .02). Children with asthma were more likely to receive respiratory support (28% vs 8%, P = .02), with no difference in need for critical care (P = .26). Children admitted to critical care had higher rates of renal dysfunction at presentation (43% vs 10%, P = .002). CONCLUSIONS: Children with comorbidities (obesity and asthma in particular) were at increased risk for critical care admission and/or need for respiratory support. Children with renal dysfunction at presentation were more likely to require critical care.

Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial.

Patients with autoimmune multilineage cytopenias are often refractory to standard therapies requiring chronic immunosuppression with medications with limited efficacy and high toxicity. We present data on 30 patients treated on a multicenter prospective clinical trial using sirolimus as monotherapy. All children (N = 12) with autoimmune lymphoproliferative syndrome (ALPS) achieved a durable complete response (CR), including rapid improvement in autoimmune disease, lymphadenopathy, and splenomegaly within 1 to 3 months of starting sirolimus. Double-negative T cells were no longer detectable in most, yet other lymphocyte populations were spared, suggesting a targeted effect of sirolimus. We also treated 12 patients with multilineage cytopenias secondary to common variable immunodeficiency (CVID), Evans syndrome (ES), or systemic lupus erythematosus (SLE), and most achieved a CR (N = 8), although the time to CR was often slower than was seen in ALPS. Six children with single-lineage autoimmune cytopenias were treated and only 2 responded. Sirolimus was well tolerated with very few side effects. All of the responding patients have remained on therapy for over 1 year (median, 2 years; range, 1 to 4.5 years). In summary, sirolimus led to CR and durable responses in a majority of children with refractory multilineage autoimmune cytopenias. The responses seen in ALPS patients were profound, suggesting that sirolimus should be considered as a first-line, steroid-sparing treatment of patients needing chronic therapy. The results in other multilineage autoimmune cytopenia cohorts were encouraging, and sirolimus should be considered in children with SLE, ES, and CVID. This trial was registered at www.clinicaltrials.gov as #NCT00392951.

Associations between intracranial haemorrhage and prescribed prophylaxis in a large cohort of haemophilia patients in the United States.

Intracranial haemorrhage (ICH) is the most serious type of bleeding for patients with haemophilia. Prior published reports regarding ICH predate the widespread provision of prophylaxis. Our study objectives were to determine risk factors for ICH and whether prophylaxis reduces ICH occurrence. We performed a nested case-control study of persons with haemophilia, ≥2 years of age enrolled in the Centers for Disease Control and Prevention Universal Data Collection project. Of 10 262 patients 199 (1·9%) experienced an ICH for an incidence rate of 390/105 patient years. Head trauma was reported in 44% (88/199). ICH mortality was 19·6% (39/199). Significant risk factors for ICH included a high titre inhibitor [odds ratio (OR) = 4·01, 95% confidence interval (2·40-6·71)], prior ICH [OR = 3·62 (2·66-4·92)] and severe haemophilia [OR = 3·25 (2·01-5·25)]. Prophylaxis was associated with a significant risk reduction for ICH occurrence in patients with severe haemophilia who were negative for human immunodeficiency virus or an inhibitor, with an OR of 0·52 (0·34-0·81) and 0·50 (0·32-0·77) respectively. The most significant risk factors for ICH included the presence of an inhibitor, prior ICH, severity of haemophilia and reported head trauma. This is the first study to demonstrate that prescribed prophylaxis conferred a protective effect against ICH in patients with uncomplicated severe disease.

Dose of prophylactic platelet transfusions and prevention of hemorrhage.

BACKGROUND: We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS: We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS: In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001). CONCLUSIONS: Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.)

Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study.

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by dysregulation of the Fas apoptotic pathway. Clinical manifestations of ALPS include autoimmune cytopenias, organomegaly, and lymphadenopathy. These findings overlap with Evans syndrome (ES), defined by presence of at least 2 autoimmune cytopenias. We hypothesized a subset of patients with ES have ALPS and tested 45 children at 22 institutions, measuring peripheral blood double-negative T cells (DNTs) and Fas-mediated apoptosis. ALPS was diagnosed in 47% of patients tested. Markedly elevated DNTs (> or = 5%) were a strong predictor of ALPS (positive predictive value = 94%), whereas no patients with DNTs less than 2.5% had ALPS on apoptosis testing. Severity of cytopenias and elevated immunoglobulin levels also predicted ALPS. This is the largest published series describing children with ES and documents a high rate of ALPS among pediatric ES patients. These data suggest that children with ES should be screened for ALPS with DNTs.

Treatment with sirolimus ameliorates tacrolimus-induced autoimmune cytopenias after solid organ transplant.

The development of autoimmune blood cell cytopenias is a potentially life-threatening complication of solid organ transplantation, resulting from T-cell dysregulation from immunosuppressive medications. Conventional treatment with corticosteroids and IVIgG is often unsuccessful as these therapies are unlikely to overcome the T-cell dysregulation. We describe two patients who developed severe autoimmune cytopenias after solid organ transplantation. They had limited response to conventional medications, but had complete resolution of autoimmunity upon transition of immunosuppression from tacrolimus to sirolimus. Altering the immunosuppressive regimen to modify T-cell dysregulation may be beneficial for patients who develop post-transplant autoimmune disease and allow continued preservation of allograft.

The clinical management of hemophilia and head trauma: a survey of current clinical practice among pediatric hematology/oncology physicians.

BACKGROUND: Determining the appropriate evaluation for a pediatric patient with hemophilia and head trauma is a diagnostic challenge with no neuroimaging guidelines and limited clinical evidence to direct care. PROCEDURE: A questionnaire, with two case scenarios, was emailed to members of the American Society of Pediatric Hematology/Oncology. The case scenarios involved asymptomatic toddlers with severe hemophilia who had either fallen from a height (case 1) or from standing (case 2). Respondents were asked to select from six management options. The case scenarios were then altered to include: a large palpable hematoma, prophylactic factor infusion 24 hr prior, the trauma occurred 48 hr prior, wearing a soft helmet, or emesis. RESULTS: The completed response rate was 23% (252/1,077). Computed tomography (CT) was selected by 68.9% (#1) and 56.4% (#2) of respondents. In both case scenarios the presence of a palpable bruise resulted in a statistically significant increase in CT usage to 83.7% and 82.8% (P < 0.001). The use of prophylaxis did not result in a statistically significant decrease in CT usage. Duration of factor replacement was variable ranging from 1 to 4 days. CONCLUSION: Physician self reported management of pediatric patients with hemophilia and head trauma is diverse. The use of CT imaging for mild head trauma in patients without signs or symptoms of intracranial hemorrhage was very common. The use of prophylaxis did not reduce the use of head CT imaging. This variation in clinical practice demonstrates the lack of evidence regarding the management of head trauma in patients with hemophilia.

Incidence of bleeding complications in pediatric patients with type 1 von Willebrand disease undergoing adenotonsillar procedures.

OBJECTIVE: To review the incidence of postoperative bleeding in children with type 1 von Willebrand disease (VWD) who were treated with a single institution protocol. STUDY DESIGN: We performed a retrospective study to determine the postoperative hemorrhage rate in pediatric patients with type 1 VWD who were treated via the Children's Hospital of Philadelphia institutional protocol. This protocol utilizes intravenous desmopressin (DDAVP), oral aminocaproic acid, and overnight observation. RESULTS: Between the years of 2000 to 2006, 41 children with type 1 VWD underwent an adenotonsillar procedure and were treated with this protocol. Seven patients (17%) experienced delayed (>24 hours after surgery) postoperative hemorrhage requiring intervention. Five of the 7 patients required cautery to control the bleeding, and the remaining 2 patients responded to DDAVP and aminocaproic acid alone. Older age and lower VW antigen levels were associated with postoperative hemorrhage (P = .05). CONCLUSIONS: Despite therapeutic intervention to decrease the risk of postoperative hemorrhage, the incidence of hemorrhage was higher in pretreated patients with type 1 VWD than in children without bleeding disorders. Further prospective studies are necessary to determine the optimal treatment to reduce bleeding complications in these patients.

Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome.

We hypothesized that sirolimus, an mTOR inhibitor, may be effective in patients with autoimmune lymphoproliferative syndrome (ALPS) and treated patients who were intolerant to or failed other therapies. Four patients were treated for autoimmune cytopenias; all had a rapid complete or near complete response. Two patients were treated for autoimmune arthritis and colitis, demonstrating marked improvement. Three patients had complete resolution of lymphadenopathy and splenomegaly and all patients had a reduction in double negative T cells, a population hallmark of the disease. Based on these significant responses, we recommend that sirolimus be considered as second-line therapy for patients with steroid-refractory disease.

A prospective observational study of IVC filters in pediatric patients.

BACKGROUND: The use of inferior vena cava (IVC) filters to prevent pulmonary embolism (PE) has increased with the advent of retrievable filters (Crowther: Am J Med 120: S13-S17, 2007). Both permanent and retrievable filters have been used in the pediatric population, though reports describing such patients and their outcomes are limited. PROCEDURE: Our center has established a longitudinal prospective cohort study of consecutive patients with acute venous thromboembolism (VTE) at our pediatric tertiary care institution. Data collection in this study includes medical history, risk factors, radiologic and laboratory studies, therapy, and follow-up. RESULTS: Two hundred ten patients were enrolled into this cohort from January 2003 to January 2007. IVC filters were percutaneously placed into 11 patients, ranging in age from 6.8 to 23.4 years. The primary reason for filter placement was a VTE and a contraindication to anticoagulation. Nine patients had retrievable filters placed and two received permanent filters. Seven of the nine retrievable filters were removed 21-97 days (median 37 days) after placement. In the remaining two patients, thrombus prevented removal in one, and the filter was electively retained in the other. One patient with a permanent filter died from malignancy. The three patients who are alive and well with IVC filters have had them for 25-60 months. No patient with an IVC filter developed a subsequent PE. CONCLUSIONS: Approximately 5% of patients in this pediatric thrombosis cohort received an IVC filter. The placement and removal of these devices is technically feasible in children.

Modern management of haemophilic arthropathy.

Currently available factor concentrates for treatment of patients with haemophilia are virally inactivated or are made by recombinant technology and their broad use in developed nations has resulted in the dramatic elimination of the treatment-related viral illnesses that decimated the haemophilia community in the late 20th century. The major morbidity experienced by patients with haemophilia today is joint disease, a result of repeated bleeding episodes into joint spaces. Although administration of factor concentrates to prevent bleeding has been demonstrated to prevent haemophilic joint disease when applied assiduously, repeated bleeding episodes induce synovitis that is irreversible and may progress despite subsequent prophylaxis. Surgical and nuclear medicine interventions are available to reduce the pain of haemophilic arthropathy and to reduce further bleeding episodes. Patients with high titre inhibitors are at great risk for the development of joint disease and present the greatest therapeutic challenges when joint surgery is needed.

CD8(+) T-cell responses to adeno-associated virus capsid in humans.

Hepatic adeno-associated virus (AAV)-serotype 2 mediated gene transfer results in transgene product expression that is sustained in experimental animals but not in human subjects. We hypothesize that this is caused by rejection of transduced hepatocytes by AAV capsid-specific memory CD8(+) T cells reactivated by AAV vectors. Here we show that healthy subjects carry AAV capsid-specific CD8(+) T cells and that AAV-mediated gene transfer results in their expansion. No such expansion occurs in mice after AAV-mediated gene transfer. In addition, we show that AAV-2 induced human T cells proliferate upon exposure to alternate AAV serotypes, indicating that other serotypes are unlikely to evade capsid-specific immune responses.

Evidence of multiyear factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with severe hemophilia B.

In a phase I study, administration of an AAV2-FIX vector into the skeletal muscle of eight hemophilia B subjects proved safe and achieved local gene transfer and FIX expression for at least 10 months after vector injection, the last time point assessed by muscle biopsy. In hemophilia B dogs we have demonstrated FIX in both muscle biopsies and circulation >4 years following AAV2-FIX injection. Because circulating FIX levels remained less than 1% of normal in human subjects from the study, the duration of AAV2-mediated transgene expression in humans is unknown. We sought to determine if FIX gene transfer and expression persisted locally at injection sites. Muscle biopsies were obtained from one subject 3.7 years following treatment and revealed transgene FIX DNA and protein by quantitative PCR, DNA fluorescence in situ hybridization, and immunohistochemistry for FIX. These results demonstrate, for the first time, multiyear FIX expression by AAV2 vector in humans and suggest that improved muscle delivery provides effective treatment for protein deficiencies or muscle-specific diseases.

Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS).

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of double-negative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r = .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans.

Cystic fibrosis as a risk factor for recurrent venous thrombosis at a pediatric tertiary care hospital.

OBJECTIVE: To evaluate risk factors for recurrent thrombosis in pediatric patients. STUDY DESIGN: This prospective observational cohort study enrolled 120 patients with acute venous thromboembolism from January 2003 to April 2005. Data collection included medical and family history, radiologic and laboratory studies, therapy, and follow-up. RESULTS: The overall prevalence of recurrent thrombosis in our cohort was 19/120 (15.8%). Patients with recurrence were older, with a median age of 14.8 years (range 2 weeks-23.6 years), compared with 10.1 years (range newborn 23.4 years) in patients without recurrence (P = .03). Six of the 19 patients with recurrent thrombosis had cystic fibrosis (CF), compared with 0/101 without recurrence (P < .001). Five of these 6 patients were colonized with Burkholderia cepacia in their sputum. Central venous catheters were associated with most, but not all, of the thromboses in patients with CF. CONCLUSIONS: In this study, patients with CF had a high risk of recurrent venous thrombosis, as well as a high prevalence of colonization with B cepacia. The cause of this risk has not been defined. This observation may have important implications for thromboprophylaxis, particularly in the setting of central venous catheters.

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.

We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.