Individualized immunoglobulin treatment in pediatric patients with primary humoral immunodeficiency disease

Primary immunodeficiency diseases (PIDD) are a group of genetic conditions that are generally considered to be under‐diagnosed, and gaps may exist in the knowledge of treatment options. This review focuses on the diagnosis of pediatric patients with primary antibody deficiency and considerations for treatment with immunoglobulin (IgG) to optimize multiple dosing variables and minimize adverse events. The possibility of individualizing IgG therapy in clinical practice represents, in this field, the next pivotal step with the goal of improving the quality of life of pediatric patients with PIDD.     

Sirolimus‐induced interstitial lung disease following pediatric stem cell transplantation

Sirolimus‐induced ILD is a known but rare complication in adults who have undergone SOT. However, little is known about this adverse effect in children. Diagnosis of sirolimus‐induced ILD can be challenging, especially in patients who have difficulty participating in lung function testing. We present a case of presumed sirolimus‐induced ILD in a pediatric stem cell transplant patient who developed polycythemia and hypoxemia. To our knowledge, no other cases of sirolimus‐induced pulmonary toxicity in children after HCT have been reported.     

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case‐based review

An array of monogenic immune defects marked by autoimmunity, lymphoproliferation, and hyperinflammation rather than infections have been described. Primary immune regulatory disorders pose a challenge to pediatric hematologists and oncologists. This paper focuses on primary immune regulatory disorders including autoimmune lymphoproliferative syndrome (ALPS) and ALPS‐like syndromes, immunodysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) and IPEX‐like disorders, common variable immunodeficiency (CVID), CVID‐like, and late‐onset combined immunodeficiency (CID) disorders. Hyperinflammatory disorders and those associated with increased susceptibility to lymphoid malignancies are also discussed. Using a case‐based approach, a review of clinical pearls germane to the clinical and laboratory evaluation as well as the treatment of these disorders is provided.     

Immunodeficiency with recurrent panlymphocytopenia,impaired maturation of B lymphocytes,impaired interaction of T and B lymphocytes,and impaired integrity of epithelial tissue: A variant of idiopathic CD4+ T lymphocytopenia?

Idiopathic CD4⁺ T lymphocytopenia (ICL) has been defined as a cause of immunodeficiency with a variable clinical course and an unknown etiology. Here we describe a now 18‐year‐old boy with ICL, chronic mucocutaneous candidiasis (CMC), recurrent abscesses, and relapsing aphthous and ulcerous lesions. In addition to ICL the patient frequently showed a panlymphocytopenia. An increased percentage of γ⁺δ⁺ T lymphocytes and IgD⁺ IgM⁺ B lymphocytes, and a decreased percentage of CD21⁺ B lymphocytes, were observed. In vitro assays showed normal T‐cell responses to candidin and T‐cell mitogens, but impaired B‐cell responses to pokeweed mitogen (PWM). B‐cell maturation after stimulation with Staphylococcus aureus Cowan I (SAC) and interleukin 2 (IL‐2) was nearly normal. The clinical course of the patient improved substantially on administration of constant low‐dose therapy with fluconazole.     

Extracorporeal photopheresis as second‐line treatment therapy in life‐threatening primary graft dysfunction following lung transplantation

ECP is an established “second‐line” treatment for CLAD/BOS. Recently, ECP was used for the first time in an adolescent CF patient as a “second‐line” treatment therapy in life‐threatening primary graft dysfunction following lung transplantation who deteriorated despite extensive treatment including ECMO and ATG. Within 10 days after initiation of ECP twice weekly, allograft function and clinical status improved significantly and the patient was weaned from mechanical ventilation support. ECP has been continued every 2 weeks since. Two hundred days after lung transplantation, the patient has an acceptable allograft function (FEV1 67%) and no signs of allograft rejection. We advocate that use of ECP and its immunomodulatory effects should be evaluated in the early period following lung transplantation.     

A single‐center experience using alemtuzumab,fludarabine, melphalan,and thiotepa as conditioning for transplantation in pediatric patients with chronic granulomatous disease

Chronic granulomatous disease (CGD) is an immune deficiency characterized by defective neutrophil function and increased risk of life‐threatening infections. Allogeneic hematopoietic cell transplantation is curative for CGD, and conditioning regimen impacts transplant‐related outcomes. We report a single‐center prospective study (NCT01821781) of four patients with CGD transplanted using a reduced‐intensity conditioning regimen (RIC) containing alemtuzumab, fludarabine, melphalan, and thiotepa. Patients had early immune reconstitution with low incidence of infections. Disease‐free survival was 75% at a median of five years after transplant. This RIC regimen presents an alternative approach for transplant of patients with CGD who may not tolerate busulfan‐based conditioning.     

EBV‐directed viral‐specific T‐lymphocyte therapy for the treatment of EBV‐driven lymphoma in two patients with primary immunodeficiency and DNA repair defects

Children with ataxia telangiectasia (AT), a primary immunodeficiency caused by mutations in ATM, which is critical for repairing DNA defects, are at risk for the development of hematologic malignancy, frequently driven by infection with Epstein‐Barr virus (EBV). Conventional chemotherapy is poorly tolerated by patients with AT, with excessive toxicity even when doses are reduced. Here, we report on two patients with AT and EBV‐positive neoplasms who were treated with EBV‐targeted viral‐specific T cells (VST). One patient had a prolonged complete response to VSTs while the other had a partial response. Therapy was well tolerated without infusion toxicity or graft‐versus‐host disease.     

Low‐dose total‐body irradiation and alemtuzumab‐based reduced‐intensity conditioning regimen results in durable engraftment and correction of clinical disease among children with chronic granulomatous disease

HSCT with MAC is associated with durable donor engraftment for patients with CGD; however, MAC is limited by high rates of RRT. We used a novel RIC regimen with LD‐TBI (200 cGy × two doses), fludarabine (30 mg/m² × three doses), and proximal alemtuzumab (0.5 mg/kg/dose × one dose) and unrelated donor grafts for consecutive patients with high‐risk CGD who were not candidates for MAC at our institution. Among four children with CGD transplanted at our institution, three PBSC recipients are alive with sustained donor engraftment (median follow‐up: two yr) and resolution of pre‐HSCT active infections while one patient with bone marrow graft is alive after graft failure and autologous recovery. RIC may be a curative option for children with high‐risk CGD.     

CD25+CD4+ regulatory T cells in patients with Kawasaki disease

OBJECTIVE: To investigate whether the CD25 + CD4 + regulatory T-cell population, which plays important roles not only in maintaining immunologic self-tolerance but also in controlling the magnitude and character of antimicrobial immune responses, is related to the pathophysiology of Kawasaki disease (KD). STUDY DESIGN: The patient group consisted of 54 patients (median age, 30 months; 27 female and 27 male patients) fulfilling the criteria for KD. Age-matched control subjects included 17 patients with active infections and 24 healthy children. We analyzed CD25 + CD4 + cells and the mRNA expression of Foxp3, cytotoxic T lymphocyte-associated antigen 4 (CTLA4), glucocorticoid-induced tumor necrosis factor receptor (GITR), and transforming growth factor beta in peripheral blood mononuclear cells and purified CD4 + T cells. RESULTS: The proportions of CD25 + CD4 + cells in patients with acute-phase KD (median, 2.35% of total lymphocytes) were significantly lower than those in healthy control subjects (median, 3.14%) and control subjects with disease (median, 3.15%). The proportions returned to the normal level after intravenous gammaglobulin treatment (median, 3.86%). The mRNA expression of Foxp3, CTLA4, and GITR showed similar tendencies. CONCLUSIONS: The decrease of CD25 + CD4 + regulatory T cells in the acute phase might have a role in the development of KD.     

Infliximab regulates monocytes and regulatory T cells in Kawasaki disease

Background

The effect of infliximab (IFX ) on immune cells has not been fully reported in Kawasaki disease (KD ). To investigate the mechanism of IFX in KD , we examined changes in the abundance of CD 14⁺CD 16⁺ activated monocytes, regulatory T cells (T_reg) cells, and T‐helper type 17 (Th17) cells following treatment with IFX .

Methods

We collected peripheral blood from patients with i.v. immunoglobulin (IVIG )‐resistant KD and analyzed absolute CD 14⁺CD 16⁺ monocyte, T_reg (CD 4⁺CD 25⁺FOXP 3⁺) and Th17 cell (CD 4⁺IL ‐17A⁺) counts on flow cytometry. We also measured changes in serum soluble interleukin (IL )‐2 receptor (IL ‐2R), IL ‐6, and tumor necrosis factor (TNF )‐α on enzyme‐linked immunosorbent assay.

Results

T_reg cells and Th17 cells significantly increased after IFX treatment compared with baseline (126 ± 85 cells/μL vs 62 ± 53 cells/μL, P < 0.01; 100 ± 111 cells/μL vs 28 ± 27 cells/μL, P < 0.05, respectively). In contrast, in a subgroup of patients with CD 14⁺CD 16⁺ monocytes above the normal range before IFX , the CD 14⁺CD 16⁺ monocytes significantly decreased following IFX treatment (72 ± 51 cells/μL vs 242 ± 156 cells/μL, P < 0.05).. Serum TNF ‐α did not change, but soluble IL ‐2R and IL ‐6 decreased after IFX treatment.

Conclusion

IFX could downregulate activated monocytes and upregulate T_reg cells towards the normal range. IFX treatment thus contributes to the process of attenuating inflammation in KD .

     

Successful treatment of post‐transplant thrombocytopenia with romiplostim in a pediatric patient with X‐linked chronic granulomatous disease

Thrombocytopenia is a frequent complication following HSCT in pediatric patients. Romiplostim is a TPO receptor agonist that has been utilized successfully in the treatment of pediatric patients with immune thrombocytopenia. We describe a three‐yr‐old male with X‐linked CGD treated with an unrelated donor bone marrow transplant. His course was complicated by the development of symptomatic thrombocytopenia. He was started on romiplostim with prompt improvement in his thrombocytopenia. We found the use of romiplostim to be an effective and safe alternative to the potential complications as well as morbidity and mortality associated with the use of immunosuppressive agents such as corticosteroids.     

The successful use of alemtuzumab for treatment of steroid‐refractory acute graft‐versus‐host disease in pediatric patients

SR‐aGVHD remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Alemtuzumab has been used with success in adult patients but has not been studied in the pediatric setting. To estimate the effectiveness of alemtuzumab for the treatment of SR‐aGVHD in pediatric patients, we retrospectively reviewed the charts of 19 patients (median age 4 yr, range 0.5–28 years) with grades II (n = 3), III (n = 10), or IV (n = 6) SR‐aGVHD who received alemtuzumab treatment. Patients received a median dose of 0.9 mg/kg alemtuzumab (range 0.3–2 mg/kg) divided over 2–6 days. Eighty‐nine percent of patients received additional courses. A complete response, defined as GVHD of grade 0 at four wk following the first alemtuzumab course, was observed in nine patients (47%). A partial response, defined as an improvement in grade after four wk, was observed in five patients (26%). There was no response in five patients (26%). The overall response rate at four wk was 73%. Infectious complications included bacteremia (47%), presumed or documented fungal infections (21%), adenovirus viremia (52%), EBV viremia (36%), and CMV viremia (36%). We conclude that alemtuzumab is effective for SR‐aGVHD in pediatric patients with a tolerable spectrum of complications.     

Soluble tumor necrosis factor receptor‐1 in preterm infants with chronic lung disease

Background: It is clear that inflammation plays an important role in developing chronic lung disease in preterm infants. The purpose of the present study is to investigate changes of serum soluble tumor necrosis factor receptor‐1 levels over time in infants with chronic lung disease. Methods: The serum levels of soluble tumor necrosis factor receptor‐1 were measured after delivery, and at 7, 14, 21 and 28 days of age in 10 infants with chronic lung disease and in 18 infants without chronic lung disease. Results: The serum level of soluble tumor necrosis factor receptor‐1 was significantly higher in infants with chronic lung disease than in infants without chronic lung disease after delivery. The differences between these two groups remained up to 28 days of age. Conclusion: Prenatal inflammation with persistence into postnatal inflammation may be involved in the onset of chronic lung disease.     

Transverse myelitis as an unexpected complication following treatment with dinutuximab in pediatric patients with high‐risk neuroblastoma: A case series

Immunotherapy with the anti‐GD2 monoclonal antibody ch14.18, or dinutuximab, represents an important therapeutic advance in the treatment of pediatric high‐risk neuroblastoma and is now considered part of standard of care in this patient population. To date, transverse myelitis as a result of dinutuximab therapy has not been reported in clinical trials or in the published literature. We describe three patients with clinical symptoms of transverse myelitis, confirmed via magnetic resonance imaging, shortly following initiation of dinutuximab. All patients were discontinued from dinutuximab treatment and received urgent treatment, with rapid improvement in symptoms and resultant functional recovery.     

Successful treatment with placenta‐derived decidual stromal cells in a pediatric patient with life‐threatening acute gastrointestinal graft‐versus‐host disease

Severe aGvHD is a life‐threatening complication after allogeneic HSCT. The GI tract is considered to play a key role in aGvHD, where the disease process can start and is one of the major target organs. Here, we present a case of a one‐year‐old child with a life‐threatening GI‐aGvHD stage IV, post‐HSCT, resistant to steroids and MMF for 4 weeks. He was successfully treated with placenta‐derived DSC.     

Association of development of chronic lung disease of newborns with neonatal colonization of Ureaplasma and cord blood interleukin‐8 level

Background: The aim of the present study was to investigate the association of chronic lung disease (CLD), neonatal Ureaplasma colonization, and interleukin‐8 (IL‐8) level of cord blood in preterm infants. Methods: In 77 infants of <32 weeks gestation, the relationship between IL‐8 level of cord blood, neonatal colonization of Ureaplasma, histological chorioamnionitis (CAM), and development of CLD was studied. Results: Five infants died and 29 infants developed CLD. The CLD group had significantly lower gestation (mean ± SD: 26.6 ± 1.8 weeks) compared with the infants without CLD (28.9 ± 1.9 weeks, P < 0.0001). Logistic analysis showed that the development of CLD was associated with gestational age (odds ratio [OR], 0.5; 95% confidence interval (CI): 0.4–0.8) and Ureaplasma colonization (OR, 4.1; 95%CI: 1.2–14.4). Ureaplasma colonization was also associated with CAM (OR, 6.5; 95%CI: 1.8–23.5), absence of respiratory distress syndrome (OR, 6.2; 95%CI: 1.3–30.5), and development of CLD (OR, 4.0; 95%CI: 1.1–15.3). Elevated cord blood IL‐8 ≥100 pg/mL was associated with female sex and the isolation of microorganisms (OR, 49.4; 95%CI: 4.6–525). Conclusion: The development of CLD defined by oxygen requirement at 36 weeks was associated with neonatal Ureaplasma colonization but not with IL‐8 level of cord blood. Elevated cord blood IL‐8 was associated with neonatal microorganisms isolation.