Approach To The Pediatric Patient: Central Diabetes Insipidus

Central diabetes insipidus (CDI) is a complex disorder in which large volumes of dilute urine are excreted due to arginine-vasopressin deficiency, and it is caused by a variety of disorders affecting the hypothalamic-posterior pituitary network. The differential diagnosis is challenging and requires a detailed medical history, physical examination, biochemical approach, imaging studies and, in some cases, histological confirmation. Magnetic resonance imaging is the gold standard method for evaluating congenital or acquired cerebral and pituitary stalk lesions. Pituitary stalk size at presentation could be normal, but it may change over time, depending on the underlying condition, while other brain areas or organs may become involved during follow up. Early diagnosis and treatment are crucial in order to avoid central nervous system damage, germ cell tumor dissemination, and to minimize complications of multiple pituitary hormone defects. We provide a practical update on the diagnosis and management of patients with CDI and highlight several pitfalls that may complicate the differential diagnosis of conditions presenting with polyuria and polydipsia. The need for a careful and close follow-up of patients with “apparently” idiopathic CDI is particularly emphasized, because the underlying condition may be recognized over time. The clinical scenario that we outline at the beginning of this article represents the basis for the discussion about how the etiological diagnosis of CDI can be overlooked, and demonstrates how a water intake and urine output improvement can be a sign of progressive damage of both hypothalamus and anterior pituitary gland with associated pituitary hormonal deficiencies.

Factors affecting orthodontic treatment time and how to predict it

Orthodontic treatment time has been associated with certain parameters that can affect the different aspects of treatment regards to the patient and orthodontist. Therefore, a large set of research has focused on studying these factors. Many factors have been proposed in the literature as significant predictors for prolonged orthodontic treatment duration. In general, these factors are related to the patient, orthodontist, procedure, and severity of the underlying condition. Acquiring more knowledge about these factors can help orthodontists speed up the treatment plan, which might enhance the treatment outcomes and enhance the levels of satisfaction. In the current study, we have provided updated evidence regarding the different factors affecting orthodontic treatment time according to evidence from studies in the literature. Many factors were reported, including factors related to the procedure and the underlying condition, and factors related to the patient and orthodontist. Increasing knowledge and experience of the orthodontist might increase the level of satisfaction as it has been reported to significantly reduce the treatment duration. However, this should be accompanied by adequate patient compliance, which was also reported to be a significant predictor for prolonged treatment duration. Investigating the application of recent modalities that can speed up the treatment plan is not adequately validated, indicating the need for future validating studies.

Bioelectric Medicine: Magicall Tools for Treatment of Many Diseases

Bioelectronic medicine is a relatively new area that focuses on developing methods for treating diseases that do not need medications. Bioelectronic medicine treatments are now possible thanks to a small embedded system that produces and delivers frequent digital doses to nerve bundles, resulting in a disease-fighting effect that can last hours or days and is based on mechanisms similar to drug therapies. Although this may sound like science fiction, electronic brain and nerve stimulators are now presence applicable to treat so many of ailments, including epilepsy, Parkinson's disease, and bladder control. Progress in treating such disorders has opened up possibilities for boosting memory, improving eyesight, strengthening a shaky gait, and even improving a golfer's swing. Those self-improvement dreams may be a long way off, but bioelectronic medicine is gaining traction as a new way to treat difficult diseases. What distinguishes bioelectronic medicine is its biological effect on the body, which goes beyond symptom management to treat the underlying condition by using the body's own mechanisms. With promising early results in many trials and further trials ongoing, bioelectronic therapies are likely to be accepted for clinical use within the next few years. To make this advancement possible, forward-thinking scientists, engineers, doctors, and innovators with specialised talents combined old and new discoveries in ways no one had before.

Infections in Secondary Immunodeficiency Patients Treated with IgPro10: A Real-Word Analysis of Patients, Including Those with Hematological Malignancies

Secondary immunodeficiency (SID) is an acquired condition caused by several factors including, but not limited to, B-cell malignancies, and may result in frequent, burdensome, and possibly life-threatening infections. Treatment guidelines recommend immunoglobulin replacement therapy (IgRT) in certain settings to prevent recurrent, persistent, or major (severe) infections. This retrospective analysis of a US healthcare database characterized patients (pts) with suspected SID, who experienced infections, and were or were not treated with IgRT (IgPro10 [Privigen ®]). Data were collected from 26 US healthcare organizations from TriNetX DataWorks™ Network between 1/1/09 - 1/31/20. Pts were required to have the following: suspected SID (defined as ≥1 underlying conditions related to SID such as: solid organ transplant [SOT], non-Hodgkin lymphoma [NHL], multiple myeloma [MM], and chronic lymphocytic leukemia [CLL]), ≥1 severe infection (defined as requiring hospitalization and/or treatment with intravenous antibiotics or anti-viral medication) or ≥2 non-severe infections between underlying condition diagnosis date and the index date, the absence of diagnosed primary immunodeficiency, and an available medical history of ≥12 months pre-index and ≥3 months post-index. The index date refers to first IgPro10 use or the corresponding date for pts not receiving IgPro10 (unexposed cohort). In the IgPro10 cohort, pts were required to have had ≥2 consecutive IgPro10 administrations within 90 days. Between the pre- and post-index periods, the following variables were compared for both cohorts: pts' treatment, underlying conditions, baseline characteristics, and change in annualized infection rate (for infections of any severity and severe infections). Pre-index immunoglobulin G (IgG) (or calculated globulin [CG]) levels were recorded as: hypogammaglobulinemia (HGG) (IgG <6 g/L or CG <18 g/L), normal (IgG ≥6 g/L or CG ≥18 g/L), or missing. A generalized estimation equation (GEE) model with logit link was used to compare the change in the proportion of pts with an annualized infection rate of zero from the pre- to the post-index period across both cohorts. The final sample comprised 222 IgPro10 pts and 11,226 unexposed pts. In the IgPro10 cohort, 143 pts were on IgPro10 for <6 months, 41 pts for 6-12 months, and 38 pts for >12 months. In both the IgPro10 and the unexposed cohorts, SOT was the most frequent underlying condition (45.5% and 44.6%, respectively), followed by NHL (21.6% and 28.2%, respectively), MM (14.4% and 10.1%, respectively), and CLL (11.3% and 7.6%, respectively). Age (mean [SD], 57.2 [13.9] vs 57.9 [17.0] years old, respectively) and sex distribution (male:female, 56.3%:43.7% vs 51%:48.8%, respectively) were similar in the IgPro10 and unexposed cohort. During the pre-index period, the IgPro10 cohort, compared with the unexposed cohort, received a greater number of antibiotic courses (median [interquartile range], 7 [20] vs 1 [5], respectively), had a substantially higher proportion of pts with HGG (HGG: 34.7% vs 3.0%; normal IgG: 43.7% vs 57.8%; missing: 21.6% vs 39.2%, respectively), and a lower proportion of pts with an annualized infection rate of zero (for infections of any severity and severe infections) (Figure 1). There was an approximate four-fold increase in the proportion of pts with no infections of any severity following IgPro10 administration; this increase was significantly larger than in the unexposed cohort (p<0.0001) (Figure 1). Additionally, there was an increase in the proportion of pts with no severe infections following IgPro10 administration. Again, this increase was significantly larger than in the unexposed cohort (p<0.0001) (Figure 1). This real-world study found that compared with pts not receiving IgRT, pts who subsequently went on to receive IgPro10 experienced more infections pre-treatment. Following IgPro10 administration, more pts had an annualized infection rate of zero (for infections of any severity or severe infections) compared with the pre-index period. Moreover, the increase in the proportion of pts with no infections was greater in the IgPro10 cohort than in the unexposed cohort, for both infections of any severity and severe infections. Taken together, these findings suggest effectiveness of IgPro10 in pts with SID, but further study, such as a prospective randomized controlled trial, is needed to confirm these initial findings. Figure 1 Figure 1. Disclosures Lahue: CSL Behring: Consultancy; Alkemi Health: Current Employment, Current holder of stock options in a privately-held company. Mallick: CSL Behring: Current Employment, Current holder of individual stocks in a privately-held company. Zhang: CSL Behring: Current Employment, Current holder of individual stocks in a privately-held company. Koenig: CSL Behring: Current Employment, Current holder of individual stocks in a privately-held company. Espinoza: CSL Behring: Current Employment, Current holder of individual stocks in a privately-held company. OffLabel Disclosure: IgPro10 (Privigen®, CSL Behring, King of Prussia, PA, U.S.), a type of immunoglobulin replacement therapy, is currently approved in the U.S. to treat patients with primary immunodeficiency (PI), chronic inflammatory demyelinating polyneuropathy (CIDP), and chronic immune thrombocytopenic purpura (ITP).

Chronic Lymphocytic Leukemia, T-Cell Large Granular Lymphocytic Leukemia in a Pediatric Patient without Underlying Condition

Background Large granular lymphocytic (LGL) leukemia is a rare hematological malignancy in children. The two types of LGL leukemia that have been described are T-cell and Natural Killer cell leukemia. It is most commonly diagnosed in older adults, average age of 60-year-old. About 20 cases of LGL leukemia have been reported in children and young adults. All the patients in the reported cases had immune dysregulation conditions, such as chronic graft versus host disease, common variable immunodeficiency disorder, Crohn's disease and autoimmune hemolytic anemia. Here we report a case of T-cell LGL leukemia in a 11-year-old boy without underlying condition who presented with chronic neutropenia associated with gingival hypertrophy, recurrent skin abscesses, aphthous ulcers, clubbing of nails and low bone density. Methods Multi-institution collaboration and literature review. Case Description 11-year-old male with two years history of episodic gum bleeding with gingival hypertrophy, skin abscesses, aphthous ulcers, chronic neutropenia and lymphocytosis presented to our clinic for further evaluation. Initial workup demonstrated moderate to severe neutropenia (absolute neutrophil count between 400/ul to 800/ul) with low segmented neutrophils of 2-4% and high lymphocytes of more than 80%, but normal white blood cell count, hemoglobin for age and platelet count. Peripheral blood smear showed several variant lymphocytes with cytoplasmic blebs and no immature cells present. Expansion of T-cell large granular lymphocytes were detected in peripheral blood by flow cytometry. Due to new symptom of lower back pain, a lumbar Magnetic Resonance Imaging was performed. Results showed low bone density with mild compression deformity of L1 and abnormal heterogeneous marrow signal with heterogeneous contrast enhancement. The abnormal bone marrow signal promoted the investigation of bone marrow aspiration and biopsy. Flow cytometry detected forty-five percent of lymphocytes with immuno-phenotype of CD3+, CD8+, CD57+, CD16+, CD7+ and CD5-. The morphology of minimal cytoplasm and mature chromatin along with immunophenotype were consistent with clonal T-cell large granular lymphocytic proliferation/leukemia. Further cytogenetic tests showed TCR gamma and beta genes rearrangement, STAT3 N647I mutation with normal male karyotype. A peripheral blood congenital neutropenia panel, which included a total of 18 genes, found a heterozygous mutation c 279 G>A in the Gata2 gene; a variant of uncertain significance. Next generation sequencing showed somatic mutations of TRGV10, TRGV8 TRGJ1, TNFAIP3 and STAT3. However, there was no germline mutations detected in sample from skin biopsy. Comprehensive evaluation by immunology, rheumatology and gastroenterology failed to detect any underlying conditions. Conclusion Due to rarity of LGL leukemia in pediatrics, standard of care guidelines are currently unavailable. Extrapolated from limited literature, two management options are considered: watch and wait approach versus early initiation of immunosuppressant chemotherapy. Improved diagnostics can aide management strategies in this patient population. Disclosures No relevant conflicts of interest to declare.

Inherited Leukoencephalopathies

Leukoencephalopathies are disorders that selectively involve the white matter of the brain. Acquired causes of leukoencephalopathy include inflammatory, infectious, vascular, neoplastic, and toxic disorders. Hereditary leukoencephalopathies encompass conditions characterized by progressive destruction or loss of previously acquired central myelin (leukodystrophies) and conditions associated with impaired formation of myelin (dysmyelination or hypomyelination). The study of clinical features, neuroimaging patterns, and biochemical and neuropathologic features of leukoencephalopathies has led to the discovery of the genetic defects responsible for many of these conditions. Variations in phenotype-genotype correlation can make prediction of the underlying condition challenging. Despite recent advances in molecular studies, approximately 50% of patients with hereditary leukoencephalopathies remain without a diagnosis. A systematic approach to guide investigations is important for a diagnosis.

1162. Antifungal Use in Immunocompromised Children in Europe: a 12-week Multicenter Modified Point prevalence Study (CALYPSO)

Background While antifungal consumption in immunocompromised patients appears high, data on children are limited. We analyzed antifungal use in hospitalized immunocompromised children across Europe in order to better organize a European pediatric antifungal stewardship programs (pAFS). Methods A multicenter 12-wk modified point-prevalence study was conducted. All patients hospitalized in hematology-oncology (HO) or bone marrow/solid organ transplant (BMT/SOT) units across Europe and receiving systemic antifungals were included. Data on ward demographics and policies were collected once at the beginning; weekly ward and patient data were prospectively collected during the 12-wk study period and entered in REDCap. Systemic antifungals administered were recorded (doses, duration, reason for administration or discontinuation). Results Twenty-one HO and 10 BMT/SOT units from 18 hospitals in 11 European countries participated in the study and 572 antifungal prescriptions were recorded. The most common underlying conditions were: 69% malignancy (81% hematologic, 19% solid tumors), 20% BMT, 6% hematologic diseases except malignancy and 4% primary immunodeficiency. Indication of antifungals was prophylaxis for 439 (77%) and treatment for 133 (23%) prescriptions (62 empirical, 43 pre-emptive, 28 targeted). Most common reasons for empirical, pre-emptive and targeted treatment were antibiotic-resistant febrile neutropenia (52%), abnormalities on chest-CT with/without positive galactomannan (72%) and candidiasis (82%), respectively. For targeted treatment, the most frequent pathogens were C. albicans (50%), C. parapsilosis (11%) and A. fumigatus (11%). Overall, fluconazole and liposomal amphotericin B were the most frequently prescribed agents both for prophylaxis (31% and 21%) and treatment (32% and 23%). However, in BMT patients the most frequently prescribed antifungal agents were fluconazole or micafungin for prophylaxis and caspofungin and voriconazole for treatment (Table). Antifungal agents used per underlying condition Antifungal agents used per underlying condition Conclusion Most systemic antifungal prescribing across European HO and BMT/SOT units is for prophylaxis, and fluconazole is the main antifungal prescribed. Results from this multicenter study can be a first step to guide a Europe-wide pAFS. Disclosures Emmanuel Roilides, MD, PhD, ECMM (Research Grant or Support, Other Financial or Material Support, ECMM grant for this study)

Mucormycosis (Black fungus): An alarming sign for COVID-19 patients

Mucormycosis (also known as zygomycosis) is a dangerous but uncommon fungal infection caused by a fungus known as mucormycetes. Mucormycosis can be caused by a variety of fungi. Mucormycetes are fungi that belong to the Mucorales scientific order. Molds can be found all over the place. Mucormycosis is a fungal infection that primarily affects persons who have health issues or who use medications that reduce the body's capacity to resist infections and illness. After inhaling fungal spores from the air, it most usually affects the sinuses or lungs. The majority of people are unaffected by these fungus. Breathing in mucormycete spores, on the other hand, can induce an infection in the lungs or sinuses, which can spread to other regions of the body in patients with compromised immune systems. It can also happen as a result of a cut, a burn, or another sort of skin injury. The fatality rate varied based on the patient's underlying condition, the type of fungus, and the affected body part (for example, the mortality rate was 46 percent among people with sinus infections, 76 percent for pulmonary infections, and 96 percent for disseminated mucormycosis). Antifungal medicines such as amphotericin-B, isavuconazole, posaconazole, and various combinations are used to inhibit the growth. Mucormycosis was studied for its spread, symptoms, treatment, prevention, and consequences.