Subcutaneous Replacement Research Articles

A heterozygous CARD11 variant in a patient with infantile atopic disease, humoral deficiency and lymphocytosis

The etiology of a vast majority of allergic diseases is presumed to be multifactorial, with environmental and nutritional exposures playing a causal role in polygenically susceptible individuals. The expanding availability of sequencing has allowed the identification of monogenic causes in patients presenting with severe atopic disease with or without other co-morbidities. Here, we describe a case of severe atopic dermatitis and hypogammaglobinemia associated with a CARD11 loss-of-function. Patient is an otherwise healthy 7-month male who presented with severe atopic dermatitis and seborrheic dermatitis. Eczematous lesions developed at 3 months of age and progressed despite standard treatment with topical steroids. There was no history of immunodeficiency or atopy in the family. Physical exam was notable for extensive scaly and xerotic plaques with lichenification. Workup revealed hypereosinophilia, high IgE (179 kIU/L), normal IgA (10 mg/dL), low IgM (6 mg/dL) and IgG (41 mg/dL). Lymphocyte analysis was significant for mild B-cell lymphocytosis (1,063 cells/cm2) with appropriate subsets. Patient was initiated on subcutaneous replacement immunoglobulin. Whole exome trio sequencing identified a de novo CARD11 variant (c.221G>A, p.G74D). Confirmatory testing in a CARD11 deficient Jurkat T-cell line demonstrated loss-of-function and dominant interference of wild-type CARD11 signaling.CARD11 encodes a membrane-associated protein that partners with BCL10 and MALT1 to form the CBM complex responsible for integrating antigenreceptor engagement with downstream activation of NF-κB. Recently, heterozygous hypomorphic mutations in CARD11 have been discovered in patients with severe atopic manifestations, otherwise known as CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS). Our case highlights the need for genetic testing in the evaluation of patients with severe and/or unusual atopy. We discovered a novel CADINS variant (p.G74D) in an infant presenting with extensive atopic dermatitis, seborrheic dermatitis, and hypogammaglobulinemia. Curiously, our patient also developed B cell lymphocytosis in the first year of life which is typically associated with BENTA disease. However, no gain-of-function activity was detected on in vitro testing. Further studies are needed to elucidate if modulation of CARD11 signaling by this variant can explain both gain-of-function and loss-of-function phenotypic features, as noted in prior cases.

Evidence of SARS-CoV-2 immunoglobulin G through subcutaneous replacement in a patient with known x-linked agammaglobulinemia

Evidence of SARS-CoV-2 immunoglobulin G through subcutaneous replacement in a patient with known x-linked agammaglobulinemia

Chronic hypogammaglobulinemia after allogeneic stem cell transplantation and their treatment with subcutaneous immunoglobulin in pediatric patients

IntroductionHypogammaglobulinemia in the first months after allogeneic hematopoietic stem cell transplantation (HSCT) is common in paediatric patients. During this phase, replacement therapy with human immunoglobulin must be administered parenterally to prevent infections. In some cases, this hypogammaglobulinemia persists over time, which forces further treatment when the patient is usually no longer a carrier of a central line, making them ideal candidates for subcutaneous replacement therapy. There is little published literature describing the use of this method in paediatric patients undergoing HSCT, widely described in replacement treatment in children with primary immunodeficiencies with very good results. Patients and methodsAn observational, descriptive, longitudinal and retrospective study is carried out. During the years 2008–2019, we evaluated all paediatric patients undergoing HSCT in our center with persistent chronic hypogammaglobulinemia (for over a year). The treatment phase with intravenous immunoglobulin (Privigen®) and the first four years of treatment with subcutaneous immunoglobulin (Hizentra®) are evaluated using a questionnaire. ResultsDuring the years 2008–2019, 175 patients underwent HSCT, 143 (82%) of whom exceeded three months after transplantation. Three (2%) of them had persistent hypogammaglobulinemia. All three share factors described in the literature involved in immune reconstitution. After analysing the questionnaire, it is observed that switching from intravenous to subcutaneous gammaglobulin has involved a great improvement in their quality of life. ConclusionsThe origin of chronic hypogammaglobulinemia in our patients shows different factors and cannot be attributed to a single cause. Due to the limited number of patients no conclusions can be drawn at the population level. We have been able to observe that replacement treatment with Hizentra 20% has been as effective as the intravenous administration without evidence of an increase in bacterial infections. Furthermore, it has also led to an improvement in quality of life and increased comfort, as the patients themselves have stated.

Hipogammaglobulinemia crónica postrasplante de precursores hematopoyéticos y su tratamiento con gammaglobulina subcutánea en pacientes pediátricos

IntroductionHypogammaglobulinemia in the first months after allogeneic hematopoietic stem cell transplantation (HSCT) is common in pediatric patients. During this phase, replacement therapy with human immunoglobulin must be administered parenterally to prevent infections. In some cases, this hypogammaglobulinemia persists over time, which forces further treatment when the patient is usually no longer a carrier of a central line, making them ideal candidates for subcutaneous replacement therapy.There is little published literature describing the use of this method in pediatric patients undergoing HSCT, widely described in replacement treatment in children with primary immunodeficiencies with very good results. Patients and methodsAn observational, descriptive, longitudinal and retrospective study is carried out. During the years 2008–2019, we evaluated all pediatric patients undergoing HSCT in our center with persistent chronic hypogammaglobulinemia (for over a year). The treatment phase with intravenous immunoglobulin (Privigen®) and the first four years of treatment with subcutaneous immunoglobulin (Hizentra®) are evaluated using a questionnaire. ResultsDuring the years 2008-2019, 175 patients underwent HSCT, 143 (82%) of whom exceeded three months after transplantation. 3 (2%) of them had persistent hypogammaglobulinemia. All three share factors described in the literature involved in immune reconstitution. After analyzing the questionnaire, it is observed that switching from intravenous to subcutaneous gammaglobulin has involved a great improvement in their quality of life. ConclusionsThe origin of chronic hypogammaglobulinemia in our patients shows different factors and cannot be attributed to a single cause. Due to the limited number of patients no conclusions can be drawn at the population level. We have been able to observe that replacement treatment with Hizentra® 20% has been as effective as the intravenous administration without evidence of an increase in bacterial infections. Furthermore, it has also led to an improvement in quality of life and increased comfort, as the patients themselves have stated.

Subcutaneous IG replacement therapy may be cost saving for PID in Spain

Subcutaneous IG replacement therapy may be cost saving for PID in Spain

Pulsatile subcutaneous hydrocortisone replacement in primary adrenal failure, a proof of concept pilot trial

Pulsatile subcutaneous hydrocortisone replacement in primary adrenal failure, a proof of concept pilot trial

Differential effects of subcutaneous pulsatile versus oral hydrocortisone replacement therapy on fMRI resting state and task based emotional processing in patients with primary adrenal insufficiency

Differential effects of subcutaneous pulsatile versus oral hydrocortisone replacement therapy on fMRI resting state and task based emotional processing in patients with primary adrenal insufficiency

Engineering a Multilayered Skin Substitute with Keratinocytes, Fibroblasts, Adipose-Derived Stem Cells, and Adipocytes.

A variety of skin substitutes that restore epidermal and dermal structures are currently available on the market. While the main focus in research and clinical application lies in dermal and epidermal substitutes, the development of a subcutaneous replacement, the hypodermis, is often neglected. This chapter describes the use of fibrin sealant as a hydrogel scaffold to generate a three-dimensional skin substitute. For the hypodermal layer adipose-derived stem cells (ASCs) and mature adipocytes are seeded within a fibrin hydrogel. On top, another fibrin clot with incorporated fibroblasts is placed for the construction of the dermal layer. Keratinocytes are added on top of the two-layered construct to form the epidermal layer. The three-layered construct is cultivated for up to 3weeks with keratinocytes being exposed to air according to the air-liquid interface cultivation model.

SUBCUTANEOUS C1-INHIBITOR FOR LONG-TERM PROPHYLAXIS IN HEREDITARY ANGIOEDEMA WITH NORMAL C1 INHIBITOR

Introduction Hereditary angioedema (HAE) is a rare disorder characterized by episodes of swelling without urticaria. HAE presents with decreased C1 inhibitor (C1INH) antigen (type I) or function (type II), or with normal C1INH (HAE-nC1INH). Case Description A 25-year-old female presented with intermittent airway, abdominal and extremity angioedema without hives every 2-4 weeks for 3 years, often coinciding with ovulation or menstruation. She had up to 24 emergency room (ER) visits and 5 hospitalizations annually, historically requiring intubation, abdominal laparoscopy and appendectomy. Pathology revealed normal appendix. C4, ANA, tryptase, C1INH antigen level, C1INH function, C1q and Factor XII gene testing were normal. Angioedema was unresponsive to high-dose antihistamines, systemic corticosteroids, and omalizumab. She was diagnosed with suspected HAE-nC1INH. Progesterone contraceptives and fresh frozen plasma were ineffective. On-demand ecallantide or icatibant reduced episode duration but she continued with frequent symptoms. Prophylactic tranexamic acid and subsequently IV C1INH 1000 units every 3-4 days resulted in modest preventative effects but she had ER visits, hospitalizations and decreased quality of life due to angioedema. In September 2017, she transitioned to prophylactic subcutaneous C1INH replacement 60 IU/kg twice weekly and has since experienced only 3 ER visits with rapid recovery, no hospitalizations, international travel and permanent employment. Discussion Plasma-derived human C1-INH has been reported as a successful acute treatment in HAE-nC1INH. A lower threshold for contact system activation might explain the benefit of higher C1INH levels in some HAE-nC1INH patients. Our report demonstrates that SQ C1INH may be effective for long-term prophylaxis in a subset of HAE-nC1INH.

Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks: An Open-Label Extension Study of the COMPACT Trial

Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks: An Open-Label Extension Study of the COMPACT Trial

Shift from intravenous or 16% subcutaneous replacement therapy to 20% subcutaneous immunoglobulin in patients with primary antibody deficiencies.

In patients with primary antibody deficiencies, subcutaneous administration of IgG (SCIG) replacement is effective, safe, well-tolerated, and can be self-administered at home. A new SCIG replacement at 20% concentration (Hizentra®) has been developed and has replaced Vivaglobin® (SCIG 16%).An observational prospective multi-centric open-label study, with retrospective comparison was conducted in 15 Italian centers, in order to investigate whether and to what extent switching to Hizentra® would affect frequency of infusions, number of infusion sites, patients’ satisfaction, and tolerability in patients previously treated with Vivaglobin® or intravenous immunoglobulins (IVIG).Any variations of dosage, frequency and duration of the infusions, and of number of infusion sites induced by Hizentra® with respect to the former treatment were recorded. Practical advantages and disadvantages of Hizentra®, with respect to the medicinal product formerly used, and the variations in patients’ therapy-related satisfaction were monitored by means of the TSQM (Treatment Satisfaction Questionnaire for Medication); number, frequency, and duration of infectious events and adverse effects were recorded.Eighty-two patients switched to Hizentra®: 19 (23.2%) from IVIG and 63 (76.8%) from Vivaglobin®. The mean interval between infusions was not affected by the shift (7.0 ± 2.0 days with previous treatment versus 7.1 ± 1.2 during Hizentra®). A decrease in the number of infusion sites with Hizentra® was recorded in 12 out of 56 patients for whom these data were available. At 6 months, 89.7% of patients were satisfied with Hizentra®; no difference in terms of effectiveness, side effects, convenience, and global satisfaction was observed. No difference in the incidence of adverse events was reported.

Comparison of Clinical Outcomes and Laboratory Measures in Patients with Common Variable Immunodeficiency on Subcutaneous Immunoglobulin Replacement Versus Intravenous Immunoglobulin Replacement

Immunoglobulin replacement can be life-saving for certain individuals with immunodeficiencies. Several options for IgG replacement exist, including preparations of both intravenous (IVIG) and subcutaneous IgG (SCIG) replacement. SCIG administration is an increasingly used method of replacement with potential advantages including fewer systemic side effects, no need for IV access, patient-reported improved quality of life, and decreased cost. In addition, patients with associated co-morbidities, for instance, those that cause protein loss, may demonstrate more stable, consistent IgG levels on subcutaneous replacement when compared to intravenous replacement.

Generation of a Fibrin Based Three-Layered Skin Substitute.

A variety of skin substitutes that restore epidermal and dermal structures are currently available on the market. However, the main focus in research and clinical application lies on dermal and epidermal substitutes whereas the development of a subcutaneous replacement (hypodermis) is often disregarded. In this study we used fibrin sealant as hydrogel scaffold to generate a three-layered skin substitute. For the hypodermal layer adipose-derived stem cells (ASCs) and mature adipocytes were embedded in the fibrin hydrogel and were combined with another fibrin clot with fibroblasts for the construction of the dermal layer. Keratinocytes were added on top of the two-layered construct to form the epidermal layer. The three-layered construct was cultivated for up to 3 weeks. Our results show that ASCs and fibroblasts were viable, proliferated normally, and showed physiological morphology in the skin substitute. ASCs were able to differentiate into mature adipocytes during the course of four weeks and showed morphological resemblance to native adipose tissue. On the surface keratinocytes formed an epithelial-like layer. For the first time we were able to generate a three-layered skin substitute based on a fibrin hydrogel not only serving as a dermal and epidermal substitute but also including the hypodermis.

Subclinical infection and dosing in primary immunodeficiencies.

Subclinical infection and dosing in primary immunodeficiencies.

Evaluation of safety and efficacy of a 20% Subcutaneous Immunoglobulin (Hizentra™), after a dose equivalent switch from intravenous or subcutaneous replacement therapy in a cohort of primary immunodeficient patients

Methods A cohort study of 57 PID patients was reviewed 3 months post-transition to the 20% Subcutaneous Immunoglobulin (HizentraTM), in order to evaluate clinical outcomes and adverse events related to a dose-equivalent switch from 10% liquid solution intravenous (Privigen and Gamunex) or 16% subcutaneous replacement therapy (Vivaglobin) to weekly infusion of HizentraTM, Descriptive analyses were performed in relations to IgG levels, total infusion volume and infusion time.

Immune Globulin Subcutaneous (Human) 20%

Immune globulin subcutaneous 20% is a new high-concentration (200 g/L) solution of highly purified human IgG (≥98%) indicated in the EU and the US for antibody replacement therapy in patients with primary immunodeficiency with antibody deficiency, and in the EU for replacement therapy in humoral immunodeficiency secondary to myeloma or chronic lymphocytic leukaemia.Immune globulin subcutaneous 20% is formulated with L-proline, which imparts long-term stability at room temperature and a relatively low viscosity.In two pivotal phase III trials in stably treated patients with primary immunodeficiency, immune globulin subcutaneous 20% at weekly subcutaneous dosages either equivalent to each patient’s previous intravenous or subcutaneous replacement therapy, or providing equivalent systemic exposure to previous intravenous therapy, produced mean serum IgG trough levels equal to or greater than pre-study levels. In each trial, there were no serious bacterial infections during treatment throughout the 28-week or 12-month efficacy periods. The rates of infectious episodes, days missed from work/school, days hospitalized or days with antibiotics were low.Immune globulin subcutaneous 20% was generally well tolerated. A high proportion of patients experienced local infusion-site reactions, but infusion-related systemic adverse events were relatively infrequent. Most adverse events were of mild or moderate intensity and did not interfere with therapy.

79-Year-Old Woman With Forgetfulness

79-Year-Old Woman With Forgetfulness

Abstract 18327: Early Estrogen Replacement After Ovariectomy Limits Liver DAG and Promotes Insulin Sensitivity in a Manner That Requires Hepatic Estrogen Signaling

The cardiovascular effects of postmenopausal estrogen replacement have been controversial. Estrogen replacement at the time of menopause may protect from cardiovascular disease, due to improvements in the complications of obesity. We designed studies to define mechanisms by which estrogen replacement may alter the impact of high-fat feeding, when given at the time of surgical menopause by ovariectomy (OVX) in C57/B6 mice. OVX-mice had a 2-fold increase in adiposity after 5 weeks of high-fat diet feeding, compared with sham mice (sham 16.5±1.2% vs. OVX 32.4±3.1% adiposity). The weight gain and increased adiposity were prevented with subcutaneous replacement of estradiol (E2) at the time of OVX (OVX-E2 5.4±0.4% vs OVX 32.4±3.1% adiposity). We defined the impact of OVX and E2 replacement on insulin sensitivity with hyperinsulinemic-euglycemic clamp studies. For OVX mice, insulin sensitivity was reduced 25% compared with sham mice, while OVX-E2 mice had a 2.2-fold increase in insulin sensitivity (sham 694±51; OVX 519±125; OVX-E2 1584.0±197 mg•ml•[kg•min•mU]-1). Compared to OVX, after hyperinsulinemia, in the liver of OVX-E2 mice, we found: 1) increased phosphorylation of ACC (inactive form), increased protein amounts of DGAT 2 (promotes TG synthesis from DAG). This potential increase in fatty-acid oxidation, coupled with increased TG synthesis was associated with reduced liver DAG content in OVX-E2 mice (OVX 4.0±0.7 vs. OVX-E2 1.74±0.53 µg•mg-1), and increased phosphorylation of ser473-AKT (insulin-signaling activated). In order to define the requirement of liver estrogen signaling in the protective effects of E2 replacement, we performed a parallel study with OVX and E2 replacement in mice with liver estrogen receptor alpha knockout (LKO). While E2 replacement reduced adiposity in LKO mice similar to controls, E2 replacement in LKO mice failed to improve whole-body insulin resistance (746±138 mg•ml•[kg•min•mU]-1), and failed to prevent liver DAG accumulation (3.2±1.1 µg•mg-1) compared to OVX mice. This study demonstrates that estrogen replacement at the time of OVX promotes insulin sensitivity by increasing TG synthesis, thereby limiting liver DAG content, and lipotoxicity. This protective effect requires hepatic estrogen signaling.

Efficacy and safety of Hizentra® in patients with primary immunodeficiency after a dose-equivalent switch from intravenous or subcutaneous replacement therapy

A prospective, open-label, multicenter, single-arm, Phase III study evaluated the efficacy and safety of Hizentra(®), a 20% human IgG for subcutaneous administration, in 51 primary immunodeficiency patients over 40 weeks. Patients previously on intravenous or subcutaneous IgG were switched to weekly subcutaneous infusions of Hizentra(®) at doses equivalent to their previous treatment. IgG levels achieved with Hizentra(®) were similar to pre-study levels with subcutaneous, and higher by 17.7% than pre-study levels with intravenous IgG. No serious bacterial infections were reported in the efficacy period. The rate of all infections was 5.18/year/patient, the rates of days missed from work/school, and days spent in hospital were 8.00/year/patient and 3.48/year/patient, respectively. Local reactions (rate 0.060/infusion) were mostly mild (87.3%). No serious, Hizentra(®)-related adverse events were reported. Individual median infusion durations ranged between 1.14 and 1.27 h. Hizentra(®) maintained or improved serum IgG levels without dose increases and effectively protected patients against infections.

Use of hypodermoclysis to manage dehydration

Older people, particularly those who are frail, are vulnerable to dehydration. Management of dehydration in older people can be more complex than in younger adults because of the physical effects of ageing. As the population ages, nurses will increasingly care for older patients in every setting. This article provides an overview of the physiological changes that affect the ability of older people to maintain a normal fluid balance. Risk factors for dehydration are reviewed and strategies for the prevention, detection and management of dehydration are discussed. The article focuses on subcutaneous fluid replacement for the management of dehydration in older adults.