An essential role for the Zn2+ transporter ZIP7 in B cell development.

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.

Emerging Paradigm of Primary Immunodeficiency Disease: Individualizing Immunoglobulin Dose and Delivery to Enhance Outcomes.

An emerging paradigm for the treatment of primary immunodeficiency disease (PIDD) with immunoglobulin (IgG) replacement therapy emphasizes the tailoring of treatments to each patient with the goal of preventing infections and minimizing side effects. Increasing evidence shows that the IgG dose needed to prevent infection varies with each patient, and both intravenous immunoglobulin (IGIV) and subcutaneous immunoglobulin (IGSC) have emerged as feasible modes of delivery. Although IGIV is currently the routine treatment, IGSC is increasingly being chosen as the preferred route of delivery due to greater flexibility and reduced side effects.

Facilitating home-based treatment of hereditary angioedema.

Hereditary angioedema (HAE) is a rare disorder causing periodic attacks of nonpruritic swelling, for which highly effective subcutaneous and intravenous therapies are available. The need to seek ongoing medical attention for HAE attacks at clinics and hospitals adds to the already considerable burden of the disease. Recent international consensus treatment guidelines have emphasized home-based therapy as a preferred managed strategy whenever possible. Here, we review various strategies for facilitating home-based treatment with injectable HAE medications (plasma-derived C1 esterase inhibitor [C1-INH], ecallantide, icatibant, and recombinant C1-INH). Medical literature relating to home-based treatment of HAE is reviewed and strategies for implementing home-based therapy are presented. Home-based treatment of HAE has been shown to reduce the time to initiation of treatment, reduce the duration and severity of attacks, and improve patients' quality of life. Several options are available to facilitate home treatment of HAE. Medical staff in a primary care setting can be educated in the care of HAE patients and can teach the technique of parenteral drug administration. Home care agencies and specialty pharmacies are present in most communities and specialize in patient education. Infusion centers are skilled at working with patients with chronic diseases who perform extensive self-care. HAE comprehensive care clinics provide expert diagnosis and disease management and may become the patient's primary source of HAE care. Home-based therapy of HAE has been shown to be safe and clinically advantageous. Various strategies are available for equipping HAE patients to administer their treatments outside of a medical facility.

Training hereditary angioedema patients to self-administer intravenous C1 esterase inhibitor concentrate.

Hereditary angioedema (HAE) is a rare disorder that causes periodic attacks of sometimes painful swelling that may affect any organ system. HAE results in significant morbidity and diminished quality of life and requires patients to seek urgent medical care. HAE can be treated with C1 esterase inhibitor concentrate (C1-INH), icatibant, and ecallantide. Recent consensus guidelines recommend that all HAE patients be considered for training in self-administration of therapy to treat acute attacks or to prevent attacks. Many patients have safely and successfully self-administered intravenous infusions of C1-INH, resulting in rapid treatment, shortened attacks, and improved quality of life. With proper patient selection and adequate guidance and follow-up, self-administered C1-INH therapy is a viable and favorable option to treat HAE, particularly in patients with a moderate to high frequency of attacks.

Subcutaneous immunoglobulin therapy given by subcutaneous rapid push vs infusion pump: a retrospective analysis.

BACKGROUND: Administration of subcutaneous immunoglobulin (SCIG) via rapid push, an alternative to infusion pump delivery, can offer heightened simplicity and convenience for patients with primary immunodeficiency disease (PIDD). OBJECTIVE: To assess dosing and administration patterns, serum IgG responses, safety, and tolerability of the subcutaneous (SC) rapid push technique. METHODS: A retrospective medical record review captured data on 173 patients with PIDD (1,140 follow-up visits) who self-administered SCIG (16% or 20%) via infusion pump or SC rapid push. RESULTS: Serum IgG levels increased from a mean (SD) trough of 903.8 (285.4) mg/dL during intravenous immunoglobulin use to a steady-state mean (SD) of 1,121.6 (257.6) mg/dL on SCIG. Mean frequency of weekly SCIG administration was 2.3 days per week with pump and 2.8 days per week with SC rapid push. Mean serum IgG levels were higher among push vs pump users (1,164 vs 1,048 mg/dL). Mean (SD) SCIG volume administered per infusion site with SC rapid push was 15.0 (7.3) mL (maximum, 60.0 mL). Most patients using SC rapid push infused in 9 minutes or less; median pump infusion duration was 49 minutes. Use of 20% SCIG was associated with smaller mean weekly product volumes vs 16% SCIG (41.7 vs 51.0 mL) and fewer mean dosing days per week (2.0 vs 2.8 days). Adverse events, primarily local, were reported on fewer visits with SC rapid push (15.6%) than with infusion pump (20.7%). CONCLUSION: The SC rapid push technique is a safe, viable alternative to an infusion pump, seemingly preferred by patients and offering more rapid administration.

Subcutaneous immunoglobulin: rapid push vs. infusion pump in pediatrics.

BACKGROUND: Subcutaneous immunoglobulin (SCIG) therapy is gaining favor for the management of primary immunodeficiency disease (PIDD) in adults and children. METHODS: A retrospective chart review captured data on 96 pediatric patients with PIDD using SCIG (16% or 20%) delivered by infusion pump or SC rapid push over 620 clinic visits. Patients previously using intravenous immunoglobulin (IVIG) were converted to SCIG dosing on a 1:1 basis. Patients/caregivers voluntarily chose an administration technique. RESULTS: Although mean SCIG dosing was lower on a g/kg/month basis compared with prior IVIG dosing, mean steady-state serum IgG levels during SCIG administration were about 100-200 mg/dl higher than IVIG trough values. On average, much more rapid infusion was achieved with the SC rapid push method, with 49% of patients reporting infusion times of 9 min or less; median duration of infusion pump administration was 45 min. The use of 20% SCIG increased dosing efficiency compared with 16% SCIG, allowing for a smaller weekly mean SCIG volume and fewer dosing days per week. Adverse event (AE) rates were lower in the pediatric subgroup compared with adults (15.8% vs. 18.8% of visits), and the majority of AEs were local. SC rapid push was reported most frequently for patients under age 2; its use decreased between ages 2 and <10 yr and then increased in adolescence and into adulthood. Only one of the pediatric patients returned to IVIG use. CONCLUSIONS: Administration of replacement Ig via SC rapid push is a safe and viable option in pediatric patients with PIDD.

Why I use subcutaneous immunoglobulin (SCIG).

Immunoglobulin (IgG) replacement is a life-saving treatment for individuals with primary immunodeficiency disease (PIDD). Today, there are many options for IgG replacement, and the choice is an individual one based on many factors. My preference for most patients is the subcutaneous (SCIG) route. It offers many advantages not offered by the intravenous (IVIG) route. These include: 1) independence from hospital-based infusion settings; 2) an alternative for patients with poor venous access; 3) better tolerability in those patients who are not able to tolerate IVIG; 4) flexibility of dosing; 5) ease of administration; 6) a very low side-effect profile; 7) a comparatively more even, almost physiological, IgG level; 8) less cost to administer than IVIG; and 9) improved quality of life in patients treated with SCIG compared with those treated with IVIG. For most patients with PIDD who require IgG replacement, SCIG offers advantages not available with IVIG.

Clinical ambiguities--ongoing questions.

Many factors need to be considered when choosing the mode of delivery of immunoglobulin (IgG) replacement therapy for a given patient with primary immunodeficiency disease (PIDD). Despite some general guidance as provided in the previous discussions, a number of ongoing questions remain. This article attempts to provide some answers and clarification for clinical situations in which the choice of intravenous IgG (IVIG) or subcutaneous IgG (SCIG) may be ambiguous.

Improved IgG3 levels and reduced infection rate in a woman with CVID switched from intravenous to subcutaneous immunoglobulin therapy.

AIM: To report the interesting case of a patient with common variable immune deficiency disease who demonstrated varied responses to intravenous (IV) and subcutaneous (SC) immunoglobulin (Ig) therapy with regard to both infection frequencies and IgG3 subclass determinations. PATIENT & METHODS: As part of routine medical care, the author monitored total and IgG subclass levels, along with infection frequencies in a 35-year-old woman, with recurrent sinopulmonary infections diagnosed with common variable immune deficiency disease. RESULTS: During treatment with IVIg, the patient's annual rate of infections decreased, although she experienced severe headaches. After being switched to daily SCIg therapy, the headaches stopped, and her annual infection rate declined further. Her IgG3 levels, which were undetectable during IVIg therapy, increased substantially during SCIg treatment. CONCLUSION: The reason for the observed correlation between IgG3 level restoration and a decline in infection rate after being switched to SCIg therapy is not entirely clear. At the minimum, it may suggest that IgG3 levels may be a simple and useful surrogate marker to monitor Ig replacement sufficiency in certain patients.

Payor issues: barriers to optimal management of patients with primary immunodeficiency.

Since 2005, when changes in Medicare reimbursement for IgG replacement therapy went into effect, physicians and patients with primary immunodeficiency disease (PIDD) have encountered a number of challenges to administering and receiving appropriate immunoglobulin therapy. A 2006 membership survey conducted by the American Academy of Allergy, Asthma & Immunology found that 95 % of responders thought that the health of their patients was at risk due to Medicare changes; many patient surveys also found a significant number adversely affected by these changes. Decisions critical for optimal care being made by third-party payors are often in conflict with guidelines on recommended standard of care. Many payors, for example, are dictating where infusions can occur despite evidence clearly demonstrating that choice of the site of care needs to be determined by the particular patient's circumstance and experience. Another critical issue is the lack of product availability due to the determination by payors of which IgG products appear on formularies. Patients, physicians, and payors all bring their own perspective to these issues, and finding a solution to these challenges requires balancing the needs of all three groups.

Local and national advocacy support.

Decisions by third-party payors that are restricting delivery of appropriate IgG treatment for primary immunodeficiency disease (PIDD) are summoning action from patients, physicians, and their organizations to ensure that high quality treatment remains accessible. Some of the strongest advocacy to date is from patient organizations, such as the Immune Deficiency Foundation (IDF), which strive to educate stakeholders on key issues that determine patient access to appropriate IgG treatment. These issues include the ability to choose the appropriate site of care based on a patient's experience and circumstance and greater awareness of product choice. Advocacy by physicians on these issues at the local level is needed, as are national efforts by organizations such as the American Academy of Allergy, Asthma & Immunology and their regional societies.

Malignancies in the setting of primary immunodeficiency: Implications for hematologists/oncologists.

Many primary immunodeficiency disorders (PIDD) are associated with elevated risks for different types of cancer. Defective immunosurveillance mechanisms in PIDD and infection with oncogenic viruses (eg, Epstein Barr, herpesvirus 8) seem to have significant contributory roles in many cases. Non-Hodgkin lymphoma and Hodgkin disease are two of the most common PIDD-associated malignancies. The impact of PIDD-associated malignancy has increased in recent years in parallel with improved patient with PIDD survival and longevity, due largely to effective immunoglobulin replacement therapy. Epidemiologic data, clinical patterns, and management considerations of the common PIDD-associated cancers are reviewed.