Rapid Push vs Pump-Infused Subcutaneous Immunoglobulin Treatment: a Randomized Crossover Study of Quality of Life in Primary Immunodeficiency Patients.

PURPOSE: Subcutaneous immunoglobulin replacement therapy (IgRT) may be administered once a week with a pump or every other day with a syringe (rapid push). The objective of the study was to compare the impact of pump and rapid push infusions on patient's life quality index (LQI). METHODS: This study was a randomized, crossover, multicenter, non-inferiority trial conducted in adults with primary immunodeficiency (PID) accustomed to weekly infusions at home by pump. Patients used pump or rapid push for 3 months each according to the randomized sequence. Main criterion was PID-LQI factor I (treatment interference). Non-inferiority ratio was set at 90%. RESULTS: Thirty patients entered the study; 28 completed the two periods. IgRT exposure was similar during each period. At the end of each period, mean LQI factor 1 was 87.0 (IC95% [80.3; 94.3]) and 77.80 (IC95% [71.5; 84.7]) for pump and rapid push, respectively. There was a slightly larger effect of rapid push on treatment interference than with pump so that the primary endpoint could not be met. No difference was found on other LQI components, satisfaction (TSQM), or quality of life (SF36v2). Eight patients declared to prefer rapid push while 19 others preferred pump. Of rapid push infusions, 67.2% led to local reactions vs 71.8% of pump infusions (p = 0.11) illustrating its good tolerance. Rapid push and pump infusions achieved similar trough IgG levels with similar incidence of infections. Rapid push saved 70% of administration cost when compared to pump. CONCLUSIONS: Since IgRT is a lifelong treatment in PID patients, individualization of treatment is of paramount importance. Rapid push is a new administration method in the physician's armamentarium which is preferred by some patients and is cost-effective. CLINICALTRIALS. GOV IDENTIFIER: NCT02180763 CLINICAL IMPLICATIONS: Self-administration of small volumes of immunoglobulins at home, every other day, using a syringe (rapid push) is a cost-effective alternative to administration of larger volumes by pump once a week. This study compared subcutaneous infusions of immunoglobulins either weekly via a pump or every other day via a syringe (rapid push). Rapid push is preferred by some patients and is cost-effective, therefore completing a physician's armamentarium.

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.

Pulmonologist perspectives regarding diagnosis and management of primary immunodeficiency diseases.

BACKGROUND: The time from symptom onset to diagnosis for patients with primary immunodeficiency diseases (PIDD) is an average of 12 years, but prompt diagnosis and treatment can promote best outcomes. OBJECTIVE: Because the manifestations of PIDD are often sinopulmonary in nature, patients with undiagnosed PIDD are frequently referred to pulmonologists. This study sought to identify opportunities among these specialists to improve diagnosis and clinical management of patients with PIDD. METHODS: A survey was sent to American Medical Association and American Osteopathic Association members whose specialty was pulmonology. Responses were compared with those from a historical survey of 71 subspecialist immunologists (American Academy of Allergy, Asthma Immunology members who devoted 10% of their practice to patients with PIDD). RESULTS: The surveys were returned by 485 pulmonologists, 49% of whom had diagnosed at least one patient with PIDD. In comparison with subspecialist immunologists, fewer pulmonologists were aware of the professional PIDD diagnosis and management guidelines and fewer followed up patients with various PIDDs. Pulmonologists and subspecialist immunologists also differed in the practice of prescribing prophylactic antibiotics and immunoglobulin replacement and in avoiding live viral vaccines. CONCLUSION: Differences in the diagnosis and treatment of patients with PIDD between these two groups of specialists revealed areas in which PIDD-focused educational initiatives may be helpful for pulmonologists.

The role of MAGT1 in genetic syndromes.

Disturbances in magnesium homeostasis, often linked to altered expression and/or function of magnesium channels, have been implicated in a plethora of diseases. This review focuses on magnesium transporter 1 (MAGT1), as recently described changes in this gene have further extended our understanding of the role of magnesium in human health and disease. The identification of genetic changes and their functional consequences in patients with immunodeficiency revealed that magnesium and MAGT1 are key molecular players for T cell-mediated immune responses. This led to the description of XMEN (X-linked immunodeficiency with magnesium defect, Epstein Barr Virus infection, and neoplasia) syndrome, for which Mg2+ supplementation has been shown to be beneficial. Similarly, the identification of a copy-number variation (CNV) leading to dysfunctional MAGT1 in a family with atypical ATRX syndrome and skin abnormalities, suggested that the MAGT1 defect could be responsible for the cutaneous problems. On the other hand, recent genetic investigations question the previously proposed role for MAGT1 in intellectual disability. Understanding the molecular basis of the involvement of magnesium and its channels in human pathogenesis will improve opportunities for Mg2+ therapies in the clinic.

Primary Immune Deficiency Treatment Consortium (PIDTC) report.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.

Stem cell transplantation for primary immune deficiency.

PURPOSE OF REVIEW: In this article, we summarize the recent advances in treating primary immune deficiency (PID) disorders by stem cell transplantation (SCT); we have focused on articles published in the past 2 years since the last major review of SCT for PID. RECENT FINDINGS: Analyses of the outcomes of SCT for PID by specific molecular defect have clarified which conditions are receptive to unconditioned transplants and which require more myeloablative conditioning. Improved outcomes for 'difficult' conditions [adenosine deaminase-severe combined immunodeficiency (ADA-SCID), major histocompatibility complex class II deficiency] and potential advantages of using cord blood as a stem cell source have also been described. Newborn screening for SCID identifies well babies with SCID: the optimal SCT protocol for such young infants remains to be determined. Reduced toxicity conditioning has been successfully used to treat conditions such as Wiskott-Aldrich syndrome and chronic granulomatous disease, offering curative engraftment with reduced transplant-related mortality. Similarly, treating children with familial hemophagocytic lymphohistiocytosis using reduced intensity conditioning SCT results in much improved outcomes. Advances in next generation sequencing have identified new diseases amenable to SCT, such as DOCK8 deficiency, resulting in improved quality of life and protection from malignancy. SUMMARY: Recent studies suggest that further improvements in treating PID with SCT are possible with a greater understanding of the genetics and immunobiology of these diseases, facilitating the matching of donor type and conditioning regimens, or indeed alternative therapies (such as gene therapy) to specific PID disorders.

Hypoplastic anemia in cartilage-hair hypoplasia-balancing between iron overload and chelation.

OBJECTIVE: To evaluate the severity of iron overload and the success of iron chelation therapy in patients with cartilage-hair hypoplasia (CHH) and hypoplastic anemia, with particular focus on adverse effects of iron chelators. STUDY DESIGN: Four of the 23 presently surviving Finnish patients with CHH under 18 years of age are dependent on regular red blood cell transfusions. Their hospital records were reviewed for history of anemia and chelation therapy. Cumulative iron load from transfusions was calculated. Efficacy of the chelation therapy was evaluated biochemically and by liver iron content assessments. RESULTS: At the introduction of iron chelation, the patients had received on average 99 (37-151) transfusions; the mean cumulative iron overload was 4640 (800-8200) mg, the annual iron accumulation rate 0.35 (0.25-0.41) mg/kg/d, and the mean plasma ferritin was 2896 (1217-6240) µg/L. Liver iron content, determined by biopsy in 3 patients, was on average 20.0 (6.6-30.0) mg/g liver dry weight. All patients, except 1 with Hirschsprung disease, tolerated deferoxamine, deferiprone, and deferasirox therapy well, showing only mild adverse effects typical for the agents. Plasma ferritin levels and liver magnetic resonance imaging T2* of iron overload showed successful chelation. CONCLUSION: Iron chelation is well tolerated in patients with CHH, with possible exception of patients with Hirschsprung disease. Successful chelation will prepare for hematopoietic stem cell transplantation in patients with CHH with persistent transfusion dependency.

¿Cómo manejar al paciente con artritis reumatoide y serología virus de hepatitis B, hepatitis C, virus de la inmunodeficiencia humana? / How does one manage patients with rheumatoid arthritis and positive serology to hepatitis B, hepatitis C, human immunodeficiency virus?

Las infecciones virales crónicas en un paciente reumático constituyen un reto diagnóstico y terapéutico. Algunos de los fármacos antirreumáticos modificadores de la enfermedad (FAME) más utilizados en la artritis reumatoide, como el metotrexato y la leflunomida, presentan riesgo de hepatotoxicidad. Con la terapia biológica, que es hoy en día ampliamente utilizada en pacientes refractarios a estos y otros FAME, se han descrito casos de reactivación de hepatitis B, incluso fulminante, especialmente con los antagonistas del TNF y rituximab, por lo que su utilización ha de ser cuidadosamente valorada y, generalmente, administrada junto con tratamiento antiviral. Sin embargo, no se han descrito casos de reactivación de hepatitis C tras terapia inmunosupresora. En los pacientes con serología VIH la administración de tratamiento inmunosupresor conlleva un elevado riesgo de infecciones oportunistas, aunque la nueva terapia antiviral altamente activa permite utilizar algunos fármacos en casos seleccionados (AU)

Chronic viral infections in rheumatic patients are a diagnostic and therapeutic challenge. Some of the disease-modifying antirheumatic drugs (DMARD) commonly used in rheumatoid arthritis, such as methotrexate and leflunomide, are hepatotoxic. With biological therapy, which is now widely used in patients refractory to these and other DMARD, some cases of reactivation of hepatitis B, even fulminant cases, have been reported, especially when employing TNF antagonists and rituximab, so their use must be carefully assessed and usually accompanied by antiviral therapy. However, there have not been reports of reactivation of hepatitis C after immunosuppressive therapy. In patients with HIV infection, administration of immunosuppressive therapy carries a high risk of opportunistic infections, although the new highly active antiviral therapy allows the use of some drugs in selected cases (AU)

Immunodeficiency disorders in horses.

Immunodeficiencies are characterized as primary (genetic) or secondary (acquired). Primary immunodeficiencies are relatively uncommon; however, clinically, they present a significant challenge to the practitioner, especially if the underlying disorder goes unrecognized. Secondary immunodeficiencies may present at any age, but failure of passive transfer in neonatal foals is most commonly encountered. This article provides a general overview of clinical signs and diagnosis of primary and secondary immunodeficiencies currently recognized in horses.

Lower serum zinc in Chronic Fatigue Syndrome (CFS): relationships to immune dysfunctions and relevance for the oxidative stress status in CFS.

The present study examines serum zinc concentrations in patients with chronic fatigue syndrome (CFS) versus normal volunteers. Serum zinc levels were determined by means of an atomic absorption method. We found that serum zinc was significantly lower in the CFS patients than in the normal controls. There was a trend toward a significant negative correlation between serum zinc and the severity of CFS and there was a significant and negative correlation between serum zinc and the subjective experience of infection. We found that serum zinc was significantly and negatively correlated to the increase in the alpha2 protein fraction and positively correlated to decreases in the expression of mitogen-induced CD69+ (a T cell activation marker) on CD3+ as well as CD3+CD8+ T cells. These results show that CFS is accompanied by a low serum zinc status and that the latter is related to signs of inflammation and defects in early T cell activation pathways. Since zinc is a strong anti-oxidant, the present results further support the findings that CFS is accompanied by increased oxidative stress. The results of these reports suggest that some patients with CFS should be treated with specific antioxidants, including zinc supplements.

Manifestaciones articulares en inmunodeficiencias primarias / Articular manifestations in primary immunodeficiencies

Las inmunodeficiencias primarias constituyen entidades clínicas que, aun cuando se presentan esporádicamente en la práctica diaria, suelen acompañarse de gran morbilidad y mortalidad si no se efectúan un diagnóstico y un tratamiento oportunos. Algunas de estas inmunodeficiencias pueden iniciar su sintomatología con manifestaciones articulares que semejan un proceso reumatológico. De las numerosas inmunodeficiencias primarias descritas hasta la fecha, la hipogamaglobulinemia común variable es la entidad que con más frecuencia se asocia con estas manifestaciones. La enfermedad se caracteriza por una deficiencia severa en la producción de anticuerpos, lo que conduce a infecciones bacterianas recurrentes. En tanto, ciertas condiciones predisponentes para algunas enfermedades reumatológicas, tales como Lupus eritematoso Diseminado, Vasculitis, Nefropatía y otras. El conocimiento de estas condiciones inmunológicas reviste una gran importancia en la patogenia y manejo de las enfermedades reumatológicas

Management of primary antibody deficiency by consultant immunologists in the United Kingdom: a paradigm for other rare diseases.

Variation in clinical practice and its effect on outcome is little known for rare diseases such as primary antibody deficiency. As part of a national audit a survey of all 30 consultant immunologists in the United Kingdom dealing with primary antibody deficiency syndromes in adults and children was carried out in 1993 to ascertain their practices in diagnosis and management. Consensus guidelines were published after the survey was completed. Comparison of the survey results of clinical practice at the time the guidelines were published with the standards identified highlighted that the practice of a minority of specialists was at variance with their peers and with the consensus document, particularly in the use of intramuscular immunoglobulin, the dose and frequency of intravenous immunoglobulin, and target trough immunoglobulin G concentration, which has implications for the quality of patient care. However, much closer agreement existed in the key areas of management, such as diagnosis and selection of intravenous immunoglobulin. The approach and the problems identified are relevant to the management of other rare diseases, in which diagnosis and management is complex and there are few specialists with the necessary knowledge to undertake such care. This survey, the first attempted audit of practice, shows that within a motivated group of specialists highly significant differences in practice may exist and the authors emphasise the importance of setting clear guidelines against which care can be assessed.

Chronic fatigue syndrome.

A 36-yr-old white female presented with severe fatigue and symptoms consistent with immune deficiency, but was later found to be suffering from chronic fatigue syndrome. This article discusses the diagnostic criteria for this condition. Chiropractic manipulation afforded relief of some symptoms for this patient.

Evaluation for immune system failures in horses and ponies.

Between January 1973 and September 1979, 2,092 horses and ponies were evaluated for immunologic disorders. A total of 418 abnormalities were detected in 416 (20%) of the animals tested. Disorders encountered were failure or partial failure of colostral immunoglobulin transfer from mare to foal (228 cases), combined immunodeficiency (159 cases), selective immunoglobulin M deficiency (19 cases), agammaglobulinemia (3 cases), transient hypogammaglobulinemia (2 cases), and lymphosarcoma (7 cases). Four conclusions were drawn from the study. (1) Immunologic abnormalities occur commonly in horses and ponies. (2) Failure and partial failure of passive transfer were the most common disorders, involving 19.7% of surveyed foals at risk. (3) Combined immunodeficiency remains a disease limited to Arabian horses. (4) Considering the high frequency of immunologic disorders in horses and the availability of diagnostic tests for the disorders, older animals with recurrent infections as well as all newborn foals should be evaluated for immune disorders.