Subcutaneous Immunoglobulin Replacement Therapy Research Articles

Subcutaneous immunoglobulin replacement therapy in patients with immunodeficiencies – impact of drug packaging and administration method on patient reported outcomes

BackgroundHere, the perspective of patients with primary and secondary immunodeficiency receiving subcutaneous immunoglobulin (SCIg) via introductory smaller size pre-filled syringes (PFS) or vials were compared.MethodsAn online survey was conducted in Canada by the Association des Patients Immunodéficients du Québec (APIQ) (10/2020–03/2021). Survey questions included: reasons for choosing SCIg packaging and administration methods, training experiences, infusion characteristics, and switching methods. The survey captured structured patient-reported outcomes: treatment satisfaction and its sub-domains, symptom state, general health perception, and physical and mental function. Respondents using PFS were compared with vial users, overall and stratified by their administration method (pump or manual push).ResultsOf the 132 total respondents, 66 respondents used vials, with 38 using a pump and 28 using manual push. PFS (5 and 10 mL sizes) were being used by 120 respondents, with 38 using a pump and 82 using manual push. PFS users were associated with a 17% lower median (interquartile range) SCIg dose (10 [8, 12] vs. 12 [9, 16] g/week, respectively), a significantly shorter infusion preparation time (15 [10, 20] vs. 15 [10, 30] mins, respectively), and a trend for shorter length of infusion (60 [35, 90] vs. 70 [48, 90] mins, respectively) compared with those on vials. Patient-reported treatment satisfaction scores were overall similar between vial and PFS users (including on the domains of effectiveness and convenience), except for a higher score for vials over PFS on the domain of global satisfaction (p=0.02).ConclusionsConsistent with prescribing that reflects a recognition of less wastage, PFS users were associated with a significantly lower SCIg dose compared with vial users. PFS users were also associated with shorter pre-infusion times, reflecting simpler administration mechanics compared with vial users. Higher global satisfaction with treatment among vial users compared with PFS users was consistent with users being limited to smaller PFS size options in Canada during the study period. Patient experience on PFS is expected to improve with the introduction of larger PFS sizes. Overall, treatment satisfaction for SCIg remains consistently high with the introduction of PFS packaging compared with vials.

A single-institution pre-post comparison of subcutaneous immunoglobulin replacement therapy in allogeneic haematopoietic cell transplantation recipients.

Immunoglobulin replacement therapy (IgRT) reduces the risk of infection in hypogammaglobulinaemia secondary to chronic lymphocytic leukaemia and multiple myeloma. However, the benefit of IgRT, especially subcutaneous IgRT (ScIgRT), has not been assessed in hypogammaglobulinaemia after allogeneic haematopoietic cell transplantation (allo-HCT). We performed a pre-post comparison of the clinical impact of ScIgRT after allo-HCT in a retrospective analysis of 209 patients who underwent allogeneic HCT at our institution from 2011 to 2019. Since ScIgRT became available at our institution in April 2017, we categorized patients treated from January 2011 to March 2017 as the Pre-ScIgRT group (n = 118) and those treated from April 2017 to December 2019 as the Post-ScIgRT group (n = 91). The 2-year overall survival rate was 65% in the Pre-ScIgRT group and 81% in the Post-ScIgRT group (p = 0.02). The cumulative incidence (CI) of non-relapse mortality at 2 years was 18% and 7% (p = 0.02). There were 78 infectious events in 44 patients in the Pre-ScIgRT group and 28 such events in 19 patients in the Post-ScIgRT group. The CI of the documented infection during the observation period was between 38% and 21% (p = 0.01). Our study suggests that ScIgRT may reduce infection rates and improve prognosis after allo-HCT.

Cytokine dysregulation despite immunoglobulin replacement therapy in common variable immunodeficiency (CVID).

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency. CVID is a heterogeneous disorder with a presumed multifactorial etiology. Intravenous or subcutaneous immunoglobulin replacement therapy (IgRT) can prevent severe infections but not underlying immune dysregulation. In this study, we evaluated the serum concentrations of proinflammatory (TNF-α, IL-1β, IL-6) and immunoregulatory cytokines (IL-10), as well as lipopolysaccharide (LPS) and soluble CD14 (sCD14) in CVID individuals with infectious only (INF-CVID), and those with additional systemic autoimmune and inflammatory disorders (NIC-CVID), and healthy donors (HD). Our results showed increased serum concentrations of TNF-α, IL-1β, IL-6, and IL-10 in both INF-CVID and NIC-CVID subjects compared to HD. However, elevations of TNF-α, IL-1β, IL-6, and IL-10 were significantly more marked in NIC-CVID than INF-CVID. Additionally, LPS concentrations were increased only in NIC-CVID but not in INF-CVID compared to HD. Circulating levels of sCD14 were significantly increased in NIC-CVID compared to both INF-CVID and HD. These findings indicate persistent cytokine dysregulation despite IgRT in individuals with CVID. Moreover, the circulating cytokine profile reveals the heterogeneity of immune dysregulation in different subgroups of CVID subjects.

An Unexpected Diagnosis of MAGT1 Deficiency in a Patient with CVID-like Features, Molluscum Contagiosum and Atopy

Case DescriptionA 6-year-old boy presented to the immunology clinic with recurrent infections. He started to have recurrent otitis media at the age of 18 months. He also had multiple sinus infections and 3–4 episodes of pneumonia. Immunologic evaluation revealed an IgG of 498 (ref 608–1229 mg/dL), an IgA of 20.8 (ref 33–200 mg/dL) and an impaired response to the Streptococcus pneumoniae vaccine. T and B lymphocyte counts were normal. He was started on subcutaneous immunoglobulin replacement therapy after which his IgG level normalized and his frequency of sinopulmonary infections improved. He also has a history of eczema, chronic cough and environmental allergies for which he receives allergen-specific subcutaneous immunotherapy in addition to treatment with an inhaled corticosteroid and omalizumab. The patient also had persistent skin warts on his hands and extensive molluscum contagiosum lesions. He underwent targeted genetic testing for a primary immunodeficiency which revealed a hemizygous pathogenic variant in the magnesium transporter 1 (MAGT1) gene (c.580dup; p.Ser194Phefs*3). This variant is a duplication at nucleotide position 580 that creates a premature stop codon 3 amino acids downstream from this location. The patient subsequently underwent a carbohydrate deficient transferrin test (CDT) for congenital disorders of glycosylation (CDG) that revealed moderately elevated transferrin mono-oligosaccharide to di-oligosaccharide and Apo CIII-1/Apo CIII-2 ratios, consistent with the diagnosis of MAGT1-CDG (XMEN; X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia). Additionally, NKG2D surface expression was reduced by ~90% on the CD8T cells, and by ~85% on the NK cells in the patient sample compared to the control sample assessed in parallel. The patient continues to test negative for EBV infection by PCR. ConclusionXMEN disease (OMIM number 300853) is a rare, combined immunodeficiency resulting from a mutation in the magnesium transporter 1 gene (MAGT1) located on the X chromosome. Only 36 patients have been reported to have this disease thus far. While the clinical phenotype is variable, the disease is often associated with EBV infection. This case is unique in that the patient was diagnosed due to a history of severe warts, atopy, and hypogammaglobulinemia in the absence of EBV infection.

Increased Access to Immunoglobulin Replacement Therapy for Patients with Primary Immunodeficiency in Poland Based on Clinical Usage Data of Immunoglobulin G over a 5-Year Period

Owing to the rising popularity and demand for immunoglobulins (IgG), obtaining supplies and rationalizing IgG use have become challenging. Herein, IgG consumption in Poland was analyzed through total IgG use and number of patients reported to the National Health Fund between 1 January 2016 and 31 December 2020. Total IgG used within 5 years increased by 27.48%, IgG use/1000 inhabitants/year was 23.13 g (2016) and 29.61 g (2020). In 2020, 35.5 % of IgG used was for neurological conditions, 25% for primary immunodeficiencies (PID), and 39.3% for all other indications. Within 5 years, 1,121,168.75 g IgG was used in PID; the use increased by 72%, from 783 in 2016 to 1153 patients in 2020. The proportion of patients who received subcutaneous immunoglobulin (SCIG) replacement therapy (IgRT) increased to 78% (2020). Within 5 years, 1,783,534.81 g IgG was used in neurological drug programs (+42.44%) and 2,327,513.88 g (+1.25%) outside neurological indications and outside PID. The annual IgG amount decreased in adult anesthesiology and intensive care (-46%), internal medicine (-55%), pneumonology (-50%), pediatric clinical immunology (-50%), and gynecology and obstetrics (-48%) and increased in dermatology (+178%), rheumatology (+103%), and clinical transplantation (+82%). IgG use significantly increased in Poland, mostly owing to PID. Subcutaneous IgG administration is currently the most common mode of IgRT in PID patients. An increase in SCIG administration may be expected for other indications. Implementing evidence-based clinical guidelines is key to prioritizing and rationalizing IgG use for immunomodulatory indications and secondary immune deficiencies.

The effect of subcutaneous immunoglobulin replacement therapy on serum IgG levels in patients with primary immunodeficiency

Objective: In a large group of patients with primary immunodeficiency (PID), immunoglobulin replacement therapy is critical for infection control. There are two main methods of immunoglobulin replacement intravenous (IVIG) and subcutaneous (SCIG). The aim of this study was to determine the efficacy of SCIG by comparing IgG levels and frequency of infections obtained during SCIG replacements in patients with PID with those obtained during IVIG administration. Method: Immunoglobulin levels of 28 patients who were followed up in our clinic with a diagnosis of PID and who started IVIG replacement and switched to SCIG replacement after follow-up, were evaluated retrospectively. Serum IgG levels and frequency of infections before starting immunoglobulin treatment, the previous year of IVIG before starting SCIG replacement, and during the first six months, second six months, and second year of SCIG replacement were compared. Results: The mean age of all the patients that received SCIG was 10.5 years (min 15 months, max 23 years) and eleven of the patients were female. The mean serum IgG level of the patients before starting immunoglobulin replacement was 701±383 mg/dl, and for the final year they received IVIG replacement before switching to SCIG replacement it was calculated to be 900±342 mg/dl. The mean value was found to be 1082±312 mg/dl in the first six months after the initiation of SCIG, 1102±287 mg/dl in the second six months, and 1145±311 mg/dl in the second year. Serum IgG levels of the patients were significantly higher during IVIG and SCIG replacement than before treatment (p<0.05). Serum IgG levels during the first six months, second six months, and second year of SCIG treatment were significantly higher than levels during IVIG treatment (p=0.000, p=0.003, and p=0.002, respectively). Conclusion: Compared to IVIG replacement, significantly higher and more stable serum IgG levels can be obtained with SCIG replacement. This is expected to ensure improved outcomes in the management of infections in PID patients.

A RARE MANIFESTATION OF KIDNEY DISEASE IN COMMON VARIABLE IMMUNODEFICIENCY

<h3>Introduction</h3> Patients with Common Variable Immunodeficiency (CVID) are at risk for developing both infectious and non-infectious complications. An uncommon complication in patients with CVID is kidney disease. <h3>Case Description</h3> A 39 year old male with history of CVID, granulomatous and lymphocytic interstitial lung disease (GLILD), immune thrombocytopenia purpura, splenomegaly, Raynaud's phenomenon and autoimmune thyroiditis was found to have an asymptomatic elevated creatinine. He developed a gradual increase in creatinine starting in 2020 with a peak creatinine of 2.17 and blood urea nitrogen of 30 in 2022. His creatinine and blood urea nitrogen were 0.91 and 18 in 2019. CVID was originally diagnosed in 2016. He was managed on subcutaneous immunoglobulin replacement therapy for several years. He did not have a known family history of chronic kidney disease. Kidney biopsy demonstrated dense lymphocytic infiltration with B and T lymphocytes. He was started on slow prednisone taper, rituximab, and trimethoprim-sulfamethoxazole for <i>Pneumocystis</i> pneumonia prophylaxis. His kidney function improved and has remained stable with a creatinine and blood urea nitrogen of 1.68 and 27, respectively. <h3>Discussion</h3> This case serves as an example of a rare complication in a patient with CVID. The mechanism of kidney disease in CVID is not well known. Previous reported cases of kidney disease in CVID have demonstrated evidence of glomerulonephritis and tubulointerstitial nephritis. This case is also unique in that the patient was treated with rituximab. Further investigation is needed into the appropriate monitoring and treatment options for kidney disease with CVID.

Monoclonal antibody treatment of COVID-19 in a pregnant woman with common variable immunodeficiency

BackgroundSince the first reported case of COVID-19, infections due to the virus have ranged from mild to severe. Patients with inborn errors of immunity are thought to be at increased risk for infections such as COVID-19 due to the nature of their disease and being immunocompromised. Similarly, pregnant women by nature of physiological changes in immunity are susceptible to infections and consequently are felt to be at greater risk of contracting COVID-19 with potential grave consequences for not only the mother but also the fetus. Early treatment with novel therapeutics against the SARS-CoV-2 virus to prevent progression and these complications is paramount.Case PresentationA 31-year-old woman with a 22-year history of common variable immunodeficiency on subcutaneous immunoglobulin replacement therapy and 24 weeks pregnant with her third child presented to the Emergency Department with two-day history of pharyngitis that progressed to include nasal and chest congestion, non-productive cough and shortness of breath. Her vitals indicated temperature of 35 degrees Celsius, heart rate of 109 beats per minute, blood pressure 142/92 mmHg, respiratory rate 22/min and an oxygen saturation of 99% on room air. A workup was done and she was found to be positive for SARS-CoV-2 virus confirmed by PCR. She had a close contact, her husband, who had tested positive a few days prior. She had been previously vaccinated with three doses of the Moderna COVID-19 (Spikevax ®) vaccine. As she met the criteria for monoclonal antibody treatment, she received Sotrovimab on the same day of testing positive and tolerated it well with no side-effects. Her symptoms resolved within two to three days.ConclusionOur case, is the first to our knowledge, of a pregnant patient with common variable immunodeficiency diagnosed with COVID-19 and symptomatic successfully receiving treatment with Sotrovimab. Her rapid resolution of symptoms makes the use of monoclonal antibodies such as Sotrovimab a safe and useful option in this unique population.

Long Term Norovirus Infection in a Patient with Severe Common Variable Immunodeficiency.

Norovirus is the most common cause of acute non-bacterial gastroenteritis. Immunocompromised patients can become chronically infected, with or without symptoms. In Europe, common variable immunodeficiency (CVID) is one of the most common inborn errors of immunity. A potentially severe complication is CVID-associated enteropathy, a disorder with similar histopathology to celiac disease. Studies suggest that chronic norovirus infection may be a contributor to CVID enteropathy, and that the antiviral drug ribavirin can be effective against norovirus. Here, a patient with CVID-like disease with combined B- and T-cell deficiency, had chronic norovirus infection and enteropathy. The patient was routinely administered subcutaneous and intravenous immunoglobulin replacement therapy (SCIg and IVIg). The patient was also administered ribavirin for ~7.5 months to clear the infection. Stool samples (collected 2013–2016) and archived paraffin embedded duodenal biopsies were screened for norovirus by qPCR, confirming a chronic infection. Norovirus genotyping was done in 25 stool samples. For evolutionary analysis, the capsid (VP1) and polymerase (RdRp) genes were sequenced in 10 and 12 stool samples, respectively, collected before, during, and after ribavirin treatment. Secretor phenotyping was done in saliva, and serum was analyzed for histo-blood group antigen (HBGA) blocking titers. The chronic norovirus strain formed a unique variant subcluster, with GII.4 Den Haag [P4] variant, circulating around 2009, as the most recent common ancestor. This corresponded to the documented debut of symptoms. The patient was a secretor and had HBGA blocking titers associated with protection in immunocompetent individuals. Several unique amino acid substitutions were detected in immunodominant epitopes of VP1. However, HBGA binding sites were conserved. Ribavirin failed in treating the infection and no clear association between ribavirin-levels and quantity of norovirus shedding was observed. In conclusion, long term infection with norovirus in a patient with severe CVID led to the evolution of a unique norovirus strain with amino acid substitutions in immunodominant epitopes, but conservation within HBGA binding pockets. Regularly administered SCIg, IVIg, and ~7.5-month ribavirin treatment failed to clear the infection.

Nodular Skin Lesions in a Patient With X-Linked Agammaglobulinemia.

A 28-year-old man with X-linked agammaglobulinemia (XLA) on subcutaneous immunoglobulin replacement therapy presented with a 2-year history of scattered nodular skin lesions. Lesions were occasionally pruritic, mildly painful, and were worse during the summer when he was more active with his carpentry. He had no fevers, weight loss, or fatigue. Physical examination was notable for some scattered pink dermal papules and larger ulceronecrotic nodules with hemorrhagic crust on the bilateral arms, forearms, and lower back (Figure 1). His serum immunoglobulin (Ig) G level was 990 mg/dL (on IgG replacement). Serum IgA and IgM levels were undetectable. Analysis of lymphocyte subsets revealed absent CD19+ B cells and a normal CD3+ T-cell count. Shave biopsy of an ulceronecrotic plaque of the left forearm revealed irregular epidermal acanthosis with central ulceration (Figure 2A). In the dermis, there were multiple clusters of basophilic granules surrounded by a thin rim of eosinophilic material (Figure 2B). Additionally, there was a dermal mixed inflammatory infiltrate, primarily comprised of neutrophils and eosinophils.

SCIG administration: A promising and patient convenient alternative for those receiving long-term IVIG.

Background: Intravenous immunoglobulin (IVIG) therapy has been used as antibody replacement therapy in primary immunodeficiency diseases (PID) for more than 50 years. In this study, we aimed to define IVIG usage and adverse reactions and complications in PID and explain how subcutaneous immunoglobulin (SCIG) replacement therapy is an alternative that improves the patient experience. In addition, the additional nursing responsibilities associated with this service were also identified.Methods: Data and service satisfaction surveys for the last 10 years were reviewed from the Allergy and Immunology Division log registry for those on IVIG and SCIG.Results: IVIG practice: Most patients currently on IVIG in our unit have PID. Adverse reactions occur during the initial 30 to 60 minutes of the infusion and are mild and self-limited. Infusion reactions are more likely to occur in patients receiving IVIG for the first time. Infusion-related complications included pyrogenic reactions, allergic reactions, and vasomotor symptoms. Complications reported in the literature such as the transmission of blood-borne pathogens and other serious complications, including thrombotic events, renal adverse events, and aseptic meningitis were never reported. Pyrogenic reactions occurred at a rate ≥ 100 mL/hr in at least 3 patients, and a slower infusion rate of ≤ 75 mL/hr mitigated this rate-related complication.SCIG program: This program started in Qatar in 2017. Usually, the clinician assesses and evaluates several factors to help select candidates for this therapy, including the perceptions of inconvenience and/or pain of IV infusions, presence of difficult vein access, and other relevant clinical and social factors. Once training in the appropriate techniques has been accomplished (3–6 sessions), it is most often self-administered in the home setting by the patient or a parent for a child. Table 1 summarizes patients on SCIG.Additional nursing responsibilities: The nursing role in subcutaneous IgG administration is primarily that of an educator and to help the patient/family become independent. This can be achieved by the assessment of appropriate patient selection for self-administration. Determining which patients are suitable include adequate patient education with return demonstration of the necessary skill set, monitoring parameters, educating patients about their medication, and providing educational resources and support.Conclusion: SCIG administration can be a convenient alternative for patients with PID receiving long-term IVIG.

Analiza kliničko-laboratorijskih parametara kod pacijenata sa hipogamaglobulinemijom sa raznolikim početkom

Introduction: Common Variable Immunodeficiency (CVID) is the most prevalent primary immunodeficiency in adult population. The diagnosis is based on low concentration of at least 2 immunoglobulin classes, mostly IgG, with low IgA and/or IgM. Beside recurrent infections, patients with CVID usually suffer from different respiratory, gastrointestinal, autoimmune and malignant diseases. Leading therapeutic approach to managing CVID is regular intravenous (IVIG) and subcutaneous (SCIG) immunoglobulin replacement therapy. Aim: The aim of the study was to analyze clinical and laboratory parameters in patients with CVID. Material and methods: The present study included 24 patients with CVID who were treated at Clinic of Allergy and Immunology, University Clinical Center of Serbia from 2012 to 2022. Demographic data, clinical and laboratory parameters were obtained from the patients' medical records. The concentrations of IgG, IgM and IgA were measured by nephelometry. Statistical analysis was performed using descriptive methods, Student t test for independent samples and Fisher exact test. Results: Respiratory manifestations were found in 70.8% of patients, gastrointestinal in 45.8%, autoimmune in 29.2% and malignancies in 20.8%. The presence of autoimmune diseases was the most common within the patients aged between 20 to 30 years, and it was statistically significantly higher comparing to other age groups (p = 0.014). Serum IgG concentration of 7.6 ± 2.7 g/l was measured. Statistically significantly higher IgG concentrations were observed in patients receiving SCIG (10.2 ± 1.6), compared to those receiving IVIG (6.7 ± 2.4) (t = -3.3, p = 0.003). Premedication was required in 44.4% of patients receiving IVIG. Conclusion: The most common complication of CVID are chronic lung diseases. Autoimmune diseases are the most frequently diagnosed in patients between the ages of 20 and 30. The use of SCIG is identified as better form of immunoglobulin replacement therapy. Total immunoglobulin serum concentration measuring in patients with recurrent infections and autoimmune diseases can contribute to timely diagnosis.

Efficacy of Subcutaneous Immunoglobulin Replacement Therapy in Treating Secondary Immunodeficiency Disorders

In 1952, the first immunoglobulin products, made from human plasma, were used to combat infectious diseases such as primary immunodeficiencies during World War II. In addition, during the last 50 years, further research has been conducted to prove whether or not immunoglobulin therapy can truly be effective against primary immunodeficiencies such as X-linked agammaglobulinemia or Common Variable Immunodeficiency Disorder through both intravenous and subcutaneous administration. Intravenous administration has been effective in increasing overall Ig serum concentration in the blood for patients with primary or secondary disorders. However, as more research was conducted, scientists had concluded that the overall cost, maintenance, and at times, lack of efficiency, makes intravenous administration a burden. Thus, scientists have looked for an alternative through subcutaneous administration. For patients with primary immunodeficiencies, subcutaneous has been proven effective in increasing immunoglobulin concentration, even more than intravenous has. The benefit of subcutaneous administration at-home, the low cost, and the heightened efficacy make subcutaneous administration far better than intravenous for primary immunodeficiency patients. However for secondary immunodeficiency patients, the efficacy of subcutaneous administration has not been fully proven and the research is scarce and unreliable. Our literary review explores the advent of immunoglobulin therapy and its past research on both intravenous and subcutaneous administration for primary and secondary immunodeficiency disorders. We sought out to find potential experimental values researchers can conduct experiments to enhance the research on subcutaneous administration for secondary immunodeficiency patients.

Facilitated Subcutaneous Immunoglobulin Replacement Therapy in Clinical Practice: A Two Center, Long-Term Retrospective Observation in Adults With Primary Immunodeficiencies.

Facilitated subcutaneous immunoglobulin (fSCIG) replacement therapy is the latest method of IgG administration; however, real-life data are limited. We retrospectively analyzed the everyday experience of fSCIG administration, particularly, the method used to switch from intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) to fSCIG and the dosing modifications required. Of the 39 adult patients with primary immunodeficiency (PID) who received fSCIG, 34 remained on the therapy at the end of the study. The median observation time was 18 (range, 3–24) months. Two patients were IgG-treatment-naïve; 23 had previously received IVIG and 14 had received SCIG. In 25 cases, a non-ramp-up dosing mode was used to switch to fSCIG (including two half-monthly doses given biweekly in 14 cases, and full monthly doses given in 11 cases), a ramp-up mode was used in six cases; other methods were used in eight cases. The median IgG trough level at baseline was 7.9 g/L (n = 38), 7.9 g/L (n = 32) at Month 6, 9.0 g/L (n = 30) at Month 12, 8.6 g/L (n = 22) at Month 18, and 9.0 g/L (n = 11) at Month 24. No serious bacterial infections or hospitalizations due to PID complications occurred. At the end of the study, 24 patients (71%) received fSCIG every 4 weeks, six (18%) received fSCIG every 3 weeks, and four (12%) received fSCIG biweekly. In conclusion, our study provides real-life evidence of clinical efficacy of personalized fSCIG treatment when switching from prior immunoglobulin replacement using various switching modes and dosing frequencies.

Quality of Life Differences for Primary Immunodeficiency Patients on Home SCIG versus IVIG

BackgroundPatients with primary immunodeficiency disease (PIDD) and antibody deficiency require lifelong immunoglobulin replacement therapy. While both subcutaneous immunoglobulin (SCIG) and intravenous immunoglobulin (IVIG) replacement therapy are effective in preventing infection, patients with PIDD still experience worse health-related quality of life (hrQOL) outcomes.ObjectiveAssess differences in hrQOL for PIDD patients receiving home SCIG versus IVIG.MethodsSF-36 surveys were administered by a specialty pharmacy to 630 PIDD patients receiving home SCIG and IVIG at baseline and then every 3 months between 2014 and 2016. Results were analyzed using two-sample t tests and linear mixed effects model. Analysis was repeated for different age categories and trended over time.ResultsPatients receiving SCIG reported statistically significant higher energy fatigue scores (+ 9 points, p < 0.001) but lower perceived role limitations due to physical health scores (− 14 points, p < 0.001). These differences were only observed in patients > 36 years of age. There were no differences in the composite SF-36 score for patients receiving SCIG versus IVIG (+ 1, p = 0.66). Immunoglobulin-naïve patients all improved their hrQOL, but a larger improvement was seen in those initiating SCIG versus IVIG.ConclusionPatients with PIDD on home IVIG versus SCIG have similar composite hrQOL scores as measured by the SF-36. In the adult population, initiating immunoglobulin replacement with SCIG may result in more hrQOL improvement compared with IVIG, although personal preferences should also be considered.Clinical ImplicationsPatients with PIDD on home IVIG versus SCIG have similar composite health-related quality of life scores as measured by the SF-36.Capsule SummaryPatients with primary immune-deficiency on home IVIG versus SCIG have similar composite health-related quality of life scores as measured by the SF-36. Personal preferences are important in deciding whether to treat with IVIG or SCIG.

Primary immunodeficiency disease: a cost-utility analysis comparing intravenous vs subcutaneous immunoglobulin replacement therapy in Australia.

Hospital-based intravenous immunoglobulin (IVIg) treatment has been the standard treatment mode for patients with primary immunodeficiency disease (PID). With the newer home-based subcutaneous immunoglobulin (SCIg) becoming approved for use in most countries, the question arises as to whether SCIg is a cost-effective treatment mode compared to IVIg in Australia. We developed a Markov cohort simulation model with six health states: PID without infection, PID with infection treated at home or hospital, bronchiectasis without infection, bronchiectasis with infection treated at home or hospital, bronchiectasis with chronic Pseudomonas aeruginosa infection, and death, from an Australian healthcare system perspective. A 10-year time horizon with weekly cycles was chosen, and the expected costs and quality-adjusted life-years (QALYs) of the two treatment options estimated. The cumulative 10-year cost per patient was 297,547 Australian dollars (A$) with IVIg and A$ 251,713 for SCIg. IVIg resulted in 5.55 QALYs and SCIg 5.57 QALYs. Thus, SCIg appears to be a cost-saving option and possibly improves QALY from the Australian healthcare system perspective (i.e., the dominant treatment option). A probabilistic sensitivity analysis showed that the SCIg option is preferred in 93.2% of simulations given willingness to pay of A$ 50,000 per QALY gained. The results suggest that home-based SCIg is a cost-effective treatment option for patients with PID in Queensland, Australia.

Treatment Satisfaction with Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Immunodeficiency: a Pooled Analysis of Six Hizentra\xae Studies

PurposePrimary immunodeficiency diseases (PIDDs) are a heterogenous group of disorders characterized by intrinsic impairment in the immune system. Most patients with PIDD require life-long immunoglobulin G replacement therapy, which has been shown to reduce the rate of infections and, related hospitalizations and reduce health-related quality of life (HRQOL). Here, treatment satisfaction and HRQOL in patients with PIDD was evaluated upon switching from intravenous (IVIG) or subcutaneous immunoglobulins (SCIGs) to 20% SCIG (Hizentra®), and during long-term steady-state Hizentra® treatment.MethodsAnalyses were based on two pivotal (switch) and four extension/follow-up (maintenance) Phase III studies of Hizentra® conducted in Europe (EU), Japan (JP), and the United States (US). Two validated questionnaires were used: Life Quality Index (LQI) for assessment of IgG-specific perceptions of HRQOL and Short Form 36 version 2 (SF-36v2).ResultsIn the EU and JP switch studies, there was significant and meaningful improvement from Screening in LQI domain scores at all time points, largely driven by patients switching from IVIG to SCIG. In the EU switch study, there were also significant increases in mean SF-36v2 domain scores for Physical Function and General Health from Screening to Week 12. These improvements were observed also at Week 24. Overall, LQI and SF-36v2 domain scores were generally sustained in the maintenance studies.ConclusionsThese results showed that switching patients from IVIG to SCIG improves patient self-reported health status and IgG-specific HRQOL perception. The maintenance studies generally showed no deterioration of this improved health status over a long follow-up period.

Advantage of the subcutaneous immunoglobulin replacement therapy in primary immunodeficient patients with or without secondary protein loss.

Gür-Çetinkaya P, Çağdaş-Ayvaz DN, Öksüz AB, Ertoy A, Hayran U, Özkan F, Erol M, Tezcan İ. Advantage of the subcutaneous immunoglobulin replacement therapy in primary immunodeficient patients with or without secondary protein loss. Turk J Pediatr 2018; 60: 270-276. In recent years subcutaneous immunoglobulin is widely used for primary immunodeficient patients. Subcutaneous administration provides a more stable and higher serum immunoglobulin levels due to continuous and steady transition from lymphatics to the systemic circulation. We aimed to evaluate the changes in serum immunoglobulin levels under subcutaneous immunoglobulin therapy in patients with primary immunodeficiency with or without secondary protein loss. Nine patients with primary immunodeficiency who switched to subcutaneous immunoglobulin were enrolled. Age, gender, diagnosis, reasons of transition to subcutaneous route, reasons of secondary protein loss were recorded. A questionnaire consisting of frequencies and types of infections, side effects observed with intravenous and subcutaneous routes; date and reason of transition to subcutaneous route were asked to all participants. Serum immunoglobulin levels at the 3rd and the 6th months before and after subcutaneous route were recorded. Of the 9 patients (M/F=4/5) the median age was 12 years (6.1-28.7) and 5 of them had protein loss. In total, 444 injections were applied, and all patients experienced local reactions. Infections were more frequent under intravenous than subcutaneous route (p=0.004). We observed an increase in immunoglobulin levels under subcutaneous route (p=0.069 at 3rd; p=0.13 at 6th month). This increase was evident at the 3rd month of transition to subcutaneous route in patients with protein loss (p=0.080). There was an increase in serum immunoglobulin levels under subcutaneous route. However, increase was not statistically significant since the study group was small. This increment was prominent in patients with protein loss. Subcutaneous administration may be a good alternative for primary immunodeficient patients with protein loss who have persistent low serum immunoglobulin levels despite increments in the intravenous immunoglobulin doses.

Cost-effectiveness analysis of subcutaneous immunoglobulin replacement therapy in Iranian patients with primary immunodeficiencies.

Background: Economic evaluation of subcutaneous immunoglobulin therapy (SCIG) is important, and it has recently been used for treatment of patients with primary immunodeficiency (PID) diseases, and can improve allocation of resources in health care systems. The present research aimed at providing an economic assessment of SCIG and IVIG (intravenous immunoglobulin therapy) administration in Iran. Methods: Data related to clinical effectiveness were obtained from a meta-analysis. Economic analysis was performed taking into account the perspective of health care providers. Incremental cost-effectiveness ratio (ICER) was applied for economic evaluation of the 2 methods, and GDP per capita was considered as a threshold. Results: The results of meta-analysis suggested a higher effectiveness of SCIG compared to IVIG in serum immunoglobulin (Ig) levels (SMD= 0.336) and adverse effects (OR= 0.497), while the cost of IVIG was higher than SCIG ($1370 vs. $121). The ICER obtained in this paper ($2939 for adverse effects and $4348 for serum Ig level) was less than the GDP per capita in Iran ($4,916.10), and thus SCIG is a more cost-effective therapy for PID patients. Conclusion: Switching from IVIG to SCIG is cost-effective for PID patients and is approved by the health care providers’ points of view in this study.

Passive blood anaphylaxis: subcutaneous immunoglobulins are a cause of ongoing passive anaphylactic reaction

BackgroundAllergic, especially anaphylactic, reactions during immunoglobulin replacement therapy are rare, but their pathophysiology and classification remain ambiguous. Recent findings show positive results of skin tests with commercially available immunoglobulins, but target antigens and responsible compounds of the tested immunoglobulins have not been strictly identified.Case description and findingsFour adult patients with recently diagnosed common variable immunodeficiency qualified for standard subcutaneous immunoglobulin replacement therapy regimen. They had no history of receiving immunoglobulins, blood or blood product transfusions. Edema, confluent wheals and erythema were observed at the site of subcutaneous immunoglobulin infusion: typical early and late phase reaction. A transient increase in various passively transferred IgG and IgE antibodies was responsible for misleading positive outcome of the serological testing for active humoral response such as type I allergy, anti-Rh, isohemagglutinins and rheumatoid factor (RF). Although the clinical presentation was very unusual and severe, the retrospective analysis showed no isohemagglutinins, RF and IgE in the patients’ serum before but it was positive after the infusion (median IgE = 18 IU/ml, RF = 8 IU/ml). Type I allergic reaction (laryngeal edema, rhinoconjuctivitis) came out at +14 days of replacement therapy when the patient visited countryside. In the second patient anaphylactic reaction was observed 5 days after ScIg administration, and only when the patient consumed peanuts. Therefore, IgE concentration was measured retrospectively in a series of commercial preparations used in the initial subcutaneous immunoglobulin replacement therapy that caused the adverse event (AE) and it was determined between 138 and 232 IU/ml (kU/l), i.e. 690–2100 IU per g of protein. Specific IgE was within a wide range from 198 (mix of food) to 2809 kUA/l (mix of grass) but many of the tested allergen-specific IgE were class 2 or 3 (i.e. 0.71–17.5 kUA/l).ConclusionsThe case resembles passive cutaneous anaphylaxis and Prausnitz–Küstner reaction but clinical significance of the classical phenomena has not yet been described. This observation indicates that anaphylactic reactions during immunoglobulin replacement therapy may result from IgE or pathological IgG content. Such IgE presence was sporadically reported (34.5–105 IU/ml, i.e. 862.5–1450 IU/g of protein) in intravenous immunoglobulins that are used and monitored by healthcare professionals. In clinical practice the definition of adverse events is inadequate since individual batches of immunoglobulins come with different specificity therefore, they should be classified as transfusion products (not bioequivalents). Such new approach implies establishing (1) new control methods and strategies to ensure introduction of the safety regulations for subcutaneous home self-administration of immunoglobulins as well as (2) guidelines for the prevention of anaphylaxis in patients receiving immunoglobulins (for example peanut).