Fatigue Is Common in Immunoglobulin G Subclass Deficiency and Correlates With Inflammatory Response and Need for Immunoglobulin Replacement Therapy

PurposeIndividuals with immunoglobulin G deficiency (IgGsd) often complain of fatigue. The correlation between systemic inflammation and fatigue is unknown. In this study perceived quality of life (QoL) and fatigue in individuals with IgGsd, on and off immunoglobulin replacement therapy (IgRT) were correlated to inflammatory markers in plasma to identify the subgroup that benefits from IgRT.MethodThirty-five IgGsd-patients were sampled on three occasions: at baseline, after being on IgRT for at least 18 months, and 18 months after discontinuation of IgRT. Short form 36, EQ-5D-5L visual analogue scale and fatigue impact scale questionnaires were used for evaluation of QoL and fatigue. Furthermore, a panel of 92 inflammatory markers were analysed in plasma. Thirty-two gender- and age-matched healthy individuals were included as controls and sampled on one occasion.ResultsQoL was lower and perceived fatigue higher in IgGsd compared to the controls. Severe fatigue and low QoL were associated with the need to restart IgRT (which is considered in IgGsd-individuals with a high burden of infections in Sweden). Twenty-five inflammatory factors were dysregulated in IgGsd and the plasma protein patterns were similar regardless of whether IgRT was ongoing or not. Enrichment analysis indicated IL-10 signalling as the most affected pathway. Severe fatigue was associated with decreased levels of the neurotrophic factors VEGFA and CSF-1.ConclusionFatigue is a major contributory factor to impaired health-related QoL in IgGsd and is related to the need for IgRT. Low-grade systemic inflammation is a potential driver of fatigue. In addition to the burden of infections, we suggest the degree of fatigue should be considered when the decision to introduce IgRT is made.

A summertime pause in immunoglobulin replacement therapy: a prospective real-world analysis

Aim: To describe the effects of a summertime pause (SP) in immunoglobulin replacement therapy (IgRT). Patients & methods: We conducted a prospective single-center observational study, including 44 patients undergoing intravenous IgRT between May and June 2019 in a French teaching hospital. Results: IgRT was interrupted in 23 patients from June to October. Patients who underwent an SP were older, more likely to have secondary immunodeficiency (SID) and received lower doses of immunoglobulin and more antibiotics during winter. Most patients who did not undergo an SP had severe primary immunodeficiency. The SP did not increase the risk of infection, improved the quality of life and reduced treatment costs. Conclusion: SP in IgRT is a safe practice and should be considered for patients with mild SID.

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

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

Immunoglobulin replacement for primary immunodeficiency: Indications for initiating and continuing treatment

Background: Immunoglobulin replacement therapy (IGRT) is the foundation of treatment for the majority of patients with primary immunodeficiency. Clinical history and laboratory evaluation define the patients for whom IGRT is necessary and appropriate. During the 70 years since the first patient was treated, new products have led to the development of several modes of administration that facilitate the individualization of treatment that enables the optimization of care. Objective: The objective was to explain the assessment of candidates for IGRT and approaches to reevaluating recipients of IGRT to decide on the need to continue treatment and to review the approaches to optimize IGRT. Methods: The relevant literature was reviewed in the context of the author's experience supervising > 20,000 IGRT treatments over a 40-year period. Results: Providing the most appropriate form of IGRT for individual patients ameliorates disease and lessens the burden of care for patients with primary immunodeficiency. Conclusion: IGRT is safe and effective when used to treat patients with primary immunodeficiency who meet established and appropriate clinical and laboratory criteria.