Serial Serum Immunoglobulin G (IgG) Trough Levels in Patients with X-linked Agammaglobulinemia on Replacement Therapy with Intravenous Immunoglobulin: Its Correlation with Infections in Indian Children

Patients with primary antibody deficiency (PAD) are being increasingly diagnosed in the developing world. However, care of these children continues to remain suboptimal due to financial and social constraints. Immunoglobulin (Ig) trough level is an important predicting factor for infections in children on replacement immunoglobulin therapy. There are no data on this aspect from the developing world. Therefore, we studied serial immunoglobulin G (IgG) trough levels in 14 children with X-linked agammaglobulinemia (XLA) receiving replacement intravenous immunoglobulin (IVIG). Infections during the course of enrolment were documented prospectively. Mean age at the time of diagnosis was 5.1 years (range 2–11 years). Mean time from onset of symptoms and initiation of therapy was 3.3 years. Two children had established chronic lung disease prior to enrolment. Total numbers of major and minor infections were 7 and 40, respectively. At a mean dose of 414 mg/kg/month of IVIG, mean trough IgG level was 435 mg/dl. Median IgG trough levels during the episodes of major and minor infections were 244 and 335 mg/dl, respectively. An escalation in IVIG dose of 100 mg/kg produced an increase in serum IgG levels by 53.6 mg/dl. Median trough IgG level of 354 mg/dl was found to be protective with 64% sensitivity and 75% specificity. A median dose of 397 mg/kg was required to keep children free of infections. Despite financial constraints and several challenges in the context of a developing country, children with XLA have good outcome on replacement immunoglobulin therapy. Furthermore, mean biological trough IgG levels are much lower than reported in for Western patients; however, studies involving larger number of subjects are required in future to draw firm conclusions.     

Modulating Effects of Intravenous Immunoglobulins on Serum Cytokine Levels in Patients with Primary Hypogammaglobulinemia

BACKGROUND: Intravenous immunoglobulins (IVIG) have usually been administered for replacement therapy of humoral immunodeficiencies, but their use in treating other disorders with an immune pathogenesis is increasing. The exact mechanism of action by which IVIG are of benefit in such diseases is complex and only partly understood. One of the proposed mechanisms of action is the modulation of cytokine release. METHODS: We selected 29 patients with primary hypogammaglobulinemia (common variable immunodeficiency), receiving long-term substitutive therapy with IVIG, and 14 healthy blood donors as a control group. Blood samples were then taken before and 1 hour after finishing the IVIG infusion. Only one blood sample was obtained from the healthy controls. The cytokines studied were interleukin (IL)-1 beta, IL-1 receptor antagonist (IL-1Ra), IL-2, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. RESULTS: Patients with primary hypogammaglobulinemia showed significantly higher serum levels of IL-6, IL-8, IL-1Ra, and TNF alpha than healthy controls. IVIG infusion significantly increased serum concentration levels of IL-6, IL-8, IL-1Ra, and TNF alpha. No significant variation was observed in serum levels of IL-beta, IFN gamma, or IL-2 after IVIG infusion. Age, IVIG commercial preparation, and IVIG dose did not influence cytokine serum levels. Moreover, a significant correlation was observed between serum level variations of IL-1Ra and TNF alpha, as well as an associative trend between maximum changes in IL-6 and IL-8 concentrations. CONCLUSIONS: IVIG administration significantly alters the serum pattern of selected cytokines, which might explain, at least in part, the mechanism of action of IVIG in autoimmune or inflammatory disorders.     

Intravenous and Subcutaneous Immunoglobulin Replacement: A Two-Way Road. Optimizing Healthcare Quality in Patients with Primary Immunodeficiencies

Purpose

To evaluate the alternate use of subcutaneous immunoglobulin (SCIG) and intravenous immunoglobulin (IVIG) in patients with primary immunodeficiencies (PID) in a third-level Pediatric University Hospital.

Methods

Retrospective study of all patients receiving SCIG from 2006 to 2012. Data collected included demographics, date SCIG was started, date of switch to IVIG and reasons, administration tolerance, and related adverse events. Effectiveness was defined as the lack of severe infections.

Results

Twenty-three patients (15 male, 8 female) with PID were studied. SCIG was initiated at a median age of 14.2 years (8.4 months-25.7 years) and median duration on SCIG treatment was 41 months (4-68). Nine patients (39.1%) temporarily switched from SCIG to IVIG for the following reasons: vacation (8), administration issues (1), and transient need for immunomodulatory therapy (1). A mean of 5.2 IVIG infusions/patient (SD=2.86) was administered while on SCIG. IVIG-related adverse events were documented in 3 patients with 6 infusions. Eight (34.8%) patients definitively discontinued SCIG use for the following reasons: convenience (5), adverse effects (1), coagulopathy (1), and autoimmune thrombocytopenia (1). There were no severe infections requiring hospital admission in any patient during the study period.

Conclusions

Alternating SCIG and IVIG use in patients with PID was associated with considerable advantages in terms of convenience for the patients and their caregivers, while maintaining the effectiveness and safety of this therapy. Healthcare units treating these patients should show flexibility with this dual therapy in order to optimize patients’ quality of life.     

Comparative Study of Subcutaneous Versus Intravenous IgG Replacement Therapy in Pediatric Patients with Primary Immunodeficiency Diseases: A Multicenter Study in Argentina

Purpose

Several studies have shown that subcutaneous immunoglobulin (SCIG) infusions demonstrate similar efficacy to intravenous Ig (IVIG) in preventing infections in patients with primary immunodeficiency diseases (PID), and are safe and well tolerated in this population. This open, prospective/retrospective, multicenter study was designed to compare the effectiveness, safety and tolerability of a 16 % liquid human IgG preparation (Beriglobina P), administered SC, with previous IVIG treatment in PID pediatric patients in Argentina.

Methods

Fifteen subjects were enrolled in the study, and a total of 13 subjects (aged 6–18 years) completed the 36-week SCIG treatment period. All children had previously received IVIG treatment. The dose of SCIG equaled the previous IVIG dose and subjects received an average weekly dose of 139 mg/kg (range 105–181) during the SCIG period.

Results

Significantly higher serum IgG trough levels were recorded on SCIG treatment at 16, 24, and 36 weeks, when compared with previous IgG trough levels on steady-state IVIG treatment. The annualized infection rate was 1.4 infections/subject/year during the IVIG administration period compared with 0.4 infections/subject/year during the SCIG period. All subjects who completed the study chose to continue administering SCIG at home after the study had ended.

Conclusions

These data confirm that self-administered SCIG therapy is a well-tolerated and effective alternative to IVIG therapy for children with PID.     

The Comparison of the Efficacy and Safety of Intravenous Versus Subcutaneous Immunoglobulin Replacement Therapy

To compare the efficacy of immunoglobulin replacement therapy given intravenously versus subcutaneously to prevent infections in patients with primary antibody deficiency syndromes, an international, multicenter, open label, crossover study was designed. Forty patients were randomized to receive either subcutaneous or intravenous immunoglobulin replacement therapy for 1 year. In the second year, patients were switched to the alternative treatment, enabling patients to act as their own controls. Equivalent doses were given by both routes. Ethical approval was obtained from the review boards of the hospitals in which the patients were seen and written consent obtained from each patient. Patients with a primary antibody deficiency syndrome, either common variable immunodeficiency or IgG subclass deficiency or specific antibody deficiency, who required immunoglobulin replacement therapy were included in the study. Patients were excluded if they had significant thrombocytopenia (defined as platelets less than 50 × 10⁹/liter), had high levels of anti-IgA antibodies (defined as greater than 1:8192), or had severe adverse reactions to a blood product within the last 2 years. The primary end point was the number of infections and their severity (moderate and major) during the two treatment periods. Secondary end points were adverse reactions, length of infections, days lost from school or work due to infections, and acceptability of treatment regimens to the patients. Based on the assumption that it was difficult to prove equivalence of therapies statistically in crossover studies, an arbitrary number of 40 patients was selected on the basis that this might be achievable in 2 years. There are no significant differences in efficacy or adverse reaction rates between immunoglobulin replacement therapy given subcutaneously or intravenously.     

A Comparative Study of Intravenous Immunoglobulin and Subcutaneous Immunoglobulin in Adult Patients with Primary Immunodeficiency Diseases: A Systematic Review and Meta-Analysis

Subcutaneous immunoglobulin (SCIG) is a new therapeutic procedure for patients with primary immunodeficiency (PI). This research is a systematic review of studies on the efficacy and safety of intravenous immunoglobulin (IVIG) and SCIG in adult patients with PI. This study includes a systematic review of cohorts and randomized clinical trials (24 articles) from 5 databases with no time limits. Random effects meta-analysis was performed for outcomes such as efficacy and safety. Standard mean difference (SMD) of serum immunoglobulin level was equal to 0.336 (P <0.01; 0.205-0.467) and the odds ratio (OR) of side effects was 0.497 (P=0.1; 0.180-1.371). The results indicate that SCIG leads to a higher level of immunoglobulin and a reduction in side effects but shows the same infection rate as IVIG. Our analysis shows that shifting from IVIG to SCIG therapy can have clinical benefits for PI patients.     

Long-Term Experience of Subcutaneous Immunoglobulin Therapy in Pediatric Primary Immunodeficient Patients with Low and Normal Body Weight

Journal of Clinical Immunology - The aim was to review the compliance, side effects and effectiveness of subcutaneous immunoglobulin (SCIG) supplementation in patients with primary...     

Carimune NF Liquid is a Safe and Effective Immunoglobulin Replacement Therapy in Patients with Primary Immunodeficiency Diseases

Subjects with primary immune deficiency diseases treated with intravenous immunoglobulin (n=42) received intravenous infusions of Carimune NF Liquid every 3–4 weeks for 6 months without routine premedication. The mean dose/patient/infusion was 278.5–800.7 mg/kg. Also, 80.4% of infusions achieved maximum rates of ≥3.5 mg/kg/min; 32% of infusions were associated with adverse events during or within 48 h of their end (upper 95% confidence interval was 39.4%, meeting the Food and Drug Administration (FDA) criterion for acceptable tolerability), and 54.8% of subjects had at least one temporally associated adverse event considered at least possibly drug-related (headache: 35.7% of subjects, 12.4% of infusions; nausea: 14.3%, 3.5%; myalgia: 14.3%, 3.2%; fatigue: 11.9%, 5.7%). The frequencies of these were highest after the first infusion. There were no serious drug-related adverse events or acute serious bacterial infections. Serum IgG trough levels were unchanged from baseline. Carimune NF Liquid, a ready-to-use, high-concentration, liquid immunoglobulin preparation is safe and effective. On behalf of the study group     

Prospective Study on CVID Patients with Adverse Reactions to Intravenous or Subcutaneous IgG Administration

Introduction The multicenter prospective study provides information on adverse reactions to intravenous and subcutaneous immunoglobulin treatment in a cohort of 262 patients with common variable immunodeficiency. Severe adverse reactions are a rare but unpredictable event that might occur also in patients who tolerate substitutive intravenous or subcutaneous immunoglobulin therapy for months or years. Results Subcutaneous therapy has been proved to be a safe option in the 13 patients who had to stop intravenous treatment and who remained out of immunoglobulin replacement for long periods of time. However, severe reactions to subcutaneous therapy occurred at the first or after several subcutaneous immunoglobulin administrations in 2 out of 13 patients. Conclusion Therefore, patients with previous severe reactions to intravenous immunoglobulin should be considered at particularly high risk for reaction to subcutaneous administration. In these cases, switching from in-hospital administration to home self-administration should be done with extreme care.     

IgG Anti-IgA Subclasses in Common Variable Immunodeficiency and Association with Severe Adverse Reactions to Intravenous Immunoglobulin Therapy

The current therapy for common variable immunodeficiency is based on the administration of intravenous immunoglobulin preparations which may cause severe adverse reactions. Some reports have associated these reactions with IgG anti-IgA antibodies, although this is not yet clear. We analyzed 20 sera from common variable immunodeficiency patients by an enzyme immunoassay to detect IgG anti-IgA and determine its subclass profile. Five patients presented high levels of these antibodies, all of them had IgG1, two had IgG2 and IgG4 and one had IgG3. Three of these five patients were receiving non IgA depleted intravenous immunoglobulin and had no severe adverse reactions. One patient had persisted with similar high levels of IgG anti-IgA during three years. Therefore, the IgG anti-IgA antibodies, regardless to their subclass profile in the common variable immunodeficiency patients sera do not seem to be associated with severe adverse reactions to intravenous immunoglobulins.     

Home-Based Subcutaneous Immunoglobulin Versus Hospital-Based Intravenous Immunoglobulin in Treatment of Primary Antibody Deficiencies: Systematic Review and Meta Analysis

Immunoglobulin replacement by the subcutaneous route (SCIg) for the prophylactic treatment of primary or secondary antibody deficient patients has been introduced as an alternative to conventional intravenous administration (IVIg). This is a systematic review of all eligible studies comparing efficacy and safety of IVIg and SCIg. Retrospective and prospective cohort studies and randomized, controlled trials comparing SCIg to IVIg were identified from MEDLINE, EMBASE, CINAHL, AMED, CSR, ISI and Cochrane Database without restriction on publication date and language. If possible, meta-analysis was performed by using the Review Manager software. A total of 47 articles with 1,484 compared cases were reviewed. Subcutaneous immunoglobulin replacement achieved acceptable IgG trough level, low incidence of side effects, efficacy similar to IVIg infusions, better health related quality of life and treatment satisfaction, and faster functional recovery with less time off work. Because of the heterogeneity of the reports, meta-analysis had to be performed by random effect method for IgG trough levels [OR (odds ratio)?=?1.00, range?=?0.84–1.15; p?<?0.01], infection rates (OR?=?0.59, range?=?0.36–0.97; p?=?0.04), and adverse events (OR?=?0.09, range?=?0.07–0.11; p?<?0.001), which showed significant preference of SCIg over IVIg. Based on the analysis of published reports, changing immunoglobulin replacement therapy from IVIg to SCIg may be of benefit to qualified patients with primary immunodeficiency. These advantages, having been demonstrated in numerous studies,make medical, practical and economic sense to consider switching patients with antibody deficiency from IVIg to SCIg.     

Safety and Efficacy of Self-Administered Subcutaneous Immunoglobulin in Patients with Primary Immunodeficiency Diseases

Intravenous immunoglobulin (IVIg) infusions at 3–4 week intervals are currently standard therapy in the United States for patients with primary immune deficiency diseases (PIDD). To evaluate alternative modes of immunoglobulin administration we have designed an open-label study to investigate the efficacy and safety of a subcutaneously administered immunoglobulin preparation (16% IgG) in patients with PIDD. After their final IVIg infusion, 65 patients entered a 3-month, wash-in/wash-out phase, designed to bring patients to steady-state with subcutaneously administered immunoglobulin. This was followed by 12 months of weekly SCIg infusions, at a dose determined in a pharmacokinetic substudy to provide noninferior intravascular exposure. This resulted in a mean weekly dose of 158 mg/kg, calculated to equal 137% of the previous intravenous dose. Two patients (4%) each reported 1 serious bacterial infection (pneumonia), an annual rate of 0.04 per patient-year. There were 4.43 infections of any type per patient-year. Mean trough serum IgG levels increased from 786 to 1040 mg/dL during the study, a mean increase of 39%. The most frequent treatment-related adverse event was infusion-site reaction, reported by 91% of patients; this was predominantly mild or moderate, and the incidence decreased over time. No treatment-related serious adverse events were reported. We conclude that subcutaneous administration of 16% SCIg is a safe and effective alternative to IVIg for replacement therapy of PIDD.     

Effectiveness of Immunoglobulin Replacement Therapy on Clinical Outcome in Patients with Primary Antibody Deficiencies: Results from a Multicenter Prospective Cohort Study

A 5-years multicenter prospective study on 201 patients with common variable immunodeficiencies and 101 patients with X-linked agammaglobulinemia over a cumulative follow-up period of 1,365 patient-years was conducted to identify prognostic markers and risk factors for associated clinical co-morbidities, the effects of long-term immunoglobulin treatment and the IgG trough level to be maintained over time required to minimise infection risk. Overall, 21% of the patients with common variable immunodeficiencies and 24% of patients with X-linked agammaglobulinemia remained infection free during the study. A reduction of pneumonia episodes has been observed after initiation of Ig replacement. During the observation time, pneumonia incidence remained low and constant over time. Patients with pneumonia did not have significant lower IgG trough levels than patients without pneumonia, with the exception of patients whose IgG trough levels were persistently <400 mg/dL. In X-linked agammaglobulinemia, the only co-morbidity risk factor identified for pneumonia by the final multivariable model was the presence of bronchiectasis. In common variable immunodeficiencies, our data allowed us to identify a clinical phenotype characterised by a high pneumonia risk: patients with low IgG and IgA levels at diagnosis; patients who had IgA level <7 mg/dL and who had bronchiectasis. The effect of therapy with immunoglobulins at replacement dosage for non-infectious co-morbidities (autoimmunity, lymphocytic hyperplasia and enteropathy) remains to be established. A unique general protective trough IgG level in antibody deficiency patients will remain undefined because of the major role played by the progression of lung disease in X-linked agammaglobulinemia and in a subset of patients with common variable immunodeficiencies.     

Home Care Use of Intravenous and Subcutaneous Immunoglobulin for Primary Immunodeficiency in the United States

Purpose

Utilization reports on immunoglobulin (Ig) use for immunodeficiency in the United States (U.S.) have focused on prescribing practices in hospitals. There have been no large-scale reports on Ig use for immune deficiency in the home. We investigated the use of Ig in 3,187 subjects diagnosed with primary immunodeficiency.

Methods

Cross-sectional data on 4,580 subjects in the U.S. receiving Ig in 2011 was obtained from a major home care provider. Demographics, route, dose, and frequency of Ig use by subjects with ICD-9 coded primary immunodeficiencies were analyzed.

Results

Of 4,580 subjects, 3,187 had ICD-9 codes suggesting primary immunodeficiencies; 1,939 (60.8 %) were females and 1,248 (39.2 %) were males, with age ranging from 0 to 95 years. The predominant diagnoses were: common variable immunodeficiency (279.06; n?=?1,764; 55.3 %), hypogammaglobulinemia (279.00; n?=?635; 19.9 %), unspecified immunity deficiency (279.3; n?=?286; 9 %), other selective Ig deficiencies (279.03; n?=?171; 5.4 %), and agammaglobulinemia (279.04; n?=?127; 4 %). 54 % of subjects received Ig by the subcutaneous (SC) route, and 46 % by intravenous (IV) route, with more SC use by older subjects. The mean dose prescribed was 483 mg/kg/month, but less Ig was ordered for subjects on SCIg (409 mg/kg/month), as compared to subjects on IVIg (568 mg/kg/month). A highly significant inverse correlation between increasing age and dosage of Ig ordered was found (P?=?<.0001).

Conclusion

Analysis of home care use of Ig in primary immune deficiency revealed that the SC route was prescribed more than the IV route, especially for older patients. By either method of administration, less immunoglobulin was prescribed for older subjects.     

Impact of Site of Care on Infection Rates Among Patients with Primary Immunodeficiency Diseases Receiving Intravenous Immunoglobulin Therapy

Purpose

Patients with primary immunodeficiency diseases (PIDD) are at increased risk of infection and may require lifelong immunoglobulin G (IgG) replacement. Infection incidence rates were determined for patients with PIDD receiving intravenously administered IgG (IGIV) in a home or hospital outpatient infusion center (HOIC).

Methods

Data were extracted from a large, US-based, employer-sponsored administrative database. Patients were eligible for analysis if they had ≥1 inpatient or emergency room claim or ≥2 outpatient claims with a PIDD diagnosis between January 2002 and March 2013, 12 months of continuous health plan enrollment prior to index date (i.e., first IGIV infusion date), and 6 months of continuous IGIV at the same site of care after the index date. Incidences of pneumonia (bacterial or viral) and bronchitis (all types) within 7 days of IGIV infusion were retrospectively determined and compared between sites of care.

Results

A total of 1076 patients were included in the analysis; 51 and 49% received IGIV at home and at an HOIC, respectively. The event/patient-year of pneumonia was significantly lower in patients receiving IGIV at home compared to an outpatient hospital (0.102 vs. 0.216, p = 0.0071). Similarly, the event/patient-year of bronchitis was significantly lower among patients infusing at home compared to an HOIC (0.150 vs. 0.288, p < 0.0001).

Conclusions

PIDD patients experienced incidence rates for pneumonia and bronchitis that were lower for patients receiving home-based IGIV treatment versus HOIC-based IGIV treatment. The lower infection rates in the home setting suggest that infection risk may be an important factor in site of care selection.

     

Higher Doses of Subcutaneous IgG Reduce Resource Utilization in Patients with Primary Immunodeficiency

The recommended dose of IgG in primary immunodeficiency (PID) has been increasing since its first use. This study aimed to determine if higher subcutaneous IgG doses resulted in improved patient outcomes by comparing results from two parallel clinical studies with similar design. One patient cohort received subcutaneous IgG doses that were 1.5 times higher than their previous intravenous doses (mean 213 mg/kg/week), whereas the other cohort received doses identical to previous subcutaneous or intravenous doses (mean 120 mg/kg/week). While neither cohort had any serious infections, the cohort maintained on higher mean IgG dose had significantly lower rates of non-serious infections (2.76 vs. 5.18 episodes/year, P < 0.0001), hospitalization (0.20 vs. 3.48 days/year, P < 0.0001), antibiotic use (48.50 vs. 72.75 days/year, P < 0.001), and missed work/school activity (2.10 vs. 8.00 days/year, P < 0.001). The higher-dose cohort had lower health care utilization and improved indices of well being compared to the cohort treated with traditional IgG doses.     

原发性肝癌患者介入治疗前后sE-CAd、SF水平的变化

目的 :探讨了原发性肝癌患者介入治疗前后 ,血清可溶性上皮钙粘蛋白 (sE -CAd)和铁蛋白水平的变化。方法 :应用放免法测定 33例原发性肝癌患者血清铁蛋白含量 ,酶联法测定上皮钙粘蛋白含量 ,并与35名正常健康人作对照。结果 :原发性肝癌患者在介入治疗前血清铁蛋白和上皮钙粘蛋白含量非常显著地高于正常人水平 (p <0 0 1) ,介入治疗后 6个月复发者铁蛋白、上皮钙粘蛋白水平持续异常 ,未复发者铁蛋白、上皮钙粘蛋白水平恢复正常。结论 :血清铁蛋白 (SF)、上皮钙粘蛋白含量变化与原发性肝癌患者的病情和愈后密切相关 ,有一定的临床实用价值