Injection of immunoglobulins in its initial form was developed during the 1940s for use in the war effort [1
] and was first used for primary immunodeficiency (PID) as a subcutaneous (SC) injection in 1952 by Dr. Ogden C. Bruton [2
]. Since then, neither an optimal dose nor serum trough level has been established [3
]. From the 1950s through the 1970s, Janeway and others administered IgG by intramuscular (IM) injections with doses of 25 mg/kg/week or 100 mg/kg/month, resulting in serum levels of 110 to 260 mg/dL, even though the landmark British Medical Research Council (MRC) study found that higher doses resulted in better outcomes [4
]. In the early 1980s, introduction of IgG preparations that could be safely given intravenously (intravenous IgG, IVIG) made it possible to administer higher doses without severe reactions [5
]. As IVIG and newer SC preparations of IgG (SCIG) were being adopted, the consensus regarding the optimal dose gradually grew to 400–800 mg/kg/month to achieve serum levels of 500 mg/dL or greater.
One potential reason for the continued evolution of the optimal IgG dose may be that the objectives of treatment have been changing through the decades, as studies showed that higher IV doses which yielded higher serum trough levels were more effective in reducing the incidence of infection. The World Health Organization (WHO) defines “health” to be a state of “complete physical, mental and social well being and not merely the absence of disease or infirmity” [6
]. Given that serious infections are efficiently prevented by IgG replacement, other outcomes that measure productivity, well being, and health utilization have been introduced in trials as measures for the comprehensive WHO definition of health [6
]. In addition, immunologists often raise the dose to try to prevent progression of chronic lung disease and other end-organ complications of PID.
The PID Committee of the American Academy of Allergy, Asthma, and Immunology (AAAAI) concluded in a 2006 report that the dose of IgG should be titrated to achieve a trough level greater than 500 mg/dL in agammaglobulinemic patients and that trough levels greater than 800 mg/dL have the potential to improve pulmonary outcomes [7
]. There have been few dose-ranging studies with IgG. In most recent licensing trials, the dose of IgG is based on the patients' previous treatment regimens without specifying how those doses were chosen by the patients' individual physicians. A survey of immunologists conducted recently by the AAAAI found that those immunologists who devote less than 10% of their practice to PID usually target a serum level of 500 to 750 mg/dL, whereas more experienced immunologists whose PID patient population exceeds 10% of their practice were significantly more likely to target serum levels above 750 mg/dL (P
= 0.02) [8
In 2010, the Canadian Blood Services published their review of dose-ranging studies and agreed that seven of the eight articles they reviewed concluded that outcomes were improved with higher doses of IVIG. Nevertheless, the authors concluded that although higher doses and serum trough levels appear to be associated with improved clinical response, clinical outcomes such as frequency of infections and days missed from school and work should be used to monitor the effectiveness of IgG therapy [9
]. Recently, Lucas et al. showed, in a cohort of 90 patients mostly with common variable immunodeficiency (CVID), that the ranges of both IgG dose and IgG trough level were very large and that the goal of replacement therapy should be to improve clinical outcome and not to reach a particular IgG trough level [10
]. Recent pooled analyses of multiple studies showed continuous relationships between IgG levels and incidence of pneumonia or other infections, with no sharp break points or plateaus [11
]. Also Bonagura et al. suggested that each patient has his/her own “biologic level” above which he/she is infection-free [13
]. No guidelines have identified a dose or serum level of IgG at which no additional clinical benefit is achieved, yet several payors have developed their own guidelines to limit reimbursement for IgG to only the dose needed to achieve a given serum IgG level regardless of the patient's clinical response. Other factors, such as periodic short supplies of IgG, have also limited the prescribing of higher doses of IgG and raising of IgG trough levels in PID patients to achieve optimal clinical responses.
The purpose of this analysis was to determine if there is a relationship between the use of a higher SC dose of IgG and improvements in patient outcomes such as missed work/school days, hospital days, days of antibiotic use, and infection rate. European and US health authorities required two different dosing levels for Hizentra® in their registration trials. This presented an opportunity to compare the outcomes from these independent cohorts of patients treated with different doses. This is the first analysis comparing patient outcomes achieved with two different SC dosing levels of Hizentra®, a recently approved 20% IgG preparation for SC use.
Comparison of the Hizentra® US and EU clinical registration trials
• 6 months of stable outcomes
• 6 months of stable outcomes
• Stable IV or SC IgG dosing
• Stable IV IgG dosing
• 3 trough levels ≥500 mg/dL
• 3 trough levels ≥500 mg/dL
Hizentra® dose during wash-in/wash-out period
Equivalent to pre-trial IgG dose
1.3 times the pre-trial IgG dose
Hizentra® dose during efficacy period
Equivalent to pre-trial IgG dose (1:1 dose)
1.5 times the pre-trial IgG dosea
Same (IgG trough levels, rate of infections, hospitalization days, days of antibiotic use, and missed work/school days)
Same (IgG trough levels, rate of infections, hospitalization days, days of antibiotic use, and missed work/school days)
The two independent patient cohorts were from two clinical trials conducted roughly in parallel, one in the USA and the other primarily in the European Union (EU), both of which shared many features of patient selection and study design as part of a single clinical development program (Table I
Both studies used an open-label, multi-center, single-arm design. The EU study enrolled patients from September 2007 to August 2009 [14
]. Patients qualified for the study if they were male or female, aged from 2 to 65 years, and diagnosed with primary humoral deficiency as defined by the Pan-American Group for Immunodeficiency (PAGID) and the European Society for Immunodeficiencies (ESID) [15
]. Prior to being enrolled in the European study, patients had to be successfully maintained on a stable (variation in dose not to exceed 10%) IV or SC dose of IgG of 200–800 mg/kg/month, to have at least three documented pre-study serum IgG trough levels of ≥500 mg/dL, and to have experienced an acceptable clinical response as judged by their physician. Study patients were converted to an equivalent dose of Hizentra® administered weekly by the SC route. This patient population is referred to as the “1:1 dose” cohort. After a 12-week wash-in/wash-out phase, patients entered the 28-week efficacy period where the dose was held constant (1:1 dose) and outcomes were monitored.
The second cohort of patients came from a study that was conducted in the USA from November 2006 through October 2008 [16
]. The study had similar pre-enrollment requirements for a stable pre-study dose with an acceptable clinical outcome. As requested by the US Food and Drug Administration (FDA), the dose for the 52-week efficacy phase was individually adjusted to give values for area under the curve of serum IgG vs. time (AUC) during SCIG therapy, which were equal to those recorded while the patients were still on the IV regimens prescribed by their physicians before enrollment. This resulted in a mean 1.5-fold increase in the SCIG dose compared to the previous IVIG dose. Additional details on the study designs are presented in the individual publications fully describing each study's effect on traditional endpoints such as infection rates and safety [14
The following secondary efficacy outcomes were assessed in both trials: missed work/school days due to infection, hospitalization days due to infection, and days of antibiotic therapy. These outcomes were reported as rate (days/patient/year) for the wash-in/wash-out and efficacy periods and served as the basis for this report. Local tolerability was assessed differently in the two studies. In the EU study, only patient's perception 24–72 h after the administration was recorded, while in the US study, the investigator assessed local tolerability within 15–45 min of the end of the infusion in addition to the patient's perception.
Differences in the distribution of categorical variables between the two cohorts were compared using Chi-square test. Mean age, weight, IgG dose, and serum IgG trough levels were compared using Student's t-test. The rates of infection, hospitalization, antibiotic use, and missed work/school days were compared between cohorts using Poisson regression, with and without controlling for key demographic differences between the cohorts, i.e., sex, age group (2–16/≥17 years), and PID type (XLA/CVID and other) using the days within the study as offset. The factor PID type was dropped from the multi-factorial analysis for hospitalization due to convergence problems. All analyses were performed using SAS Version 9.2 of the SAS System, SAS Institute Inc., Cary, NC, USA. A level of significance of 5% was set. No adjustment for multiplicity and no checks of model assumptions were performed.
The characteristics of the two patient cohorts are summarized in Table II
. Because similar study protocols were used to recruit patients from different continents, the two patient populations were generally similar. However, the EU population included more male, pediatric, and X-linked agammaglobulinemia (XLA) patients.
Summary of baseline and dosing characteristics of the patients in each trial
Age group (%)
PID diagnosis (%)
Mean weekly doses before study start (mg/kg)
Median IgG levels before study start (mg/dL)
| || |
Weekly dose of Hizentra® during the efficacy period (mg/kg)
Meanc (range) [SD]
120 (59–243) 
213 (72–379) 
Mean trough level during the efficacy period (mg/dL)
In the EU study, the mean weekly IgG dose administered during the efficacy period was 120 mg/kg (range 59–243 mg/kg), resulting in a mean trough level of 810 mg/dL (standard deviation [SD] 144 mg/dL). In the US study, the mean weekly IgG dose administered during the efficacy period was 213 mg/kg (range 72–379 mg/kg), resulting in a mean trough level of 1,253 mg/dL (SD 321 mg/dL). Of note, patients in the EU cohort had received lower mean IgG doses during their previous therapy (mean ± SD 107 ± 29 mg/kg/week for IVIG treatment and 132 ± 50 mg/kg/week for SCIG) compared with patients in the US cohort (145 ± 48 mg/kg/week).
No serious bacterial infections were reported in either study (Table III
). However, the rate of other infections was 2.76 events/patient/year in the 1.5:1 dose cohort vs. 5.18 events/patient/year in the 1:1 dose cohort (P
< 0.0001). The rate of days hospitalized in the 1.5:1 dose group was 0.2 days/patient/year vs. 3.48 days/patient/year in the 1:1 dose group (P
< 0.0001). The proportion of patients who became hospitalized was lower in the 1.5:1 dose group (2.6 compared to 8.7 for the 1:1 cohort); however, the difference observed was not statistically significant (P
= 0.2423). The rate of days of antibiotic use was 48.50 days/patient/year in the 1.5:1 dose group vs. 72.75 days/patient/year in the 1:1 dose group (P
< 0.001). Work/school days were missed at a rate of 2.06 days/patient/year in the 1.5:1 dose group vs. 8.00 in the 1:1 dose group (P
< 0.001). The proportion of patients missing one or more work/school days per year was lower in the 1.5:1 dose cohort, but the difference observed did not reach statistical significance (P
= 0.2637). The results of the EU study were substantially affected by the data of a child with recurrent pneumonia who missed 71 work/school days and spent 63 days in hospital [14
]. Therefore, a sensitivity analysis excluding this child was performed. The results of this analysis were similar to those for the entire populations (Table III
Comparison of health outcomes in the two cohorts of PID patients treated with different doses of subcutaneous Hizentra®
Rate of serious infections (events/patient/year)
| || |
Rate of infections (events/patient/year)
Rate of days of hospitalization due to infection (days/patient/year)
Percent of patients hospitalized due to infection
Rate of days with antibiotics for treatment or prophylaxis of infection (days/patient/year)
Sensitivity analysis a
Rate of days missed off work/school due to infection (days/patient/year)
Sensitivity analysis a
Percent of patients missing ≥1 day off work/school per year due to infection
Sensitivity analysis a
An analysis of rate of infection by month of the year was performed to account for the different duration of the two studies. The results showed an even distribution of onset of infections over the year in the US study (infection rate range, 1.14–3.82 infections/patient/year), while a seasonal variability was noted in the EU study. In the EU study, the rate of infection by month of onset ranged between 2.27 and 11.21 infections/patient/year, with the lowest rates of infection observed in June (2.27 infections/subject/year) and July (2.71 infections/subject/year) and the highest rates in January (11.21 infections/subject/year) and December (9.34 infections/subject/year). However, the overall rates of infection did not show any particular trend; thus, the rates for September, October, and November were similar to those for February, April, and August (5.17–6.65).
The rate of non-serious infections was significantly different between the two cohorts. To analyze further the reasons for this difference, an analysis of infection rates in patients experiencing more than four infections during the efficacy periods of the two studies was performed (Table IV
). A substantial contribution to the annualized rate of infections in the EU study was due to 12 patients who experienced a total of 79 infection episodes in the efficacy period, resulting in a statistically significant difference between the two cohorts (12.05 in the 1:1 cohort and 8.38 in the 1.5:1 cohort; P
= 0.0430). In the 1.5:1 cohort (USA), seven patients experienced a total of 51 infection episodes (Table IV
Analysis of infection rates in the two cohorts of PID patients
Number (%) of patients without infections in efficacy period
Number (%) of patients with 1–4 infection episodes in efficacy period
Number (%) of patients with >4 infection episodes in efficacy period
Annualized rate of infection in patients with >4 infection episodes in efficacy period
Because the two cohorts differed in gender, age, and PID type, a Poisson regression was conducted by controlling these differences as covariates in the analysis across the efficacy period of each study. The results of this analysis confirmed the significant differences in all four study outcomes (P
< 0.0001, Table III
). In addition, an analysis controlling for the length of the observation period was performed to compare the 1.5:1 and 1:1 cohorts up to the 28-week time point. During the first 28 weeks of the efficacy period in the 1.5:1 cohort, the rates of infection (2.7 events/patient/year), hospitalization (0 days/patient/year), antibiotic use (49.5 days/patient/year), and missed work/school days (1.61 days/patient/year) were similar to those observed during the entire 54-week efficacy period. Consequently, all efficacy outcomes observed in the 1.5:1 dose group were improved compared to those in the 1:1 dose group, regardless of the length of the observation period.
The most common adverse event reported in each study was local reactions at the injection site. The rate of local reactions was 0.59 events/infusion in the 1.5:1 cohort and 0.06 events/infusion in the 1:1 cohort. Most of the local reactions were of mild or moderate intensity (99.7% in the 1.5:1 cohort and 99.1% in the 1:1 cohort). The difference in the rate of local reactions between the studies was likely due to the different assessment of local tolerability.
Two independent trials of Hizentra® were conducted in the USA and the EU with similar designs except that regulatory authorities in the USA required that patients be converted to a SC dose that was 1.5 times higher than the IV dose they were previously using. The US FDA requested that SCIG dose be adjusted to achieve an equivalent AUC of IgG serum levels when patients were converted from monthly IV dosing to weekly SC dosing. Calculations based on IgG serum levels obtained from patients under IVIG indicated that it would require a SC dose that was 1.5 times the IV dose to achieve an equivalent AUC. On the other hand, the European Medicines Agency (EMA) accepted the direct conversion of the monthly IV dose to a weekly SC dose by simple division of the monthly dose into weekly increments, as long as this resulted in non-inferior IgG levels compared to the trough on previous therapy. Indeed, experts disagreed when asked if IgG efficacy is driven by peak, trough, or AUC serum levels [12
]. As a result, two parallel registration trials with similar designs were initiated with different SCIG dose levels, creating a unique opportunity to explore the effect of IgG dose on treatment outcomes in stable well-managed PID patients.
By comparing the two cohorts, we found that the 1:1 and 1.5:1 doses of SCIG were equally effective in achieving freedom from serious life-threatening bacterial infections. However, we showed that in the 1.5:1 dose (USA) cohort, there were significantly better function (fewer work/school days missed), significantly less health care utilization (fewer hospitalization days and less antibiotic use), and a significantly lower rate of non-serious infections. This two-cohort approach offers some valuable insights and strongly suggests a positive effect of 1.5:1 IgG dose on outcomes.
These findings should be interpreted with caution as the comparison of results from two independent studies differs from that of results collected in a single randomized trial. Factors not controlled statistically or by randomization may be contributing to the differences observed (baseline PID severity, practice differences between the EU and the USA, etc.). As the differences in behaviors (work/school attendance, antibiotic use) correlated with differences in infection rate, it seems unlikely that the improvement in clinical outcomes in the US study was purely a function of the differences in patient behavior between the USA and the EU. Also, there were several differences between the two studies that might limit a direct side-by-side comparison. First, the US study was longer than the EU study (54-week vs. 28-week efficacy period, respectively). Second, the pre-specified primary endpoints were different. In the US study, the primary endpoint was the annual rate of serious bacterial infections, while in the EU study, the primary endpoint was the total serum IgG trough level. Third, the EU study had more pediatric and XLA patients, while the US study had a larger sample size and a higher dropout rate (43% vs. 16% for the EU study [14
]). Nevertheless, by controlling the gender, age, and PID type as covariates, the significant differences in all four study outcomes were confirmed, thereby strongly suggesting that the differences in study design and population were very unlikely responsible for the better outcomes observed in the US cohort. Fourth, US patients were treated with higher doses for a longer period of time as they had received higher pre-study IgG doses (144 vs. 122 mg/kg in the EU study). However, this difference does not change the overall result that the more IgG patients received, the better indices of health they had.
An alternate explanation for these findings could be that the PID patients enrolled in the USA had milder disease or had better outcomes in their pre-study period compared to the EU cohort. Unfortunately, no efficacy assessment was done prior to study initiation to determine if the two groups were similar at baseline.
In spite of these research design limitations, it is interesting to note that these findings do not contradict previous dose-ranging studies. Indeed, of the ten previously published IgG dose–response studies [3
] summarized in Table V
, only the first two studies published in 1984 did not show a dose-response relationship. None of the ten studies identified a plateau or flattening in the dose–response function at the top of the dose range above which no further outcome improvement was achieved. Moreover, it was recently shown by Orange et al., in a meta-analysis that included 17 studies with 676 patients treated with IVIG and 2,127 patient-years of follow-up, that pneumonia risk was directly related to trough level of IgG and that this risk could be progressively reduced by higher trough IgG levels of up to at least 1,000 mg/dL [12
]. Similarly, Berger showed that the incidence of non-serious infections was inversely proportional to the steady state serum IgG levels achieved in different SCIG studies [11
A summary of the dose comparison studies of IgG in PID published to date
0.05 g/kg was superior to 0.025 g/kg (reduced frequency of febrile episodes, otitis media, and pneumonia)
No patient outcomes, time from 500 mg/kg dose to serum level under 400 mg/dL
150 and 500 mg/kg were not differentiated
Two-arm randomized, 12 month
Number of infections, antibiotic use, days missed
100 and 400 mg/kg are equally effective
Two-arm randomized cross-over with retrospective vhistory, 12 month
Fever, infections, antibiotic use, lung function
500 mg/kg is superior to 150 mg/kg, especially in children with more symptoms
Two-arm randomized cross-over
Infections, lung function
600 mg/kg is superior to 200 mg/kg; >500 mg/dL is superior to <500 mg/dL
Retrospective chart review
Pneumonia, days hospitalized
400 mg/kg q3 weeks IV is superior to 200 mg/kg q3 weeks IV or 100 mg/kg q3 weeks IM
600 or 400 mg/kg is superior to 200 mg/kg;
Retrospective chart review
Hospitalization for infection
>800 mg/dL is superior to 500–800 mg/dL or <500 mg/dL
Two-arm randomized cross-over, 9 month
Infection rate and duration
600/800 mg/kg is superior to 300/400 mg/kg; 940 mg/dL is superior to 630 mg/dL
Findings based on post-hoc analysis of data
>900 mg/dL is superior to >700–900 mg/dL; >700–900 mg/dL is superior to <700 mg/dL
Observational, 116 patient-years
400 mg/kg q3 weeks is superior to 200 mg/kg q3 weeks
Open-label, multi-center, single-arm
Infections, missed work/school days due to infection, hospitalization days due to infection, and days of antibiotic therapy
Mean weekly IgG dose of 120 mg/kg improved secondary efficacy outcomes compared to 213 mg/kg
Yes, for some outcomes
None of these studies assessed if the outcomes achieved by patients from higher-dose groups were comparable to healthy (non-PID) individuals with a “normal” rate of infection or comparable to individuals with a state of “complete physical, mental and social well being.” In our study, the PID patients in the 1.5:1 dose group have missed 2.06 work/school days/patient/year due to infection alone. The US Bureau of Labor Statistics reports that, on average, in 2010, US workers missed 2.3 days/year due to any infections, other illnesses, or injuries [26
]. This would indicate that PID patients treated with the 1.5:1 dose may still have sub-optimal experience of normal activity if other reasons for missed activity are considered. While all PID studies focus on the lack of disease, specifically a reduction in the rate of infections, not all include measures assessing the extent to which a patient achieves the WHO definition of health or some other measure of well being or function.
Efficacy measures such as antibiotic use, hospitalization rate, and missed work/school days serve as clinical and economic indicators in clinical trials; however, they do not represent the total spectrum of the patient benefit which can be achieved through optimal IgG dose. Other associated patient benefit effects may be occurring with 1.5:1 IgG doses, even if they were not measured. For example, a child may not miss school with low-grade infections but cannot partake in the more physical aspects of classroom and playground life. An adult may not be so sick as to warrant time off work, but persistently lacks the energy for a normal social life. The 1.5:1 dose is therefore expected to be associated with a greater normalcy of life experiences, moving patients closer to a life without breakthrough infections or chronic lack of well being. Moreover, the long-term sequelae of frequent infections accumulate over time, leading to structural changes in lung or sinus tissue. Preventing such sequelae may lead to further improvements in long-term patient outcomes and potential reductions in long-term health care costs. Higher IgG doses may also help reduce the frequency of chronic infections. Living a life with fewer infections may offer opportunities for PID patients which may otherwise not be afforded.
The objectives of PID treatment continue to evolve. Successful treatment can no longer be measured solely by the degree to which serious bacterial infections are prevented. Other clinical and functional outcomes must be measured as well. The findings that we report here suggest that increasing the doses of IgG might produce improvements in such outcomes, at least in some patients with frequent infections.
As the agenda of treatment of PID patients move forward beyond life or death interventions, the goals of IgG therapy may move toward optimization of health state outcomes and the full achievement of health and a normal life. The higher-dose cohort in this comparison recorded improved indices of well being compared to those treated with traditional doses of IgG. This study, despite its limitations, suggests that increasing the SCIG doses is associated with significantly fewer infections, days of hospitalization, days of antibiotic use, and days of missed activities, resulting in reduced resource utilization.
We would like to acknowledge the assistance of John-Philip Lawo for the statistical analyses and Dr. John Mackowiak in preparing the early stages of this manuscript.
Disclosure of potential conflicts of interest
Dr. Haddad reports consultant fees from CSL Behring and Talecris, and research support from CSL Behring and Talecris; Dr. Wang was an employee of CSL Behring during the early stages of this study and manuscript preparation; Dr. Berger, Dr. Jones, Dr. Bexon, Dr. Baggish, and J.P. Lawo are employees of CSL Behring. No other potential conflicts of interest were reported.
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
This is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (https://creativecommons.org/licenses/by-nc/2.0
), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.