The study consisted of the patients in which, 7 (24%) were adults, and 22 (76%) were children. Of these, 22 patients were undergoing Intravenous Immunoglobulin (IVIG) treatment at the time of enrollment, six were receiving conventional Subcutaneous Immunoglobulin (SCIG), and one case was IgRT-naive. Fourteen (48%) of patients were female, 15 (52%) were male, and the median age was 15 (min–max: 2–40.9) for all participants and for 22 pediatric patients as 12.6 (min–max: 2–16.4) years. The median age of onset of symptoms was 2 (min–max: 0.25–11) years. The mean age of the patients' diagnosis was 8.03 (± 4.77) years. The median diagnostic delay was 3 years (min–max: 0–13.5).

Concerning the PID category, the distribution of diagnosis was as follows: predominantly antibody deficiency accounted for 65% (19 patients), combined immunodeficiency with associated or syndromic features constituted 21% [6 patients], combined immunodeficiency alone represented 7% (2 patients), and diseases of immune dysregulation comprised the remaining 7% (2 patients). Patients' baseline IgRT dose varied between 0.45 and 0.86 g/kg/4 weeks, with infusion ranging from 5–30 days (min–max SCIG: 5–7, IVIG: 15–30). Upon initiating fSCIG, the dose of IgRT fell in the range of 0.44 to 0.70 g/kg/4 weeks, with infusion ranging from 15 to 30 days. The distribution of application intervals was as follows: 5 (3%) applications every 15 days, 27 (17%) applications every 21 days, 63 (41%) applications every 28 days, and 60 (39%) applications every 30 days. Patients receiving fSCIG administered all 155 applications of rHuPH20 and immunoglobulin with an infusion pump assistance.

Patients were switched from IVIG to fSCIG due to venous access problems in 14% (3 patients), elimination of absenteeism from school or work in 27% (6 patients), and frequent visits due to IVIG prescription and infusions at hospital in 59% (13 patients). Among the 6 patients who switched from SCIG to fSCIG, 67% (4 patients) did so due to recurrent local skin problems (pain, itching, redness) of multiple injection, while the remaining 33% (2 patients) recognized the need for less frequent dosing associated with fSCIG. The sole IgRT-naive patient preferred fSCIG to avoid school absenteeism with IV dosing.

We surveyed the patient's fSCIG application was obtained from at least 2 infusions from each 4 consecutive month period. In the analysis of 155 fSCIG applications among switch patients, we found that the administered dose of immunoglobulin per body weight per infusion was higher with fSCIG than with previous IgRT treatments (fSCIG vs. IVIG p = 0.029, fSCIG vs. SCIG: p < 0.001). However, there was no significant difference in total IgRT doses per month (4 weeks) (fSCIG vs. IVIG p = 0.874, fSCIG vs. SCIG: p = 1). Additionally, the volume of the injected drug in fSCIG (median: 250, min–max: 50–450 ml) was higher compared to other SCIG forms (median: 100, min–max: 50–200 ml) (p = 0.003) but not IVIG (median: 250, min–max: 50–600 ml) (p = 1) (Table 1). The volume per kg given was not correlating with age (p = 0.84).

The interval of drug injections remained unchanged for patients switching from IVIG to fSCIG (p = 0.981). However, fewer injections were administered after switching to fSCIG (median: 28, min–max: 15–30 days) from other SCIG treatments (median: 7, min–max: 5–7 days) (p < 0.001) (Table 1).

Among the studied formulations, SCIG had the shortest duration of Ig infusion. When comparing IVIG with fSCIG, the latter showed a shorter application time (Table 1). Notably, smaller needles (both in length and gauge) were used after switching from IVIG or SCIG to fSCIG (Table 1). When examining the anatomical sites for drug application, IVIG drugs were consistently infused through the antecubital vein, while SCIG administrations were targeted at the abdominal region. Among the 155 fSCIG applications, a minor proportion (3.9%, n = 6) occurred in the thigh, with the majority (96%, n = 149) administered in the abdomen, apply 2 fingers above the imaginary transverse umbilical line. Notably, both IVIG and fSCIG drugs were administered through a single site, in contrast to previous SCIG treatments that involved two separate sites (Table 1).

The baseline IgG median for the 29 patients was 988 mg/dl (25–75%: 807–1118). At 2–4 months (n = 22), the IgG median was 1060 mg/dl (25–75%: 955–1305), at 5–8 months (n = 11) the median was 1118 mg/dl (25–75%: 948–1321), and at 9–12 months (n = 8) the median was 1085 mg/dl (25–75%: 882–1204). Notably, all treatment methods, including SCIG, IVIG, and fSCIG, achieved the target trough or stable IgG levels. Statistically, no significant differences were detected among the various treatment methods (p = 0.415).

There were no observed changes in the frequency of major infectious diseases, including sepsis, meningitis, acute bacterial pneumonia/pneumonia, otitis, sinusitis, and gastroenteritis, after the initiation of fSCIG compared to the pre-treatment period. However, the frequency of minor infections, such as acute upper respiratory tract infections, demonstrated a significant decrease following fSCIG administration. Before fSCIG, the median frequency was 1 (25–75%: 0–2) ranging from 0 to 4 while after fSCIG, it reduced to 0 (25–75%: 0–0) (p = 0.035) with a range of 0–3 per year.

Moreover, the number of missed school/work days per year exhibited a noteworthy reduction following fSCIG. The median decreased from 11 days (25–75%: 5–15) before fSCIG to 0 day (25–75%: 0–2.75 days/year) after fSCIG (p = 0.036).

We conducted a comprehensive survey to assess the occurrence of adverse events following fSCIG treatment, specifically focusing on hypotension, fever, urticaria, and anaphylaxis. Notably, none of these adverse events were observed (refer to Table 2 for details). However, local adverse reactions were documented, revealing the following distribution: swelling was observed in 79% (n = 23) of the applications, erythema in 59% (n = 85), pain during application in 42% (n = 60), itching in 24% (n = 34), and ecchymosis in 8% (n = 12). Local adverse reactions, with all instances, resolved spontaneously within 48–72 h. The mild systemic adverse reactions encompassed headache (25%), fatigue (15%), myalgia (8%), and nausea or vomiting (6%). Interestingly, in patients experiencing both local and systemic effects, there was a mild but not discernible tendency for a decrease in adverse reactions as the number of applications increased during the observation period (Fig. 1). Statistical analysis involved the use of the Friedman test, followed by post-hoc analyses using the Durbin-Conover method and significant differences were not detected in subsequent dosing cycles among local and systemic adverse reactions related to fSCIG. When evaluating local and systemic effects by age groups, no significant difference was found in the adverse reactions exhibited by the different age groups (0–6, > 6 and ≤ 12, > 12 and < 18 years, and adults).

Heatmap data of for ARs related to fSCIG administration during first 6 cycles of infusions. Percentages are shown on the relevant box for each. AR, adverse reaction; fSCIG, facilitated subcutaneous immunoglobulin

Among the patients, four had a history of headaches following IVIG administration. Upon transitioning to fSCIG, two individuals persisted in experiencing headaches, managed effectively with acetaminophen premedication before infusion. In contrast, the remaining two subjects no longer reported headaches with fSCIG. Furthermore, one patient previously described vomiting and fever following IVIG infusion. Upon switching to fSCIG, these complaints subside, eliminating the necessity for premedication.

During the follow-up, four patients underwent a transition from fSCIG to alternative IgRTs. Two individuals shifted to conventional 10% SCIG due to ongoing mild systemic symptoms despite premedication during fSCIG treatment. Specifically, one patient made the switch after the fourth dose of fSCIG due to ongoing nausea and headaches, while another patient transitioned after the eighth dose of fSCIG due to persistent fatigue. Additionally, two subjects opted for a switch to 20% SCIG following the sixth application of fSCIG, citing inconvenience during the pump infusion procedure of rHuPH20 and/or IgG. It's noteworthy that none of the patients discontinued fSCIG or changed to other drugs due to local adverse reactions.

The KINDL scale for children and parents and the SF-36 questionnaires showed no statistically significant difference between various time points (Table 3).

Patients' treatment satisfaction with TSQM-9 surveys resulted in significant difference (p = 0.003) by the observation period with a increase in drug satisfaction was observed in the subsequent months; baseline (median: 68, 25–75%:48–88.5) and 2-4th months (median: 83, 25–75%: 64–90) p = 0.102; baseline vs. 5-8th months (median: 88, 25–75%: 72–92) p = 0.006, baseline vs. 9-12th months (median: 88, 25–75%: 73.5–93) p < 0.001. The effectiveness subdomain of the survey displayed significant differences, with markedly higher scores at the 2-4th months (median: 88.9; 25–75%: 68.1–98.6) (p < 0.001), 5-8th months (median: 100, 25–75%: 72.2–100) (p < 0.001), and 9-12th months (median: 100, 25–75%: 70.8–100) (p = 0.002) compared to the baseline (median: 75; 25–75%: 58.3–88.9) (Fig. 2a). According to the basal evaluation (median: 66.7; 25–75%: 59.7–83.3), the convenience subdomain had increased only in the 9-12th (median: 72.2; 25–75%: 70.8–88.9) month assessment (p = 0.021) and global satisfaction subdomain had increased only 9-12th months (median:85.7, 25–75%: 78.6–100) acording the baseline evaluation (median: 75, 25–75%: 55.4–85.7) (p = 0.048) (Table 3).

a) Comparison of TSQM-9 treatment satisfaction questionnaire and subdomains at baseline, 2-4th, 5-8th, and 9-12th months for IEI patients receiving fSCIG, (b) Comparison of TSQM-9 treatment satisfaction questionnaire and subdomains at baseline, 2-4th, 5-8th, and 9-12th months for IEI patients switched from IVIG and receiving fSCIG. The scores are presented as median (IQR 25–75%). *p < 0.05, **p < 0.001. Statistical analysis involved the use of the Friedman test, followed by post-hoc analyses using the Durbin-Conover method. Bonferroni correction has been applied. TSQM-9, Treatment Satisfaction Questionnaire for Medication-9; IEI, inborn errors of immunity; fSCIG, facilitated subcutaneous immunoglobulin; IVIG, intravenous immunoglobulin

The analysis of TSQM-9 revealed a notable increase in treatment satisfaction among patients transitioning from IVIG at baseline (median: 70, 25–75%: 55.5–88.5) to fSCIG (2-4th months: median: 88, 25–75%: 64–90; 5-8th months: median: 88, 25–75%: 78–92; 9-12th months: median: 88, 25–75%: 76–91) (p = 0.001). When comparing baseline with 2-4th, 5-8th, and 9-12th months for TSQM-9, all p-values indicated significant changes (p < 0.001 for all comparisons), underscoring a consistent and meaningful improvement in treatment satisfaction over these time intervals (Fig. 2b). The effectiveness subdomain of treatment satisfaction, compared to baseline IVIG treatment, showed p < 0.001 at baseline (median:77.8, 25–75%: 61.1–86.1) vs. 2-4th (median: 91.7, 25–75%: 66.7–100), 5-8th (median: 100, 25–75%: 83.3–100), and 9-12th (median: 100, 25–75%: 75–100) months in the TSQM-9 analysis. In the effectiveness subgroup, baseline vs. 2-4th, 5-8th, and 9-12th months the respective p-values were p < 0.001. The convenience subdomain of treatment satisfaction showed statistically significant improvement (p = 0.003) at only 9-12th (median: 72.2, 25–75%: 68.1–84.7) vs baseline (median:66.7, 25–75%: 63.9–83.3). Moreover, global satisfaction subdomain of TSQM-9 survey showed similar trend from baseline (median:71.4, 25–75%: 57.1–85.7) to 9-12th months (median:85.7, 25–75%: 80.4–96.4) (p = 0.048).