Facilitated Subcutaneous Immunoglobulin Treatment Patterns in Pediatric Patients with Primary Immunodeficiency Diseases

Abstract

Aim:

This retrospective study investigated real-world hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) treatment patterns in pediatric patients with primary immunodeficiency diseases (PIDs) in Poland.

Methods:

Clinical and demographic information, fSCIG treatment parameters and clinical outcomes were extracted from medical records of 28 participants (aged ≤18 years) with PIDs who received fSCIG.

Results:

18 participants (64.3%) started fSCIG with a ramp-up (median duration: 35.5 days). 27 patients (96.4%) were administered fSCIG every 4 weeks and one patient every 3 weeks. 25 patients (89.3%) used one infusion site. No serious bacterial infections occurred.

Conclusion:

Data support the feasibility of administering fSCIG to children and adolescents with PIDs every 3–4 weeks using a single infusion site and indicate flexibility in modifying fSCIG infusion parameters.

Clinical Trial Registration: NCT04636502 (ClinicalTrials.gov)

Plain language summary

Antibodies, also known as immunoglobulins, are proteins that are made by the immune system to help fight infections. In primary immunodeficiency diseases (PIDs), part of the immune system may be missing or not working properly. This study looked at the use of an antibody treatment called hyaluronidase-facilitated subcutaneous immunoglobulin (or fSCIG) in Polish children aged 18 years or younger with PIDs. Information on patients, their disease, how fSCIG was being used and how patients responded to treatment was taken from medical records. Out of 28 patients, 18/28 (64.3%) had their fSCIG dose slowly increased, which took an average of 35.5 days. Overall, 27/28 patients were treated with fSCIG every 4 weeks (96.4%), and 25/28 patients used one place to inject fSCIG (89.3%). No serious infections caused by bacteria happened during the study. The study results suggest that children with PIDs could be treated every 3 to 4 weeks with fSCIG, and that flexibility in how fSCIG is injected may offer options suited to individual patients.

Tweetable abstract

Real-world Polish data on hyaluronidase-facilitated subcutaneous immunoglobulin use in pediatrics with primary immunodeficiency diseases support the feasibility of infusion every 3–4 weeks using a single site, and flexibility in modifying infusion parameters. Read more below.

Keywords::

• facilitated subcutaneous immunoglobulin
• hyaluronidase
• inborn errors of immunity
• pediatric
• primary immunodeficiency disease
• real-world

Primary immunodeficiency diseases (PIDs) are inborn errors of immunity that manifest as increased susceptibility to infectious diseases, autoinflammatory diseases, allergies, autoimmunity and/or malignancies. In adults and children with PIDs who have impaired antibody production and function, immunoglobulin (Ig) replacement therapy is the standard of care [1,2]. The goal of this therapy is to reduce the rate of serious bacterial infections. Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) involves a subcutaneous infusion of hyaluronidase to catalyze the depolymerization of hyaluronan, which facilitates the dispersion and absorption of high volumes in the subcutaneous space. The bioavailability of fSCIG treatment has been shown to be similar to that of intravenous immunoglobulin (IVIG) therapy [3], and the treatment strategy allows for better Ig delivery (i.e., infusion of larger volumes of Ig per site at higher speed) [3,4]. The infusion of a larger volume of the drug allows extension of the interval between successive doses, which significantly improves the patient’s quality of life and adherence to therapy [5,6]. fSCIG can be particularly beneficial for pediatric patients by eliminating problems with venous access as well as children’s reluctance to undergo time-consuming and painful medical procedures [5,7]. In addition, home-based Ig infusions reduce the disease burden for children with PIDs and their parents [8] and the risk of hospital-acquired infections associated with a visit to the medical facility [9].

Clinical trials have demonstrated the efficacy and safety of fSCIG in patients with PIDs, including in the pediatric population [3–6]. In the real-world, however, treatment parameters are tailored to optimize clinical outcomes for the individual patient with PID and to meet the patient’s preferences [10]. Therefore, the experiences gained during the clinical practice of treating pediatric patients with fSCIG are valuable [11]. To date, there are few studies of real-world fSCIG treatment patterns in the pediatric PID population. In addition, these studies usually involve small cohorts of patients, and some of them are still ongoing. Data on fSCIG treatment in the Polish pediatric population with PIDs are lacking.

In Poland, fSCIG was first reimbursed for the treatment of adult patients with PIDs in 2016 [12]. For the pediatric population (those under 18 years of age) with PID, fSCIG therapy has been available in Poland since July 2018 under the National Drug Program, which is a reimbursement therapeutic program established by the Polish Ministry of Health to ensure patient access to highly specialized therapies [13]. This multicenter, retrospective study evaluated the clinical outcomes and treatment patterns of fSCIG in the pediatric population with PIDs in Poland.

Materials & methods

Patients & study design

The retrospective IG TATRY study (NCT04636502) was conducted to analyze the use of fSCIG (HyQvia^®; Baxalta US, Inc., part of Takeda, MA, USA) [14] and conventional subcutaneous immunoglobulin 20% (SCIG) (Ig20Gly; Cuvitru^®; Baxalta US, Inc., part of Takeda) [15] in pediatric patients with PID. The present publication describes the results of fSCIG treatment.

Patients were recruited at four pediatric immunology/hematology clinics in Poland. Eligible participants were aged 18 years or younger, were diagnosed with PID according to the criteria developed by the European Society for Immunodeficiencies [16], required immunoglobulin G (IgG) replacement therapy and received fSCIG or Ig20Gly. Data for those patients were collected from 1 July 2018 (when fSCIG obtained reimbursement for children and adolescents with PIDs in Poland) to 30 June 2020 (end of observational period). Patients were followed up from the first dose of fSCIG until permanent termination of treatment (switch back was recorded). Permanent termination of treatment could occur for medical reasons (i.e., adverse events) or when the patient turned 18 years of age and was transferred to an adult center. To accurately capture patient flow, the minimum follow-up period was not predetermined.

Assessments

Data obtained during fSCIG therapy were retrieved from patients’ medical records. Demographic and clinical data included age, sex, height and weight, diagnosis of PID and duration of disease, previous Ig replacement therapy, comorbidities and concomitant medication. Variables collected on fSCIG administration included ramp-up schedule, dose per kilogram of body weight and in total, infusion volume per site and in total, treatment interval, infusion rate, site of injection, number of infusion sites, method of administration (type of pump) and reason for discontinuation/switch. Data on the incidence of serious bacterial infections, all infections and hospitalizations due to infections were also recorded. Serum IgG levels during the fSCIG treatment were measured at various time intervals after the infusion. Safety evaluation was not the study objective because the tolerability of fSCIG has been proven in previous studies [3–5,7,17].

Statistical analyses

No statistical calculations were made to predetermine the study sample size because this was determined by feasibility aspects. Data were summarized using standard descriptive statistics and presented as the number of patients, arithmetic mean, standard deviation, minimum, median and maximum. Weighted averages calculated for each patient were used to compute fSCIG dosing frequency, dosing interval, dose received monthly, infusion volume per site and the number of infusions per month. For categorical variables, frequencies and percentages were determined. The patient population was categorized into two age groups: children (patients aged ≤12 years) and adolescents (patients aged 13–18 years). Statistical calculations and graphics were performed using R software version 4.0.3 or later.

Ethics approval & consent to participate

All patients or/and patients’ caregivers provided written informed consent, and the study was approved by the Ethics Committee at the Children’s Memorial Health Institute (approval number 45/KBE/2020).

Results

Patients’ characteristics

The study included 28 patients with PIDs. 21 (75%) patients were children (aged ≤12 years; mean [standard deviation; SD] age 7.5 [3.2] years), and seven patients (25%) were adolescents (aged 13–18 years; mean [SD] age 14.3 [1.6] years; Supplementary Table 1). The study cohort included 22 males (78.6%) and six females (21.4%). The mean (SD) body mass index (BMI) in children was 16.9 (2.4) kg/m² and 22.8 (5.0) kg/m² in adolescents. On the basis of their BMI, four children (19.0%) and two adolescents (33.3%) were overweight (Supplementary Table 1).

According to the tenth revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) classification, agammaglobulinemia (n = 7, 33.3%) and hypogammaglobulinemia (n = 7, 33.3% including nonfamilial hypogammaglobulinemia [n = 4, 19.0%], selective deficiency of IgG subclasses [n = 1, 4.8%], antibody deficiency with near-normal immunoglobulins or with hyperimmunoglobulinemia [n = 1, 4.8%] and immunodeficiency with predominantly antibody defects, unspecified [n = 1, 4.8%]) were the most common forms of PID in children (Supplementary Table 1). Common variable immunodeficiency (n = 4, 57.1%) and agammaglobulinemia (n = 2, 28.6%) were the most frequent PID forms in adolescents. The mean (SD) age at diagnosis in children was 4.0 (3.0) years, and in adolescents, it was 8.0 (5.2) years (Supplementary Table 1). The mean (SD) disease duration in these two age groups was 5.2 (3.1) and 8.0 (4.9) years, respectively. Prior to this study, four patients (14.3%) were Ig treatment naive (2 children and 2 adolescents).

24 patients (85.7%) had at least one comorbid disease. 11 patients (39.3%) had 1 comorbid disease, three patients (10.7%) had two comorbidities and 10 patients (35.7%) were affected by 3–5 comorbidities (Supplementary Table 1). The most common comorbidities were respiratory, thoracic and mediastinal disorders, diagnosed in 12 patients (42.9%) (asthma [n = 7, 25.0%] and rhinitis allergic [n = 9, 32.1%]), followed by gastrointestinal disorders, diagnosed in seven patients (25.0%; including two patients [7.1%] with inflammatory bowel disease). Sixteen patients (57.1%) used concomitant medications (the same proportion in children and adolescents). The most common concomitant medications received were antibacterials for systemic use (n = 2; two children [7.1%] received antibiotic prophylaxis of respiratory tract infections and chronic sinusitis), drugs for obstructive airway diseases (n = 2), and antidiarrheals, intestinal anti-inflammatory/anti-infective agents (n = 2; Supplementary Table 1).

Patient flow

fSCIG was administered to 28 patients. 23 patients (82.1%) started Ig treatment with fSCIG, and five (17.9%) switched from Ig20Gly to fSCIG owing to a preference for fewer infusions per month (Figure 1). During the study, two patients interrupted fSCIG treatment owing to limited drug availability and switched to Ig20Gly. However, these two patients returned to fSCIG therapy in the second quarter of the study, when the drug was available again. Two other patients discontinued fSCIG and switched to Ig20Gly because of systemic and/or local adverse events (low-grade fever, generalized malaise/discomfort, hives, erythema at the infusion site). In summary, at the end of the study, of the 28 enrolled patients, 25 (89.3%) were still on fSCIG therapy, two (7.1%) had withdrawn owing to medical reasons (adverse events) and one patient had reached the age of 18 years and was transferred to an adult center.

Figure 1. Flow of pediatric patients with primary immunodeficiency diseases receiving hyaluronidase-facilitated subcutaneous immunoglobulin.

During fSCIG treatment, individual patients were enrolled and some patients had medication changed or discontinued. The boxes in the middle indicate study time points (start of the study, transition to the next quarter [Q], end of the study).

fSCIG: Hyaluronidase-facilitated subcutaneous immunoglobulin; Ig20Gly: Subcutaneous immunoglobulin 20%.

Treatment patterns

Ramp-up schedule

In total, 18 patients (64.3%) started fSCIG on the dose ramp-up schedule, including four (22.2%) switching to fSCIG from another treatment (Table 1). This cohort consisted of 13 (72.2%) children and five (27.8%) adolescents. The median initial monthly dose of fSCIG was 0.3 g/kg for children and 0.2 g/kg for adolescents. For both patient groups, the dose increased to the end of the ramp-up period to 0.4 g/kg. Accordingly, the median infusion volume per site increased during the ramp-up period: the initial median ramp-up infusion volume in children was 75.0 ml (interquartile range [IQR]: 50.0–100.0 ml), while in adolescents it was 100.0 ml (IQR: 100.0–100.0 ml), and at the end of the ramp-up, the median infusion volume was 150.0 ml (IQR: 100.0–150.0 ml) and 200.0 ml (range: 200.0–200.0 ml) in these age groups, respectively. During the ramp-up period, infusion rates reached median values of 120.0 ml/h (IQR: 80.0–160.0 ml/h) in children and 240 ml/h (IQR: 140.0–300.0 ml/h) in adolescents (Table 1).

Table 1. Ramp-up schedule of fSCIG in pediatric patients with primary immunodeficiency diseases.

Parameter	Overall (N = 18)	Age ≤12 years (n = 13)	Age 13–18 years (n = 5)
Patients entering the study on fSCIG, n (%)	14 (77.8%)	11 (84.6%)	3 (60.0%)
Patients switched to fSCIG, n (%)	4 (22.2%)	2 (15.4%)	2 (40.0%)
Initial dose at ramp-up period, g/kg/month, median (IQR)	0.2 (0.2–0.3)	0.3 (0.2–0.3)	0.2 (0.2–0.2)
Final dose at ramp-up period, g/kg/month, median (IQR)	0.4 (0.4–0.5)	0.4 (0.4–0.5)	0.4 (0.3–0.4)
Initial infusion volume per site, ml, median (IQR)	100.0 (56.2–100.0)	75.0 (50.0–100.0)	100.0 (100.0–100.0)
Final infusion volume per site, ml, median (IQR)	150.0 (131.2–193.8)	150.0 (100.0–150.0)	200.0 (200.0–200.0)
Initial infusion rate, ml/h, median (IQR)	10.0 (5.0–10.0)	5.0 (5.0–10.0)	10.0 (10.0–10.0)
Final infusion rate, ml/h, median (IQR)	120.0 (100.0–160.0)	120.0 (80.0–160.0)	240.0 (140.0–300.0)
Number of ramp-up infusions, median (IQR)	3.0 (2.0–3.0)	3.0 (2.0–3.0)	3.0 (3.0–3.0)
Duration of ramp-up, days, median (IQR)	35.5 (20.0–44.2)	36.0 (15.0–45.0)	35.0 (27.0–40.0)

fSCIG: Hyaluronidase-facilitated subcutaneous immunoglobulin; IQR: Interquartile range.

Children and adolescents received a median of 3.0 ramp-up infusions. The ramp-up period in the whole study cohort lasted a median of 35.5 days (IQR: 20.2–44.2 days) and was comparable in adolescents (35.0 days, IQR: 27.0–40.0 days) and in children (36.0 days, IQR: 15.0–45.0 days) (Table 1).

Treatment parameters

As shown in Table 2, the median exposure of patients to fSCIG was 15.1 months (IQR: 6.7–17.0 months), with adolescents having a shorter treatment duration (median 11.7 months, IQR: 8.0–15.2 months) than children (median 15.9 months, IQR: 6.3–17.2 months). Three patients were treated with fSCIG for less than 6 months, either because of enrollment at the end of the study period (two patients) or transfer to an adult center (one patient) (Figure 1). The overall median interval between consecutive dosages was 28.0 days (IQR: 28.0–28.0 days) (Table 2). In our real-world study, the dosing regimen of fSCIG in each treatment period was a result of changes in dosing, frequency of patient visits and infusion volume over that period. We identified 71 periods of treatment during which the study patients took the drug with varying frequencies, and used them to calculate the dosing frequency according to the rule: administration every 4 (3 or 2 or 1) week(s), took place in X out of a total of 71 treatment periods, giving the numerical result: X/71 (%) (Figure 2). Twenty-seven patients (96.4%) administered fSCIG every 4 weeks; however, during the first 9 months of treatment, three of these patients had episodes of receiving fSCIG every 2 weeks, owing to optimization of treatment outcomes or adjustment to the patient’s preference. One patient (3.6%) was administered fSCIG every 3 weeks throughout the study.

Table 2. Treatment parameters for fSCIG in pediatric patients with primary immunodeficiency diseases.

Parameter	Overall (N = 28)	Age ≤12 years (n = 21)	Age 13–18 years (n = 7)
Exposure to fSCIG, months, median (IQR)	15.1 (6.7–17.1)	15.9 (6.3–17.2)	11.7 (8.0–15.2)
Dose received monthly^†, g/kg, median (IQR)	0.4 (0.3–0.5)	0.4 (0.3–0.5)	0.3 (0.3–0.4)
Infusion volume per site^†, ml, median (IQR)	124.8 (100.0–152.6)	100.0 (85.2–150.0)	200.0 (155.2–200.0)
Treatment interval between doses^†, days, median (IQR)	28.0 (28.0–28.0)	28.0 (28.0–28.0)	28.0 (28.0–28.0)
Number of infusions per month^†, median (IQR)	1.0 (1.0–1.0)	1.0 (1.0–1.0)	1.0 (1.0–1.0)
Infusion rate, ml/h, median (IQR)	120.0 (98.3–163.0)	100.0 (89.3–127.0)	200.0 (169.0–270.0)
Site of injection and infusion volume per site, ml
Abdomen
n^‡ (%)	25 (89.3%)	18 (85.7%)	7 (100.0%)
Median (IQR)	139.7 (100.0–150.0)	106.3 (100.0–150.0)	200.0 (150.0–200.0)
Thigh
n^§ (%)	6 (21.4%)	5 (23.8%)	1 (14.3%)
Median (IQR)	45.4 (37.7–50.0)	50.0 (40.9–50.0)	20.6 (20.6–20.6)
Length of needle, mm, n (%)
6	4 (14.3%)	4 (19.0%)	0 (0.0%)
9	16 (57.1%)	13 (61.9%)	3 (42.9%)
12	8 (28.6%)	4 (19.0%)	4 (57.1%)

† Computed using weighted averages calculated for each patient (taking into account the length of each study period with given parameters in relation to the entire treatment time).

‡ The number of patients who received the drug in the abdomen or in the abdomen and thigh.

§ The number of patients who received the drug in the thigh or in the thigh and abdomen.

fSCIG: Hyaluronidase-facilitated subcutaneous immunoglobulin; IQR: Interquartile range.

Figure 2. Hyaluronidase-facilitated subcutaneous immunoglobulin administration schedules in pediatric patients with primary immunodeficiency diseases, overall and by treatment period.

The number of patients administering hyaluronidase-facilitated subcutaneous immunoglobulin during the given treatment period is indicated on the x-axis.

M: Month.

The median monthly dose of fSCIG for children was the same as for the whole study population and amounted to 0.40 g/kg (IQR: 0.30–0.50 g/kg) (Table 2). In adolescents, the median monthly dose was 0.30 g/kg (IQR: 0.30–0.54 g/kg). The median monthly dose of fSCIG remained relatively stable for the whole study population (range: 0.32 g/kg at month 21 to 0.40 g/kg at month 15) (Figure 3).

Figure 3. Hyaluronidase-facilitated subcutaneous immunoglobulin treatment patterns in pediatric patients with primary immunodeficiency diseases, by treatment month.

fSCIG: Hyaluronidase-facilitated subcutaneous immunoglobulin; M: Month.

10 patients (35.7%) had fSCIG dose modification (six patients more than once). The dose was increased because of unsatisfactory serum levels of IgG during treatment (n = 6 [21.4%]), inadequate infection control (n = 1 [3.6%]), prevention of autumn/winter infections (n = 1 [3.6%]) or post-infection with influenza virus (n = 1 [3.6%]). The dose was reduced because of adequate control of infections and normalized IgG levels (n = 3 [10.7%]) or dosing frequency reduction during the holiday period (n = 2 [7.1%]). For one patient, the reason for dose reduction was not specified. The monthly median dose of 0.2 g/kg (IQR: 0.2–0.3 g/kg) was administered to adolescents with common variable immunodeficiency, and the median monthly dose of 0.3 g/kg was administered to adolescents with agammaglobulinemia (IQR: 0.3–0.4 g/kg) and children with hypogammaglobulinemia (IQR: 0.2–0.3 g/kg). The highest median monthly doses (0.6 g/kg [IQR: 0.6–0.6] and 0.5 g/kg [IQR: 0.5–0.5 g/kg] in children and adolescents, respectively) were administered to patients with other immunodeficiencies. The widest dose range of fSCIG was used in children with agammaglobulinemia (0.2–0.7 g/kg).

The site of infusion was mainly the abdomen (used by 85.7% of children and all adolescents). The thigh was used by 23.8% of children and one adolescent (14.3%). 25 patients (89.3%) infused into one site (22 patients into abdomen and three patients into thigh) and three patients (10.7%) split the dose over two sites (abdomen and thigh).

fSCIG was administered in a median volume per infusion site of 100.0 ml (IQR: 85.2–150.0 ml) for children and 200.0 ml (IQR: 155.2–200.0 ml) for adolescents (Table 2). Considering the whole study population, the median fSCIG infusion volume per site varied during the study period (Figure 3). The peak value was 137.5 ml at Month 6, and then gradually decreased to 100.0 ml at Month 15. A median fSCIG infusion volume of 100.0 ml per site was used until the end of the follow-up (Figure 3).

The median infusion rate in the whole study population was 120.0 ml/h (IQR: 98.3–163.0 ml/h) (Figure 3). As depicted in Table 2, children were infused fSCIG at a median rate of 100.0 ml/h, which was half the median rate in adolescents (200.0 ml/h). However, 32.1% of patients (seven children and two adolescents) infused the drug at a maximum rate of 160 or 300 ml/h/infusion or at a rate near to the maximum (>150 ml/h/infusion and >240 ml/h/infusion) for those with a body weight <40 kg and ≥40 kg, respectively [14]. All these patients were using Ig replacement therapy prior to participating in this study.

20 patients (71.4%) were infused using 6- or 9-mm needles. The 12-mm needles were used in four children and four adolescents (of whom, three children and two adolescents were overweight). One overweight child used 9-mm needles for infusions.

Safety evaluation was not the study objective. Nonetheless, of note, there were no serious adverse events associated with fSCIG treatment in this study. However, two patients switched to Ig20Gly owing to systemic and/or local non-serious adverse events (Figure 1).

Infections

During the study, no serious bacterial infections occurred. 13 patients (46.4%; 11 children [52.4%] and two adolescents [28.6%]) experienced non-serious infection episodes. The rates of non-serious infections per patient-year were 1.88, 2.13 and 1.00, in the whole study population, children and adolescents, respectively (Table 3). 11 patients (nine children and two adolescents) were treated with antibiotics. The mean duration of antibiotic therapy was 9.6 days in children and 27.5 days in adolescents (Table 3). There were no hospitalizations due to worsening of PID symptoms.

Table 3. Infections in pediatric patients with primary immunodeficiency diseases receiving hyaluronidase-facilitated subcutaneous immunoglobulin.

Parameter	Overall (N = 28)	Age ≤12 years (n = 21)	Age 13–18 years (n = 7)
Number of serious bacterial infections per patient-year^†	0	0	0
Number of non-serious infections per patient-year^†	1.88 (n = 83)	2.13 (n = 70)	1.0 (n = 13)
Duration of antibiotic therapy, days, mean (SD)^‡	12.8 (17.1) (n = 11)	9.6 (10.6) (n = 9)	27.5 (38.9) (n = 2)

† Data calculated for the total sum of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) treatment duration.

‡ Data calculated for the sum of fSCIG treatment duration among patients longer than 365 days on therapy.

SD: Standard deviation.

IgG levels

The median IgG serum level was calculated for three different time intervals after fSCIG administration: days 8–14, 15–21 and 22–28. The number of IgG measurements taken in an individual time interval after fSCIG administration was 12, 10 and 51 (in the first, second and third interval, respectively). For the whole study population, the median IgG level was 9.6 g/l in the first interval, 9.5 g/l in the second interval and 7.8 g/l in the third interval.

In children, median serum IgG concentrations remained at similar levels during the first and second intervals (9.3 and 9.6 g/l, respectively). In the third time interval, the median IgG concentration was 7.6 g/l. Owing to the insufficient number of measurements taken in adolescents, it was not possible to infer median IgG levels in this age group. Median serum IgG levels across all time intervals and age groups were ≥7.6 g/l.

Data on serum IgG levels for all the most common PID diagnoses in the study population were available for the time interval of 22–28 days after fSCIG administration. During this period, the lowest median IgG concentration (7.0 g/l, IQR: 6.1–7.6 g/l) was recorded in patients with agammaglobulinemia (14 measurements). In those with common variable immunodeficiency and in those with hypogammaglobulinemia, the median IgG levels were 7.8 g/l (IQR: 6.8–8.6 g/l, 16 measurements) and 8.1 g/l (IQR: 7.7–9.0 g/l, 14 measurements), respectively. In contrast, the highest IgG concentrations (9.1 g/l, IQR: 6.6–11.4 g/l) were found in patients with other immunodeficiencies (seven measurements).

Discussion

fSCIG is a useful treatment option in pediatric patients with PIDs. This therapy offers several advantages over IVIG (including fewer systemic side effects, no need for venous access and the ability to self-administer the drug at home) and conventional SCIG (fewer needle sticks, longer infusion intervals, higher infusion rate), thereby reducing the burden of lifelong disease [8,18,19]. Apart from observations from clinical trials, there are few data on the real-world treatment pattern of fSCIG in the pediatric population with PIDs. Our report complements the observations from clinical trials with data from daily clinical practice on the fSCIG treatment patterns and clinical outcomes in Polish pediatric patients with PIDs.

In our study, 64.3% of patients initiated fSCIG dosing on a ramp-up schedule. The ramp-up is designed to increase the patient’s tolerance to the fSCIG and facilitate patient training. During this period, the infusion rate and dose intervals were gradually increased until the target dose. According to the fSCIG dosing guidelines, the ramp-up period may take up to several weeks and include three or four infusions [14]. Our patients received a median of three (IQR: 2–3) ramp-up infusions. Although the median duration of the ramp-up period for the whole study population was 35.5 days (similar in adolescents [35.0 days] and children [36.0 days]), in five patients the ramp-up period lasted more than 50 days. Patients with a prolonged ramp-up received three ramp-up infusions. Four of these patients achieved the target dose on the first ramp-up infusion and one on the third ramp-up infusion. It should be noted that eight patients required only one ramp-up infusion. Thus, our findings indicate that the ramp-up specifics can be tailored in clinical practice to individual pediatric patients’ needs. Cases of shortening the ramp-up schedule in clinical practice without increasing the incidence of adverse events have already been already reported [17]. During the ramp-up, the median dose of fSCIG increased from an 0.3 g/kg in children and 0.2 g/kg in adolescents to a target dose of 0.4 g/kg in both age groups. Accordingly, the median infusion volume per site also increased during the ramp-up: from 75.0 ml to 150.0 ml in children and from 100.0 ml to 200.0 ml in adolescents. The infusion rate during the ramp-up reached the value of 120 ml/h for the whole study population. For the six patients recorded as overweight according to BMI, dosing according to actual body weight was used (rather than lean body mass), though individualization based on clinical response is recommended over fixed weight-based dosing [20].

Considering the target treatment phase after the ramp-up period, the dose of fSCIG administered to these patients (i.e., 0.4 g/kg) was similar to the dose used to treat 26 pediatric patients with PIDs in the study by Baumann et al. in Germany [21] and in 14 pediatric patients with PIDs in the European multicenter study (FIGARO) [22]. In addition, the median infusion rates in these children and adolescents were similar to those in the German study (100 and 200 ml/h, respectively) [21]. Seven children and two adolescents (32.1% of patients) infused the drug at a maximum rate of 160 or 300 ml/h/infusion (depending on patient body weight [14]) or at a rate near to the maximum. The median infusion rate for the whole study population peaked at 145.0 ml/h in Month 9. This phenomenon may have been related to the high proportion of patients administering the drug at a maximum/near to maximum rate and (high proportion of adolescents) in that period. Conversely, at Month 15, when the study population contained one of the smallest proportions of patients administering fSCIG at the maximum/near to maximum rate, the median infusion rate for the whole population was the lowest.

The fSCIG infusion volumes per site administered in our study to children and adolescents (median values: 100 ml and 200 ml, respectively) were similar to those in the studies by Baumann et al. [21] and Borte et al. [22]. Gruenemeier et al. reported a median volume per infusion site for the whole pediatric population (n = 13) of 200.0 ml (100.0–300.0 ml) [23]. They also presented the data on the infusion volume per site for each pediatric patient: for patients who used a single needle set (n = 9), the volumes per infusion site were 100 ml (n = 2), 200 ml (n = 6) and 250 ml (n = 1), and for patients using a bifurcated needle set (n = 4), the volumes per infusion site were 87.5 ml (n = 1), 100 ml (n = 1), 120 ml (n = 1) and 150 ml (n = 1) [23].

In our study, most patients (71.4%) used 6- or 9-mm needles for infusion. Of the six overweight patients (based on BMI), five individuals used 12-mm needles. This observation could support the notion that longer infusion needles are used more often in overweight patients than in patients with normal BMI [24]. However, in another study, also conducted on a small group of pediatric patients with PIDs, no correlation was found between the length of the infusion needle and the BMI category [23]. It has been suggested that each patient should be assessed individually for needle choice to ensure the best comfort and tolerance, regardless of BMI [23].

Fear of needles usually begins in childhood and can further develop into a chronic form [7]. It is common, affecting 33–63% of children, and can contribute to negative experiences with needle procedures administered by patients and caregivers [7]. It can also be the reason for the discontinuation of Ig infusions [5,17]. Therefore, therapy requiring fewer infusion sites and less frequent infusions are desired for the pediatric population. The administration schemes used in this study were based on those in clinical trials, in which fSCIG was mainly infused every 4 and every 3 weeks (by 75.0 and 16.7% of patients, respectively) [3,5]. Throughout the study, 27 patients (96.4%) received fSCIG every 4 weeks. Three of these patients (11.1%) episodically received fSCIG more frequently during the first 9 months of treatment because of dose adjustments; however, thereafter until the end of the study, they infused the drug at 4-week intervals. One patient (3.6%) was administered fSCIG every 3 weeks throughout the study. In addition, 89.3% of our patients used one site for infusion. Thus, treatment regimen in our study was also like that in other real-life studies in which patients predominantly received fSCIG every 3–4 weeks and used a single infusion site [21–23].

No cases of serious bacterial infection were reported during our study. 83 non-serious infections occurred in 13 patients (46.4%), resulting in 1.88 infection per patient-year. For comparison, in a clinical trial involving 24 pediatric patients with PIDs, the rate of all infections during fSCIG exposure per patient-year was 3.02, which is considered low [5]. Overall, our results support that the use of fSCIG in routine clinical practice provides good infection prevention across the age spectrum of pediatric patients with PIDs. In our study, good protection against infection corresponded with satisfactory serum IgG levels in the study cohort: In the first two periods of follow-up after fSCIG administration, the median IgG concentration in the whole study population remained relatively stable (range 9.5–9.6 g/l) and decreased to 7.8 g/l thereafter. It is noteworthy that the median IgG concentrations in all age groups across all study intervals were not less than 7.6 g/l. It should be mentioned that the number of serum IgG measurements during days 8–14 and 15–21 after fSCIG administration was limited, and the results may therefore not be reliable. The highest number of measurements was taken during days 22–28 after fSCIG administration, which was associated with the scheduled visits in the medical center. Other studies investigating the pediatric population treated with fSCIG have also achieved good clinical outcomes along with satisfactory serum IgG concentrations. In the real-life setting, Baumann et al. reported a minimum level of IgG measured 6 months after the initiation visit of 9.0 g/l (range: 7.0–17.0 g/l) in the whole study population and in children, and 10 g/l (range: 7.0–11.0 g/l) in adolescents [21]. In another real-world study by Borte et al., at 12 months, in 15 pediatric patients (14 patients with PID and one patient with secondary immunodeficiency) receiving 0.5 g/kg/month of fSCIG every 4 weeks, the median trough IgG concentration was 8.1 g/l (IQR: 7.1–8.8 g/l) [22]. In our study, the lowest median IgG level was recorded in patients with agammaglobulinemia. This is an important observation in view of the literature data, which shows that many patients with agammaglobulinemia, even with regular immunoglobulin replacement therapy, experience ongoing respiratory infections and progressive bronchiectasis with worsening lung function [25]. Therefore, in childhood agammaglobulinemia, more intensive treatment may be necessary to fully prevent complications of the disease [26]. The type of therapy may also play a role here because it was demonstrated that significantly more patients treated with IVIG than with SCIG developed bronchiectasis [25]. However, the debate on the optimal serum IgG concentration and the severity of therapy in patients with agammaglobulinemia is ongoing.

One limitation of this study is its retrospective nature, which is associated with a potential recording bias. Moreover, because the data were collected from existing medical records (and partly during the COVID-19 pandemic), some information is missing and errors may have occurred during data entry. The size of the study cohort, which was determined by aspects of feasibility, may also raise concerns. Nevertheless, although PIDs are rare conditions, the number of pediatric patients included in our study was higher than those in clinical trials [3,5] and other real-world studies [21,22,27]. When considering IgG levels, it should be noted that IgG measurements were sparce, especially during days 8–14 and 15–21 after fSCIG administration, and therefore, also because of the small sample size, it was not possible to draw conclusions about IgG levels in adolescents. Furthermore, the heterogeneity of the population in terms of age and type of immunodeficiency may limit generalizability of any conclusions drawn. Another limiting factor is that the study was conducted in four specialist centers in Poland, and therefore our results cannot be generalized to other regions with different standards of care and clinical practice. This study did not aim to collect information on adverse drug reactions reported through ongoing post-marketing surveillance; however, as such reactions may affect infusion parameters, further research is required in this area.

Conclusion

We have presented the first real-world data on the fSCIG treatment regimen and clinical outcomes of pediatric PID patients in Poland. Our findings support the feasibility of administering fSCIG in children and adolescents with PIDs every 3–4 weeks using a single infusion site. Moreover, our data show flexibility in terms of fSCIG delivery parameters, such as modification of the ramp-up schedule, infusion frequency and number of infusion sites, which may allow clinicians to tailor treatment to the specific needs of individual pediatric patients with PID.

Summary points

• This is the first study, to the knowledge of the authors, that presents real-world data on hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) treatment patterns and clinical outcomes in pediatric patients with primary immunodeficiency diseases (PIDs) in Poland.

• Data supported the feasibility of administering fSCIG every 3–4 weeks using a single infusion site in the pediatric population with PIDs.

• The median duration of fSCIG exposure was 15.1 months.

• 64.3% of patients initiated fSCIG dosing on a ramp-up schedule and the median duration of the ramp-up period was 35.5 days.

• Flexibility in fSCIG delivery parameters may allow for individualized treatment options.

• There were no cases of serious bacterial infection.

• The non-serious infection rate was 1.88 per patient year.

• Overall, median serum IgG levels at 15–21 and 22–28 days after fSCIG administration were 9.5 and 7.8 g/l.

Author contributions

M Mach-Tomalska, S Drygała and E Heropolitańska-Pliszka conceived the study. M Kamieniak, S Drygała and E Heropolitańska-Pliszka contributed to the design of the study. All authors participated in data collection. S Drygała, M Kamieniak and J Kasprzak analyzed the data. S Drygała coordinated the project and funding for the project. All authors contributed to the manuscript and approved its final version.

Ethical conduct of research

All patients or/and patients’ caregivers provided written informed consent, and the study was approved by the Ethics Committee at the Children’s Memorial Health Institute (approval number 45/KBE/2020).

Data sharing statement

The data sets generated and/or analyzed during the current study are available from the corresponding author on reasonable request, to researchers who provide a methodologically sound proposal. The data will be provided after their de-identification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymization.

Acknowledgments

The authors would like to express their deep gratitude and thank the patients and their parents for being involved in the data collection for the IG TATRY study. The authors are grateful to the following persons for their contribution to data collection, analysis, assistance with statistical analysis and critical review of the article: E Klemba, M Płaszczyca and M Kowalski.

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/imt-2023-0305

Financial disclosure

This study is a part of the IG TATRY study funded by Takeda Pharma Sp. z o.o. M Mach-Tomalska received lecture fees and/or travel grants from CSL Behring, Octapharma and Takeda. AP Pukas-Bochenek received lecture fees and/or travel grants from Takeda. M Malanowska received lecture fees and/or travel grants from CSL Behring, Octapharma and Takeda. M Pac received lecture fees and/or travel grants from Biogen, CSL Behring, Grifols, Octapharma, Pfizer and Takeda. S Drygała was an employee of Takeda Pharma Sp. z o.o.at the time of the study and is currently employed by AstraZeneca. M Kamieniak is an employee and shareholder of Takeda Development Center Americas, Inc. J Kasprzak is a permanent employee of Takeda Pharma Sp. z o.o. E Heropolitańska-Pliszka received lecture fees and/or travel grants from CSL Behring, Kedrion, Octapharma and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

Medical writing support and editorial assistance was provided by M Kołtowska-Häggström, A Linkiewicz-Zegan and W Kurowska of Proper Medical Writing Sp. z o.o. and was funded by Takeda Pharma Sp. z o.o.