Primary immunodeficiency diseases (PIDs), also referred to as inborn errors of immunity, are a group of approximately 485 genetic conditions that affect the immune system [1, 2]. Clinical manifestations of PIDs are highly variable and may present as an increased susceptibility to infection, autoimmunity, autoinflammatory disease, allergy, bone marrow failure, and/or malignancy [1, 2]. Secondary immunodeficiency disease (SID; or acquired forms of immunodeficiency) is caused by external factors that include underlying diseases (such as cancer) or medication (including steroids) [3]. Patients with PIDs or SID experience increased morbidity and mortality owing to recurrent and severe infections that lead to a reduced quality of life [3, 4].

The current standard of care for patients with PIDs and an antibody deficiency is lifelong immunoglobulin replacement therapy (IgRT), delivered by intravenous infusion (IVIG) or subcutaneous infusion (SCIG) [5,6,7]. Standard IVIG therapy typically involves one infusion per month at a maintenance dose of 0.4–0.6 g/kg [8]. SCIG therapy is typically administered once weekly or every two weeks at a maintenance dose of 0.1 g/kg/week [8], with difference in infusion schedules largely dependent on patient preference. Although treatment with IVIG is effective in preventing infection, it can be associated with adverse events (AEs), including headaches, fever, allergies, and other systemic reactions [7]. Additionally, the requirement for repeated venous access and patient visits to physician offices or outpatient infusion centres may negatively affect patient health-related quality of life (HRQoL) [7], although this may vary by region. For example, in Canada, IVIG can only be administered in a healthcare setting by a healthcare professional (HCP) [9]; in comparison, IVIG may be administered at home independently in the UK or with nursing support in the USA [10, 11], both of which may lessen some of the patient burden of visiting a healthcare centre.

Importantly, SCIG offers an alternative therapy for patients who experience AEs using IVIG or have difficulty with venous access. SCIG infusion has been shown to be as effective as IVIG at preventing infections in patients with PIDs, and results in fewer systemic adverse reactions [7, 8, 12]. However, patients who report less satisfaction with SCIG than IVIG often identify increased frequency of infusions and local site reactions as primary reasons [8]. Although SCIG infusions require more frequent administration than IVIG, SCIG can be more easily administered at home, and patients/caregivers can adjust the method of delivery, infusion volume, infusion rate, number of sites, and number of infusions per week, depending on patient preference and needs [7, 12]. Additionally, estimates suggest that the annual cost of SCIG to healthcare systems is less than IVIG, owing to the lower direct costs associated with medical supplies and the reduced nursing support required for administration [13].

Several SCIG formulations are available for the treatment of patients with PIDs, including differing immunoglobulin (Ig) G (IgG) concentrations (10%, 16%, 16.5%, and 20%) [14,15,16] and infusion with recombinant human hyaluronidase (an enzyme that depolymerizes hyaluronan in the extracellular matrix to transiently increase tissue permeability to Ig) [7, 17]. SCIG delivery facilitated by recombinant human hyaluronidase enables the delivery of larger volumes of IgG at a single infusion site every 3–4 weeks and can be administered at the same dose as a patient’s previous IVIG therapy [7, 12]. The first liquid IgG 20% formulation approved globally for subcutaneous administration in patients with PIDs was immune globulin subcutaneous (human) 20% solution, stabilized with proline (IgPro20; Hizentra [CSL Behring, King of Prussia, PA, USA]) [18]. Compared with less-concentrated SCIG therapies, SCIG 20% allows for smaller infusion volumes and higher infusion rates [19]. Between April and September 2018, the Canadian Blood Services formulary phased in another SCIG 20% therapy: immune globulin subcutaneous (human) 20% solution, stabilized with glycine (Ig20Gly; Cuvitru [Baxalta US, Inc., a Takeda company, Lexington, MA, USA]) [20, 21].

In Europe, Ig20Gly is indicated as a replacement therapy in adults and children of any age for PIDs associated with impaired antibody production, and for SID in patients who experience severe or recurrent infections, ineffective antimicrobial treatment, and either proven specific antibody failure or a serum IgG level of less than 4 g/L [22]. For patients with PIDs, after steady-state IgG levels are attained, it is recommended that maintenance doses are administered at repeated intervals to reach a cumulative monthly dose of 0.3–1.0 g/kg [22]. In the USA, Ig20Gly is indicated as a replacement therapy for PIDs with antibody deficiency in adult and paediatric patients aged 2 years and above [23]; Ig20Gly can be administered at regular intervals, daily, or up to every 2 weeks, depending on the patient’s pharmacokinetic and clinical response profile [23]. Two pivotal phase 2/3 clinical trials conducted in North America (NCT01218438) and Europe (NCT01412385) demonstrated favourable efficacy, safety, and tolerability of Ig20Gly delivered by infusion pump in patients with PIDs; 4327 infusions were administered in 74 patients in the North American trial and 2349 infusions were administered in 49 patients in the European trial [19, 24]. Overall, both trials showed that Ig20Gly can establish protection against infection with stable steady-state IgG levels [19, 24].

Following the European approval in November 2021 of manual administration of IgPro20 via a syringe for use in patients with PIDs [25], manual administration of Ig20Gly via a syringe was approved in Europe in September 2023 as an alternative to infusion pump administration [22]. Manual administration of SCIG avoids technical and logistical requirements associated with infusion pump use (e.g. software problems, battery failures, or inadequate interface design), permitting easier infusion at home [26]. Importantly, prior studies using manual administration for the delivery of SCIG therapies have demonstrated the efficacy, safety, and tolerability of manual administration in adults and paediatric patients with PIDs; these studies are summarized in Table 1 [15, 16, 27,28,29,30,31].

During the COVID-19 pandemic, owing to patient preference for at-home treatment and a reduced availability of infusion pumps, there was accelerated uptake of SCIG manual administration. Nonetheless, practical guidance and assessment of patient suitability for manual administration remains limited. Therefore, this article reviews infusion parameters, safety, patient-reported outcomes (PROs), and the economic benefits of Ig20Gly manual administration, as well as providing practical guidance for use of this method.

To date, two published studies have discussed infusion parameters, safety, and PROs following treatment with Ig20Gly infused via manual administration. The first was the CANadian CUvitru Non-interventional study (CANCUN; NCT03716700) of patients with PIDs or SID transitioning to Ig20Gly from a prior SCIG therapy; this publication included a subgroup analysis in which manual administration of Ig20Gly was evaluated [20]. CANCUN was a phase 4, prospective, single-arm study in six centres across Canada (excluding Quebec) with a maximum 12-month (− 1/ + 2 months) follow-up period [20]. Overall, 125 patients aged 2 years and above with PIDs or SID were included; of these, 54 patients (43.2%) infused Ig20Gly via manual administration [20]. Of patients infusing by manual administration, median (range) age was 63 (19–82) years and 72.2% of patients were female; in total, 51.9% of patients infusing manually had PIDs and 48.1% had SID [20]. The second publication reported on a retrospective analysis of the IG-TATRY (NCT04636502) study, which was conducted to analyse real-world data on the use of Ig20Gly in paediatric patients with PIDs from four immunology/haematology clinics in Poland [32]. In total, 75 paediatric patients (aged < 18 years) with PIDs were included, of whom 16 (21.3%) infused Ig20Gly by manual administration (7 patients [9.3%] infused only by manual administration; 9 patients [12.0%] used both infusion pump and manual administration). Of patients using manual administration, 3 patients were aged 6 years and under, 7 patients were aged 7–11 years, and 6 patients were aged 12–17 years [32].

In the CANCUN study, compared with patients using an infusion pump at the 12-month follow-up, patients using manual administration did so with a lower median (interquartile range [IQR]) volume per infusion (30.0 [20.0–40.0] mL vs 43.0 [40.0–60.0] mL) [20]. The median (IQR) volume per site infused by manual administration was lower in the IG-TATRY study (12.5 [10.0–20.0] mL) than in the CANCUN study, likely owing to the enrolment of only paediatric patients in the IG-TATRY study (Table 2) [32]. Consistent with age-dependent infusion volumes, median volume per site was shown to increase with age in the IG-TATRY study, starting at 10.0 mL in patients aged up to 6 years, 15.0 mL in patients aged 7–11 years, and 17.5 mL in patients aged 12–17 years [32]. However, despite the difference in reported volumes per infusion between infusion pump and manual administration, it is possible to administer similar volumes of Ig20Gly using either method. For the first infusion by manual administration, 20.0 mL per site is generally considered appropriate to assess patient tolerability. The typical maximum syringe volume used for manual administration is 30.0 mL, but patients can infuse greater volumes, if tolerated, by switching the type of syringe.

With respect to infusion duration, in the CANCUN study at 12 months, the median (IQR) duration of infusion was shorter for patients using manual administration than for use of an infusion pump (24 [10–40] min vs 60 [45–73] min) [20]. Consistent with these observations, reduced infusion time with manual versus infusion pump administration was demonstrated in a retrospective chart review of 173 paediatric and adult patients with PIDs receiving IgPro20 (< 9 min vs 49 min) [30]. Two other studies reported similar infusion times for manual administration of IgPro20, ranging from a mean duration of 23 min to 47 min [27, 28]. One potential modifier of infusion duration is the rate of infusion, with one study showing a mean weekly duration of IgPro20 administered by manual administration of 23–28 min at a 2.0 mL/min infusion rate and 103–108 min at a 0.5 mL/min infusion rate [27].

Overall, in the CANCUN study at 12 months, median (IQR) infusion rate for manual administration was 30.0 (30.0–60.0) mL/h/site (unpublished observation), compared with 40.0 (34.0–59.0) mL/h/site for all patients [20]. By comparison, for the paediatric population in the IG-TATRY study, patients using manual administration had a higher median (IQR) infusion rate than those using an infusion pump (92.5 [50.0–170.2] mL/h and 40.0 [29.5–55.5] mL/h, respectively; unpublished observations). Notably, the higher infusion rates in the IG-TATRY study may result from differences in age (paediatric vs adult) or rate calculations (mL/h vs mL/h/site); rate per infusion site was not reported in the IG-TATRY study.

In the IG-TATRY study, paediatric patients using manual administration received a lower median (IQR) monthly dose of 0.3 (0.2–0.4) g/kg than the entire cohort (0.4 g/kg), which also included patients who used an infusion pump [32]. The higher reported median monthly dose of Ig20Gly for the entire cohort was similar to doses reported in prior studies: 0.40–0.55 g/kg between 6- and 12-month follow-up visits [33, 34]. Additionally, for the 16 patients using manual administration in the IG-TATRY study, the median (IQR) infusion interval was 8.5 (7.0–10.0) days, equating to a median (IQR) of 3.5 (3.0–4.0) infusions per month [32].

In the CANCUN study, patients using manual administration were more likely to use two or fewer infusion sites than patients using an infusion pump (96.3% vs 55.0%) [20]; more patients infused at three or more sites using an infusion pump than using manual administration (45.0% vs 3.7%). Studies with other SCIG therapies (including IgPro20 and SCIG 16% [Vivaglobin; CSL Behring GmbH, Marburg, Germany]) were concordant with these findings, showing that patients using manual administration typically infuse at two or fewer sites [16, 28]. Patients administering SCIG 16% using an infusion pump were more likely to infuse at three or more sites than patients using manual administration [16]. Individual patient dexterity, leading to difficulty infusing at more than two infusion sites for any given infusion via manual administration, may contribute to this observation of increased infusion frequency to achieve the target dose. However, with the support of a caregiver, it is possible to use multiple syringes for manual administration at more than two sites simultaneously.

Patients infusing by manual administration in the CANCUN study also tended to infuse at more frequent dosing intervals than those using an infusion pump (40.5% of patients infused 2–6 times/week for manual administration, compared with 3.1% of patients infusing at this frequency via an infusion pump) [20]. Nevertheless, for both manual administration and infusion pump administration, the most frequent dosing interval was once weekly (59.5% and 87.5% of patients, respectively) [20].

Median (IQR) serum IgG trough levels in the CANCUN study were similar for manual administration (9.1 [8.3–11.0] g/L) and infusion pump cohorts (8.6 [7.9–10.6] g/L) [20]. Consistent with this observation, serum IgG trough levels in the IG-TATRY study were comparable between paediatric patients who infused Ig20Gly by manual administration and the overall population (patients who infused with manual administration or infusion pump) [32]. In the IG-TATRY study, the median (IQR) serum IgG trough level was 9.0 (8.2–9.6) g/L for patients using manual administration (measured 1–7 days post-dose) and 8.0 (7.0–9.3) g/L for the entire cohort (measured 1–14 days post-dose; it was not possible to analyse the serum IgG trough levels up to 14 days post-dose in patients using manual administration because of an insufficient number of IgG measurements) [32]. Importantly, in all patients in both studies, the median IgG levels were above a putative minimum protective threshold of 5.0 g/L in all age groups (although in clinical practice, higher thresholds are sometimes used depending on individual patient characteristics) [22, 35,36,37]. Considering delivery of any SCIG therapy, serum IgG trough levels following manual administration are often higher than those following infusion pump administration [16, 29, 30, 38, 39], although no pharmacokinetic analyses have been conducted to explain these observations.

In the IG-TATRY study, Ig20Gly was well tolerated. Overall, five patients (6.7%) discontinued the study; no patient reported manual administration of Ig20Gly as the reason for study discontinuation [32]. Reasons for study discontinuation included no requirement for further treatment owing to satisfactory and stable IgG levels, patient request, and a single death in an 8-year-old patient with PID (no AEs were reported for this patient during the study period) [32]. Tolerability findings were not explicitly reported for patients using manual administration in the CANCUN study.

In the CANCUN study, for patients using infusion pump and manual administration, the number of reported AEs of interest (defined as any AE described as a warning/precaution in the product monograph, reported in a previous trial, or observed during post-marketing surveillance) was similar: 9 AEs of interest in 6/71 (8.5%) patients and 14 AEs of interest in 10/54 (18.5%) patients, respectively [20, 40]. All AEs of interest associated with manual administration were mild or moderate in nature (n = 7 each in 7 and 4 patients, respectively); for patients using an infusion pump, 7 AEs were reported in 4 patients as mild, 1 AE was reported in 1 patient as moderate, and 1 AE was reported in 1 patient as severe (defined as any event that interrupted usual activity of daily living, significantly affected clinical status, or may require therapeutic intervention) [20]. Of the AEs of interest associated with manual administration, 5 were considered related, 5 were possibly related, and 1 was probably related to Ig20Gly infusion; no serious AEs were reported in patients using manual administration [