PURPOSE:To investigate the efficacy, safety, tolerability, and serum IgG trough levels of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% in US pediatric patients with primary immunodeficiency diseases (PIDDs). METHODS:This phase 3, open-label, prospective study (NCT03277313) was conducted at 17 US centers. Eligible patients aged 2 to < 16 years had PIDDs and had received immunoglobulin G (IgG) at a consistent dose for ≥ 3 months before screening. Participants received fSCIG 10% via dose ramp-up for up to 6 weeks (Epoch 1), then every 3-4 weeks for ≤ 3 years (Epoch 2). The primary endpoint was the rate of acute serious bacterial infections (ASBIs). RESULTS:Data were provided by 44 participants for Epoch 1 (mean ± SD age: 9.0 ± 3.6 years) and 43 (97.7%) for Epoch 2; 34 (77.3%) completed the study. Two ASBIs (both bacterial pneumonia) were reported in one participant with specific antibody deficiency. The mean rate of ASBIs was 0.04 events/participant-year (99% upper confidence interval limit: 0.20), significantly lower than the regulatory-defined threshold of 1.0 (p < 0.001). The mean rate of all infections was 3.12 events/participant-year. Stable mean serum IgG trough levels were maintained during Epoch 2 (10.4, 9.2, and 9.2 g/L at Months 0, 6, and 12, respectively). Most related treatment-emergent adverse events were mild or moderate in severity. No participant developed anti-recombinant human hyaluronidase neutralizing antibodies; 1/44 participants (2.3%) developed binding antibodies. CONCLUSION:fSCIG 10% effectively prevented ASBIs in pediatric patients with PIDDs, with a favorable safety profile consistent with previous clinical studies.

Facilitated subcutaneous immunoglobulin (fSCIG) 10% is an immunoglobulin replacement therapy that utilizes recombinant human hyaluronidase (rHuPH20) to enhance immunoglobulin dispersion and absorption, allowing for longer treatment intervals similar to intravenous immunoglobulin (up to once monthly). fSCIG 10% is indicated in the USA for treating adults and children aged >= 2 years with primary immunodeficiency diseases (PIDs). This prospective, non-interventional, open-label, multicenter, post-authorization safety study (NCT02593188) was conducted in the USA from November 2015 to October 2021 to assess the long-term safety of fSCIG 10% in routine clinical practice. Patients with PIDs aged >= 16 years who were prescribed and/or had started fSCIG 10% treatment were enrolled. In total, 253 patients were enrolled and included (full analysis set). Participants received fSCIG 10% treatment for a median (interquartile range) of 10.0 (3.5-11.8) months, with the majority of infusions administered every 4 weeks (54.4% [1197/2201 infusions]) and at home (62.6% [1395/2230 infusions]). Overall, 98.5% of infusions were administered without rate reduction, interruption, or discontinuation due to adverse events (AEs). Treatment-related, non-serious AEs were experienced by 52 patients (20.6%, 284 events). Two patients (0.8%) each experienced one treatment-related serious AE (aseptic meningitis and deep vein thrombosis). Development of antibodies against rHuPH20 was uncommon; 14/196 patients (7.1%) tested positive for binding antibodies (titer >= 1:160) with no neutralizing antibodies detected. There was no relationship between anti-rHuPH20 antibody positivity and the occurrence of treatment-related serious or non-serious AEs. Long-term, repeated self-administration of fSCIG 10% was well tolerated in US clinical practice by patients with PIDs.

Facilitated subcutaneous immunoglobulin (fSCIG) 10

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening monogenic autoimmune disorder primarily caused by biallelic deleterious variants in the autoimmune regulator (AIRE) gene. We prospectively evaluated 104 patients with clinically diagnosed APECED syndrome and identified 17 patients (16%) from 14 kindreds lacking biallelic AIRE variants in exons or flanking intronic regions; 15 had Puerto Rican ancestry. Through whole-genome sequencing, we identified a deep intronic AIRE variant (c.1504-818 G>A) cosegregating with the disease in all 17 patients. We developed a culture system of AIRE-expressing primary patient monocyte-derived dendric cells and demonstrated that c.1504-818 G>A creates a cryptic splice site and activates inclusion of a 109-base pair frame-shifting pseudoexon. We also found low-level AIRE expression in patient-derived lymphoblastoid cell lines (LCLs) and confirmed pseudoexon inclusion in independent extrathymic AIRE-expressing cell lines. Through protein modeling and transcriptomic analyses of AIRE-transfected human embryonic kidney 293 and thymic epithelial cell 4D6 cells, we showed that this variant alters the carboxyl terminus of the AIRE protein, abrogating its function. Last, we developed an antisense oligonucleotide (ASO) that reversed pseudoexon inclusion and restored the normal AIRE transcript sequence in LCLs. Thus, our findings revealed c.1504-818 G>A as a founder APECED-causing AIRE variant in the Puerto Rican population and uncovered pseudoexon inclusion as an ASO-reversible genetic mechanism underlying APECED.

The COVID-19 pandemic forced healthcare institutions and many clinical research programs to adopt telehealth modalities in order to mitigate viral spread. With the expanded use of telehealth, there is the potential to increase access to genomic medicine to medically underserved populations, yet little is known about how best to communicate genomic results via telehealth while also ensuring equitable access. NYCKidSeq, a multi-institutional clinical genomics research program in New York City, launched the TeleKidSeq pilot study to assess alternative forms of genomic communication and telehealth service delivery models with families from medically underserved populations. We aim to enroll 496 participants between 0 and 21 years old to receive clinical genome sequencing. These individuals have a neurologic, cardiovascular, and/or immunologic disease. Participants will be English- or Spanish-speaking and predominantly from underrepresented groups who receive care in the New York metropolitan area. Prior to enrollment, participants will be randomized to either genetic counseling via videoconferencing with screen-sharing or genetic counseling via videoconferencing without screen-sharing. Using surveys administered at baseline, results disclosure, and 6-months post-results disclosure, we will evaluate the impact of the use of screen-sharing on participant understanding, satisfaction, and uptake of medical recommendations, as well as the psychological and socioeconomic implications of obtaining genome sequencing. Clinical utility, cost, and diagnostic yield of genome sequencing will also be assessed. The TeleKidSeq pilot study will contribute to innovations in communicating genomic test results to diverse populations through telehealth technology. In conjunction with NYCKidSeq, this work will inform best practices for the implementation of genomic medicine in diverse, English- and Spanish-speaking populations.

This study assessed the efficacy and safety of facilitated subcutaneous immunoglobulin (fSCIG; immunoglobulin G [IgG] 10% and recombinant human hyaluronidase [rHuPH20]) in US pediatric patients with primary immunodeficiency disease (PIDD). This phase 3, open-label, prospective study (NCT03277313) was conducted at 17 centers in the US. Patients were eligible for enrollment if they were aged 2 to <16 years, diagnosed with PIDD requiring immunoglobulin replacement therapy and had received a consistent IgG dose for ≥3 months prior to screening. Patients received fSCIG 10% using a dose ramp-up over ≤6 weeks (Epoch 1) followed by fSCIG 10% treatment every 3 or 4 weeks for ≤3 years (Epoch 2). The primary endpoint, rate of acute serious bacterial infections (ASBIs), was compared with the regulatory-defined threshold (< 1.0 ASBIs per patient-year). Final data were provided by 44 patients for Epoch 1 (mean age [range] 9.0 [3–15] years, 59.1% male) and 43 patients for Epoch 2; 34 patients completed the study. Two ASBIs (both bacterial pneumonia) were reported in the same patient. The mean rate of ASBIs (0.04 events/patient-year [99% upper confidence interval: 0.20]) was significantly lower than the regulatory-defined threshold. The mean rate of all infections was 3.12 events/patient-year. Stable mean serum trough IgG levels were maintained during Epoch 2 (10.4, 9.2, and 9.2 g/L at Months 0, 6 and 12, respectively). Excluding infections, 336 fSCIG-related treatment-emergent adverse events (TEAEs) were reported in 34 patients (Epochs 1 and 2 combined); most were mild (247 events in 32 patients) and two TEAEs in two patients were severe (celiac disease flare and headache). One serious TEAE of tonsillar hypertrophy was considered unrelated to fSCIG 10%. One patient developed anti-rHuPH20 binding antibodies (titer ≥160) without neutralizing anti-rHuPH20 antibodies. At end of Epoch 2, the majority of patients stated that they would choose to continue fSCIG 10%. fSCIG 10% effectively prevented ASBIs in US pediatric patients with PIDD with a safety profile consistent with previous clinical studies. Takeda Development Center Americas, Inc. and Baxalta funded this study. Takeda Pharmaceuticals International AG funded writing support.

Cow's milk allergy has been studied extensively in infants and young children and has public health importance around the globe. We describe the clinical and demographic characteristics of 3 cases of a rare presentation of adult-onset IgE-mediated cows' milk allergy.

Metabolic detoxification with enzyme replacement therapy (ERT) promotes immune recovery in patients with adenosine deaminase (ADA)–deficient severe combined immunodeficiency (ADA-SCID). Elapegademase is a PEGylated recombinant bovine ADA ERT developed to replace the now-discontinued bovine-derived pegademase. This study was a 1-way crossover from pegademase to elapegademase in 7 patients with ADA-SCID to assess efficacy and safety outcomes for elapegademase. After once-weekly pegademase dosage was adjusted to achieve therapeutic metabolic detoxification and trough ADA activity, patients transitioned to a bioequivalent dose of elapegademase. Maintenance of metabolic detoxification and adequate ADA activity were evaluated periodically. One patient withdrew after 2 doses of an early elapegademase formulation due to injection-site pain caused by EDTA. The 6 remaining patients completed 71−216 weeks of elapegademase therapy with a formulation that did not contain EDTA. In these patients, elapegademase improved ADA activity compared with pegademase and maintained metabolic detoxification. Total lymphocyte counts increased for all completer patients from between 1.2- and 2.1-fold at the end of study compared with baseline. Elapegademase had a comparable safety profile to pegademase; no patient developed a severe infectious complication. Three patients had transient, non-neutralizing antibodies to pegademase, elapegademase, and/or polyethylene glycol ≤ 47 weeks of treatment without effect on trough plasma ADA activity or trough erythrocyte deoxyadenosine nucleotide levels. Elapegademase was safe, well tolerated, achieved stable trough plasma ADA activity with weekly dosing, was effective in maintaining metabolic detoxification, and was associated with maintenance or improvements in lymphocyte counts compared with pegademase therapy in patients with ADA-SCID.

Facilitated subcutaneous immunoglobulin (fSCIG) 10% is an immunoglobulin replacement therapy that utilizes recombinant human hyaluronidase (rHuPH20) to enhance immunoglobulin dispersion and absorption. fSCIG 10% is approved in the USA for adult patients with primary immunodeficiency diseases (PIDDs). This study aimed to assess the long-term safety of fSCIG 10% in routine clinical practice. This prospective, non-interventional, open-label, multicenter, post-authorization safety study (NCT02593188) was conducted in the USA from Nov-2015 to Aug-2022. Patients with PIDD, aged ≥16 years, prescribed or receiving fSCIG 10% were enrolled. Treatment regimens were planned by the attending physician in accordance with routine clinical practice. Adverse event (AE) data were collected from enrollment to study completion or discontinuation and the presence of anti-rHuPH20 antibodies was evaluated on a voluntary basis. In total, 253 patients were enrolled and included in the full analysis set (mean age [standard deviation] 54.3 years [15.6]; 79.1% female). The most common PIDD diagnosis was common variable immunodeficiency (71.9%). Patients received fSCIG 10% treatment for a median (interquartile range) duration of 10.0 (3.7–11.8) months, with most infusions administered every 4 weeks (54.4% [1197 of 2201 infusions]) at home (62.6% [1395 of 2230 infusions]). Overall, 98.5% of infusions were administered without a rate reduction, interruption, or discontinuation due to AEs. Treatment-related, non-serious AEs were experienced by 52 patients (20.6%, 284 events). Two patients (0.8%) each experienced one treatment-related serious AE (aseptic meningitis and deep vein thrombosis). Two fatal AEs (0.8%) were reported; neither were treatment-related. Of 196 patients tested, 14 (7.1%) were positive for treatment-emergent binding anti-rHuPH20 antibodies (titer ≥1:160; maximum titer 10 240); no neutralizing antibodies were detected. There was no relationship between anti-rHuPH20 antibody positivity and the occurrence of treatment-related serious or non-serious AEs. Long-term, repeated, self-administration of fSCIG 10% is well-tolerated in US clinical practice by patients with PIDD. Development of non-neutralizing antibodies against rHuPH20 was uncommon and did not correlate with treatment-related AEs. Baxalta US Inc., a Takeda company, funded this study. Takeda Pharmaceuticals International AG funded writing support.

The first emergency use authorization for COVID-19 vaccines was issued in December/2020. The effectiveness of current vaccines ranges between 50-95% in the general population. However, their efficacy in patients with primary immunodeficiency (PID), especially those with defects in humoral immunity, is largely unknown. This is a retrospective chart review study. Subjects were patients with PID receiving care at the Center for Clinical Immunology from Dec/2020 to July/2021. Patients included were those who received any FDA approved vaccine against SARS-CoV-2 and had SARS-CoV-2 IgG Spike Antibody measured. The data was analyzed using simple linear regression. We reviewed 217 charts. The most common diagnoses were CVID, hypogammaglobulinemia and anti-polysaccharide antibody deficiency. Patients' ages ranged from 3-92 years, with a mean age of 56. Of the 198 patients who were vaccinated, 92 had testing for antibodies against SARS-CoV-2 IgG Spike protein. The mean time between vaccination and testing was 76 days. Of those tested, 85/92 (92.4%) had measurable antibodies (CVID 34/36 - 94.4%, hypogammaglobulinemia 27/32 - 84.3%, anti-polysaccharide antibody deficiency 11/23 - 47.8%), with 7/92 (7.6%) having no measurable antibody response. Our data suggests that over 90% of patients with PID vaccinated against SARS-CoV-2, including those with poor antibody responses to traditional vaccines, were able to develop antibodies against SARS-CoV-2 Spike protein. This emphasizes the importance of vaccinating this population, and adds to the limited data available on this topic. Further research is necessary to determine the efficacy of these antibodies, as well as their long-term preservation and their correlation with T-cell responses.

fSCIG (facilitated immune globulin infusion 10% [human] with recombinant human hyaluronidase [rHuPH20]) is a subcutaneously administered IG, approved for patients with primary immunodeficiency diseases (PIDD). The objective of this study was to acquire data from clinical practice on long-term safety of fSCIG in patients with PIDD. This ongoing prospective, non-interventional, uncontrolled, multicenter, post-authorization safety study was initiated in the US in November 2015 (NCT02593188) in patients ≥16 years receiving fSCIG for PIDD. Dosage regimen and treatment schedule are at the discretion of the treating physician. AEs are collected from enrollment to study completion/discontinuation. The presence of anti-rHuPH20 antibody titers is evaluated on a voluntary basis. This interim analysis (May 2, 2019) includes 264 patients (mean age 54.7 years; 79.2% female); 81 of whom are still under follow-up. No serious AEs (SAEs) related to fSCIG were reported. Infusions were administered at home (60.4%) or at the clinical site (39.6%), most commonly using 4-week infusion intervals. Over 98% of infusions were administered without a rate reduction, interruption, or discontinuation due to AEs. Twenty-seven patients experienced a causally related non-serious local AE (10.2%; 0.35 events/patient-year, 0.05 events/infusion), and 37 patients experienced a causally related non-serious systemic AE (14.0%, 0.72 events/patient-year, 0.10 events/infusion). No neutralizing rHuPH20 antibodies were detected among patients with available immunogenicity data (n=194). These data support previous observations that fSCIG is well tolerated in clinical practice by patients with PIDD. Baxalta US Inc. (a Takeda company) funded this study and writing support.

Common variable immunodeficiency (CVID), the most prevalent humoral immunodeficiency, is characterized by hypogammaglobulinemia, impaired vaccine responses, and recurrent sinopulmonary infections.1 Although known risk factors for more severe COVID-19 infection include older age, hypertension (HTN), obesity, and cardiovascular disease,2 the association of immunocompromised patients and severity of COVID-19 infection is not well established. Studying specific immunocompromised cohorts may clarify risk of morbidity and mortality to these patients from COVID-19 infection.

Adenosine deaminase (ADA) deficiency is an autosomal recessive severe combined immunodeficiency that typically presents within the first year with severe infections. Other features of ADA deficiency include the following: autoimmunity, myeloid dysplasia, pulmonary disease, neurodevelopmental delay, skeletal dysplasia, hepatic dysfunction, and lymphoma. 1 Kohn D.B. Hershfield M.S. Puck J.M. et al. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol. 2019; 143: 852-863 Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Hematopoietic stem cell transplant (HSCT) and gene therapy (GT) have been successful in the treatment of ADA deficiency. 2 Scott O. Kim V.H. Reid B. et al. Long-term outcome of adenosine deaminase-deficient patients—a single-center experience. J Clin Immunol. 2017; 37: 582-591 Crossref PubMed Scopus (14) Google Scholar ,3 Cagdas D. Gur Cetinkaya P. Karaatmaca B. et al. ADA deficiency: evaluation of the clinical and laboratory features and the outcome. J Clin Immunol. 2018; 38: 484-493 Crossref PubMed Scopus (11) Google Scholar Enzyme replacement therapy (ERT) has traditionally been used as a bridge to HSCT or GT and not as first-line, long-standing treatment. However, compliance is essential for long-term successful ERT.

Common variable immunodeficiency is a heterogenous disorder of the immune system associated with immunodeficiency, lymphoproliferation, autoimmunity, and malignancy. Certain laboratory characteristics of common variable immunodeficiency patients can be associated with an increase of related clinical sequelae, though there is limited data on predictive characteristics for clinical sequelae in CVID patients. The purpose of this study was to analyze a unique large CVID patient cohort for predictive laboratory characteristics of clinical sequelae. A retrospective chart review was performed of a longitudinal cohort of CVID patients treated at a single institution, largely by a single provider with higher dose replacement immunoglobulin, that has not been previously described. 219 CVID patients were followed for 1,990 patient-years. 86% of the patients were on immunoglobulin with an average IgG trough of 1260 mg/dL. Low IgG at time of diagnosis, low CD19 absolute cell count, and poor mitogen induced lymphocyte proliferation were associated with increase of CVID clinical sequelae. In particular, this cohort demonstrates the novel finding that low IgG at time of diagnosis prior to immunoglobulin replacement is associated with a higher incidence of lymphoma, bronchiectasis, granulomatous disease, lymphoid hyperplasia, splenomegaly, and hepatic disease.

An amendment to this paper has been published and can be accessed via the original article.