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A prospective study and its long-term extension examined whether weekly treatment of patients with primary immunodeficiencies (PIDs) with a 16.5% subcutaneous immunoglobulin (SCIg; cutaquig®) confers acceptable efficacy, safety, and tolerability over a follow-up of up to 238 weeks (>4 years). Seventy-five patients received 4462 infusions during up to 70 weeks of follow-up in the main study and 27 patients received 2777 infusions during up to 168 weeks of follow-up in the extension. In the main study, there were no serious bacterial infections (SBIs), and the annual rate of other infections was 3.3 (95% CI 2.4, 4.5). One SBI was recorded in the extension, for an SBI rate of 0.02 (upper 99% CI 0.19). The annual rate of all infections over the duration of the extension study was 2.2 (95% CI 1.2, 3.9). Only 15.0% (1085) of 7239 infusions were associated with infusion site reactions (ISRs), leaving 85.0% (6153) of infusions without reactions. The majority of ISRs were mild and transient. ISR incidence decreased over time, from 36.9% to 16% during the main study and from 9% to 2.3% during the extension. The incidence of related systemic adverse events was 14.7% in the main study and 7.4% in the extension. In conclusion, this prospective, long-term study with cutaquig showed maintained efficacy and low rates of local and systemic adverse reactions in PID patients over up to 238 weeks of follow-up. Over the whole main study period, 77.7% of the 4,462 infusions resulted in no infusion site reactions (ISRs). In the extension study, most of the 2,777 infusions (96.5%) induced no ISRs. In both adult and pediatric patients, mild ISRs were by far the most common, and in children mild ISRs made up 96% of local reactions. [ABSTRACT FROM AUTHOR]

Objective. Fluticasone propionate aqueous nasal spray (FP) at the highest recommended doses does not affect hypothalamic-pituitary-adrenal (HPA) axis function in adults or older children, but its potential effects in children younger than 4 years have not been previously studied. This randomized, double-blind, placebo-controlled study evaluated the effects of FP on HPA axis function measured by 12-hour urinary-free cortisol levels in children 2 to 3 years of age. Methods. Patients ages 2 to 3 years with symptoms of allergic rhinitis were administered FP 200 tag/day (FP200 QD) or vehicle placebo for 6 weeks. Results. The FP200 QD group (n = 33) was equivalent to the placebo group (n = 32) in mean change from baseline in the primary safety measure of 12-hour creatinine-corrected urinary-free cortisol concentration (geometric mean difference [standard error; SE] for placebo--FP200 QD = 0.96 [1.20]; 95% confidence interval 0.66, 1.39) at the end of the treatment period. The adjusted geometric mean change from baseline value was 0.98 for FP200 QD (SE = 1.14) and 0.94 for placebo (SE = 1.15); a value of 1.0 reflects no change from baseline. Cough and fever were the most common adverse events reported in either group. Conclusions. FP200 QD was equivalent to placebo with respect to effects on HPA axis function measured by 12-hour urinary-free cortisol in 2- and 3-year-old patients. FP200 QD was well-tolerated in these very young children with allergic rhinitis., ABBREVIATIONS. HPA, hypothalamic-pituitary-adrenal; FP, fluticasone propionate aqueous nasal spray; FP200 QD, fluticasone propionate aqueous nasal spray 200 [micro]g/day; SD, standard deviation; SE, standard error. Well-tolerated and effective, intranasal corticosteroids are [...]

Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a clinical diagnosis in children who have an acute manifestation of varied neuropsychiatric symptoms, including obsessive compulsive disorder, eating disorders, tics, anxiety, irritability, and problems with attention/concentration. PANS may develop as a result of a postinfectious syndrome and may represent a new form of postinfectious autoimmunity. To test the hypothesis that multiple, consecutive infusions of intravenous immunoglobulin (IVIG) for PANS can be efficacious, a multisite, open-label study was designed. Methods: The primary endpoint was evaluation of the efficacy of IVIG [Octagam 5%] in PANS over a period of 6 months (six infusions) based on mean changes in psychological evaluation scores using 6 different assessments, including the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), Clinical Global Impression of Severity, and the Parent-Rated Pediatric Acute Neuropsychiatric Symptom Scale (PANS Scale). Results: The final cohort consisted of 21 subjects (7 per site) with moderate to severe PANS. The mean age was 10.86 years (range: 4-16 years). Results demonstrated statistically significant reductions in symptoms from baseline to end of treatment in all six assessments measured. CY-BOCS results demonstrated statistically significant reductions in obsessive compulsive symptoms (p < 0.0001), resulting in >50% improvement sustained for at least 8 weeks after the final infusion and up to 46 weeks in a subset of subjects. Conclusions: In PANS, which may be associated with an underlying immune dysregulation, sequential infusions of IVIG [Octagam 5%] successfully ameliorated psychological symptoms and dysfunction, with sustained benefits for at least 8 weeks, and up to 46 weeks in a subset of subjects. In addition, baseline immune and autoimmune profiles demonstrated significant elevations in a majority of subjects, which requires further evaluation, characterization, and study to clarify the potential immune dysfunction by which PANS manifests and progresses. [ABSTRACT FROM AUTHOR]

It has been hypothesized that low levels of C1 esterase inhibitor (C1-INH), a key inhibitor of the complement pathway, may play a role in the occurrence of adverse events (AEs) associated with intravenous immunoglobulin (IVIG) therapy. This open-label pilot study evaluated C1-INH replacement, with recombinant human C1-INH (rhC1-INH), as a potential therapy for adults requiring IVIG and experiencing AEs. Patients received two rounds of IVIG infusion [pre-treatment phase (no rhC1-INH), 4–8 weeks] and then three rounds of one dose of intravenous rhC1-INH 50 U/kg (maximum, 4,200 U) with subsequent IVIG infusion (treatment phase, 6–12 weeks). Nineteen adults completed the study; all had an autoimmune condition linked to common variable immunodeficiency (CVID) or polyneuropathy, and 57.9% had low baseline C1-INH levels. Mean ± SD total scores improved significantly with the Headache Impact Test (from 62.8 ± 6.2 at pre-treatment to 57.7 ± 9.1 after treatment; mean Δ, −5.0; p = 0.02) and Modified Fatigue Impact Scale (from 59.3 ± 13.1 to 51.2 ± 15.4; mean Δ, −8.1; p = 0.006). Significant improvements in the Migraine Disability Assessment were observed for three of five items (p ≤ 0.002). Mean ± SD C1-INH level increased from 26.8 ± 5.9 mg/dl after the second round of IVIG (pre-treatment) to 32.1 ± 7.8 mg/dl after the third rhC1-INH treatment; functional C1-INH levels increased from 115.8 ± 34.7% to 158.3 ± 46.8%. Future research is warranted to explore the benefit of C1-INH therapy for reduction of IVIG-related AEs, as well as the role of C1-INH in patients with CVID and autoimmune disease. Clinical Trial Registration: ClinicalTrials.gov , identifier NCT03576469. [ABSTRACT FROM AUTHOR]

Introduction: Subcutaneously administered immunoglobulin (SCIG) is increasingly used to treat patients with primary immunodeficiencies (PIDs). Octanorm (marketed as cutaquig® in USA and Canada) is a new 16.5% solution of human SCIG, manufactured by a process based on that of the intravenous preparation (IVIG) octagam®. Objectives: To investigate the efficacy, safety and tolerability of octanorm in a prospective, open-label, single-arm phase 3 study involving adult and pediatric patients with PIDs (NCT01888484; clinicaltrials.gov/ct2/show/NCT01888484). Methods: Patients who were previously treated with IVIG received a total of 64 weekly SCIG infusions, including 12 weekly infusions during the wash-in/wash-out period, followed by 52 weekly infusions during the evaluation period. Results: A total of 61 patients aged 2–73 years received 3,497 infusions of octanorm. The mean dose per patient was 0.175 g/kg/infusion. The mean calculated dose conversion factor from the patients' previous IVIG dose for octanorm was 1.37. No serious bacterial infections developed during the study. The rate of other infections per person-year during the primary observation period was 3.43 (upper 95% CI 4.57). All but one non-bacterial infection were mild or moderate in intensity. IgG trough levels were constant during the course of the study. Eleven patients (18.0%) experienced 14 mild or moderate systemic adverse events (AEs) related to octanorm. The rate of related AEs per infusion was 0.004. In 76.7% of infusions, no infusion site reactions were observed and only two (0.3%) reactions were deemed severe. The incidence of site reactions decreased with successive infusions. Conclusion: The new 16.5% SCIG octanorm was shown to be efficacious in preventing infections in PIDs, and was well tolerated. [ABSTRACT FROM AUTHOR]

Intravenous immunoglobulin (IVIG) therapy is commonly used to treat patients with primary antibody deficiency. This prospective, open-label, non-randomised, multicentre, phase III trial investigated the pharmacokinetics of a new 10% liquid IVIG product (panzyga®; Octapharma) in 51 patients aged 2–75 years with common variable immunodeficiency (n = 43) or X-linked agammaglobulinaemia (n = 8). Patients were treated with IVIG 10% every 3 (n = 21) or 4 weeks (n = 30) at a dose of 200–800 mg/kg for 12 months. Total immunoglobulin G (IgG) and subclass concentrations approximately doubled from pre- to 15 min post-infusion. The maximum concentration of total IgG (mean ± SD) was 21.82 ± 5.83 g/L in patients treated 3-weekly and 17.42 ± 3.34 g/L in patients treated 4-weekly. Median trough IgG concentrations were nearly constant over the course of the study, remaining between 11.0 and 12.2 g/L for patients on the 3-week schedule and between 8.10 and 8.65 g/L for patients on the 4-week schedule. The median terminal half-life of total IgG was 36.1 (range 18.5–65.9) days, with generally similar values for the IgG subclasses (26.7–38.0 days). Median half-lives for specific antibodies ranged between 21.3 and 51.2 days for anti-cytomegalovirus, anti- Haemophilus influenzae , anti-measles, anti-tetanus toxoid, anti-varicella zoster virus antibodies, and anti- Streptococcus pneumoniae subtype antibodies. Overall, IVIG 10% demonstrated pharmacokinetic properties similar to those of other commercial IVIG 10% preparations and 3- or 4-weekly administration achieved sufficient concentrations of IgG, IgG subclasses, and specific antibodies, exceeding the recommended level needed to effectively prevent serious bacterial infections. [ABSTRACT FROM AUTHOR]

Research has shown that a subset of the autism spectrum disorder (ASD) population presents with immune dysregulation. To explore this topic further, we investigated the efficacy and tolerability of intravenous immunoglobulin (IVIG) infusion in children with ASD. In this study, participants were recruited based on a diagnosis of autistic disorder, Asperger's disorder, or pervasive developmental disorder not otherwise specified. Participants also showed evidence of immune dysfunction based on abnormal levels of specific biomarkers, including CD40 ligand (CD154), lymphocyte stimulation, and T or B cell dysfunction. Of 17 screened patients, 14 completed the trial and received IVIG treatment (1 g/kg dose) for ten 21‐day treatment cycles. The primary endpoint was disease improvement assessed using standardized cognitive and behavioral tests (Children's Communication Checklist [CCC‐2], Social Responsiveness Scale [SRS], Aberrant Behavior Checklist [ABC], Clinical Global Impressions‐Severity [CGI‐S] and ‐Improvement [CGI‐I], Autism Diagnostic Observation Schedule [ADOS], and Peabody Picture Vocabulary Test [PPVT]). Secondary endpoints included experimental biomarkers such as CD154, toll‐like receptor‐4, memory B cells, FOXP3, and lymphocyte stimulation. Significant improvements from baseline to study endpoint were observed in several subscales of the CCC‐2, SRS, CGI‐I, CGI‐S, and ADOS, including Associated Maladaptive Behaviors (P ≤ .043), Reciprocal Social Interaction (P = .015), Communication (P < .001), and Stereotyped Behaviors and Repetitive Interests (P ≤ .013). Statistically significant reductions were also seen in numerous secondary outcomes of immunological biomarkers indicative of neuroinflammation. IVIG was well tolerated; no subjects withdrew due to an adverse event, and clinical data showed no evidence of thromboembolic events. Autism Res2018, 11: 421–433. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary: Since research has demonstrated a link between autism spectrum disorder (ASD) and immune dysfunction, this study investigated the efficacy and tolerability of intravenous immunoglobulin (IVIG) infusion in children with ASD. Fourteen patients received IVIG treatment and were assessed using standardized cognitive and behavioral tests. Following treatment with IVIG, significant improvement was observed across several subscales of the clinical tests and significant reductions were seen in the markers of neuroinflammation. These data suggest that inflammatory etiologies may play a role in select cases of autism, and IVIG treatment may exert a positive impact on behaviors and markers of inflammation in ASD. [ABSTRACT FROM AUTHOR]

Research on the role of subcutaneous immunoglobulin in primary immunodeficiency disease (PIDD) is ongoing. We analyzed pivotal studies for four subcutaneous immunoglobulin products: IGSC 10% (Gammagard® Liquid), IGIV-C 10% (Gamunex®-C), IGSC 16% (Vivaglobin®) and IGSC 20% (Hizentra®). To identify similarities and differences between products, we examined infusion parameters, adverse event profiles and improvements in tolerability over time. Maximum volume infused was 30 mL/site for IGSC 10%, 34 mL/site for IGIV-C 10%, 15 mL/site for IGSC 16% and 25 mL/site for IGSC 20%. Maximum number of simultaneous infusion sites was 10 for IGSC 10%, 8 for IGIV-C 10%, 6 for IGSC 16% and 4 for IGSC 20%. Local adverse reaction rate per infusion was 0.02 for IGSC 10%, 0.59 for IGIV-C, 0.49 for IGSC 16% and 0.58 for IGSC 20%. IGSC products have similar efficacy profiles; however, their tolerability profiles vary. Reasons for these differences are unknown and warrant further research. [ABSTRACT FROM AUTHOR]

Examines the ability of the antihistamine drug ketotifen to modify the course of eosinophilic gastroenteritis. Signs and symptoms; Role of ketotifen in stabilizing mast cells; Total serum immunoglobulin E levels; Clearing of eosinophilic infiltrates after treatment with ketotifen.

Background: Recombinant human hyaluronidase (rHuPH20)-facilitated subcutaneous infusion of immunoglobulin (fSCIG; HyQvia) is a new Ig treatment combining the advantages of intravenously and conventional subcutaneously-administered immunoglobulin (Ig) with infusion at rates, volumes and frequencies similar to intravenous Ig (IVIG), and favorable systemic tolerability. Objectives We report the efficacy, adverse events, and tolerability of fSCIG in patients aged < 18 years treated in the pivotal phase 3 study and its extension. Methods: Patients aged < 18 years with PID received IVIG for 3 months, then fSCIG every 3 or 4 weeks for ~18 months, followed by up to 21 months. Results: Of the 26 enrolled patients (aged 4-17 years), 24 received fSCIG for up to 3.3 years at the established dose (49 patient-years). No serious fSCIG-related adverse events were reported. The rate of validated acute serious bacterial infections was 0.08/patient-year (upper limit of 99 % CI = 0.20) and the rate of all infections with fSCIG was 3.02/patient-year. The rate of related local adverse events was 0.10/infusion; results were similar when stratified by age group or maximum infusion volume/site. Of 706 fSCIG infusions, 97 % did not require administration changes. Three patients developed binding anti-rHuPH20 antibody at titers ≥ 1:160 on ≥ 1 occasion with no associated adverse reactions; titers declined, despite continued treatment. No patient developed neutralizing anti-rHuPH20 antibodie. Conclusions: In patients aged < 18 years who were treated with fSCIG, infection rates were low, and infusions were well-tolerated, despite infusion volumes and rates like IVIG. The results in pediatric patients were like those in adults. [ABSTRACT FROM AUTHOR]

Background: fSCIG can be administered at similar doses/volumes and dosing intervals as intravenous immunoglobulin G (IgG) (IVIG) but, similar to conventional subcutaneous IgG, is associated with a lower risk of systemic and higher risk of local adverse reactions (ARs). Objective: We report local AR rates over time in patients with PID aged ≥ 16 years treated with fSCIG for up to ~3.5 years in the fSCIG pivotal phase 3 study and its extension. Methods: Following a 3-month IVIG treatment period, patients initiated fSCIG on a dose ramp-up schedule and thereafter received fSCIG every 3 (Q3W) or 4 weeks (Q4W) for ~18 months, followed by up to an additional 21 months. Local AR (temporally associated and/or causally related adverse events) rates were evaluated over time. Results: Of the 63 enrolled patients aged ≥ 16 (16-78) years, 61 received fSCIG for up to ~3.5 years at the established dose. Overall, the local AR rate per infusion was 0.191; discomfort/pain was the most commonly reported local AR. Rates of ARs per infusion decreased over time: 0.28 (months 1-12), 0.15 (months 13-24), and 0.08 (months 25-33.6). The percentage of patients experiencing ≥ 1 local AR per infusion was highest during the dose ramp-up period (33.3-41.7 % [Q3W] and 29.2-37.5 % [QW4]), and rapidly declined over time. Conclusions: In adults treated with fSCIG for up to ~3.5 years, rates of local ARs per infusion and the percentage of patients experiencing ≥ 1 local AR markedly declined over time. [ABSTRACT FROM AUTHOR]

The association between ADHD and allergy remains controversial. Our previous findings suggest that nerve growth factor may link the nervous and immune systems. The primary objective of this study was to determine if a combination of cetirizine + methylphenidate is effective in children with comorbid ADHD and allergic rhinitis. We also examined the role of nerve growth factor in these comorbidities. Our randomized, double-blind, placebo-controlled, crossover study enrolled 38 children diagnosed with comorbid ADHD and allergy using cetirizine (n = 12), sustained-release methylphenidate (n = 12), or cetirizine + methylphenidate (n = 14). Endpoints compared baseline to posttreatment evaluations for allergic rhinitis and ADHD scores. Serum nerve growth factor levels were measured using ELISA. For allergy endpoints, combination therapy produced results superior to individual therapy. For ADHD, similar scores were achieved for individual therapy; however, combination therapy resulted in improved scores. Nerve growth factor levels were downregulated following this trend. We conclude that ADHD and allergic rhinitis may have common mechanism and represent a comorbid condition that links the nervous system to the immune system. Further studies are needed. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Gaucher''s disease (GD) is an inborn error, autosomal recessive lysosomal lipid storage disorder characterized by the lack of the enzyme glucocerebrosidase. We observed some abnormalities in the plasma of a traumatized patient with GD. Case Report: We report of a traumatized patient with GD that developed a severe systemic immune response during the course of an extended hospital stay. Plasma paraoxonase (PON) activity was assayed and found to be extremely low possibly due to the existence of GD in this particular patient. Also, a potentially novel post-translational modification (PTM) of albumin was noticed in the patient''s plasma that coincided with enzyme replacement therapy (ERT) with Cerezyme®. Conclusions: The decreased plasma PON activity measured might be a contributive factor in the development of an accentuated systemic immune response in a traumatized patient with GD. A modified albumin species could serve as a biomarker for ERT in Gaucher patients. [Copyright &y& Elsevier]

This retrospective study examined whether changes in patient pre- and post-treatment symptoms correlated with changes in anti-neuronal autoantibody titers and the neuronal cell stimulation assay in the Cunningham Panel in patients with Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection (PANDAS), and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). In an analysis of all tests consecutively performed in Moleculera Labs' clinical laboratory from April 22, 2013 to December 31, 2016, we identified 206 patients who were prescribed at least one panel prior to and following treatment, and who met the PANDAS/PANS diagnostic criteria. Patient follow-up was performed to collect symptoms and treatment or medical intervention. Of the 206 patients, 58 met the inclusion criteria of providing informed consent/assent and documented pre- and post-treatment symptoms. Clinician and parent-reported symptoms after treatment or medical intervention were categorized as "Improved/Resolved" (n = 34) or "Not-Improved/Worsened" (n = 24). These were analyzed for any association between changes in clinical status and changes in Cunningham panel test results. Clinical assay performance was also evaluated for reproducibility and reliability. Comparison of pre- and post-treatment status revealed that the Cunningham Panel results correlated with changes in patient's neuropsychiatric symptoms. Based upon the change in the number of positive tests, the overall accuracy was 86%, the sensitivity and specificity were 88% and 83% respectively, and the Area Under the Curve (AUC) was 93.4%. When evaluated by changes in autoantibody levels, we observed an overall accuracy of 90%, a sensitivity of 88%, a specificity of 92% and an AUC of 95.7%. Assay reproducibility for the calcium/calmodulin-dependent protein kinase II (CaMKII) revealed a correlation coefficient of 0.90 (p < 1.67 × 10−6) and the ELISA assays demonstrated test-retest reproducibility comparable with other ELISA assays. This study revealed a strong positive association between changes in neuropsychiatric symptoms and changes in the level of anti-neuronal antibodies and antibody-mediated CaMKII human neuronal cell activation. These results suggest there may be clinical utility in monitoring autoantibody levels and stimulatory activity against these five neuronal antigen targets as an aid in the diagnosis and treatment of infection-triggered autoimmune neuropsychiatric disorders. Future prospective studies should examine the feasibility of predicting antimicrobial and immunotherapy responses with the Cunningham Panel. Unlabelled Image • Neuropsychiatric and behavioral disorders encompass a diverse spectrum of symptoms • The Cunningham Panel measures autoantibodies directed against neurologic targets • Changes in levels of these autoantibodies are associated with changes in neuropsychiatric symptoms • Pediatric Acute-onset Neuropsychiatric Disorder is autoimmune-based, triggered by infections • Many other neuropsychiatric disorders may have similar etiology [ABSTRACT FROM AUTHOR]