Overview of subcutaneous immunoglobulin 16.5% in primary and secondary immunodeficiency diseases

Most primary immunodeficiency diseases, and select secondary immunodeficiency diseases, are treated with immunoglobulin (IG) therapy, administered intravenously or subcutaneously (SCIG). The first instance of IG replacement for primary immunodeficiency disease was a 16.5% formulation administered subcutaneously in 1952. While most SCIG products are now a 10 or 20% concentration, this review will focus on SCIG 16.5% products with a historical overview of development, including the early pioneers who initiated and refined IG replacement therapy, as well as key characteristics, manufacturing and clinical studies. In determining an appropriate IG regimen, one must consider specific patient needs, characteristics and preferences. There are advantages to SCIG, such as stable serum immunoglobulin G levels, high tolerability and the flexibility of self-administered home treatment.

Infection rates and tolerability of three different immunoglobulin administration modalities in patients with primary immunodeficiency diseases

Aim: This post hoc analysis evaluated the efficacy and overall tolerability of immunoglobulin (Ig) treatment modalities (intravenous Ig [iv.Ig], subcutaneous Ig [sc.Ig] and facilitated sc.Ig [fsc.Ig]). Materials & methods: A total of 30 participants with primary immunodeficiency diseases aged ≥2 years sequentially received iv.Ig, sc.Ig and fsc.Ig during consecutive clinical studies. Results: For iv.Ig, sc.Ig and fsc.Ig, rates of validated acute serious bacterial infections/participant-year (0, 0.09 and 0.04, respectively) and all infections/participant year (4.17, 3.68 and 2.42, respectively) were similarly low; rates of systemic and local causally related adverse events/participant-year were 5.60, 1.93 and 0.88, respectively and 0.13, 0.92 and 1.57, respectively. Conclusion: fsc.Ig provided similar efficacy to iv.Ig and sc.Ig. Clinical Trial registration: NCT00546871 , NCT00814320 , NCT01175213 (ClinicalTrials.gov)

Reversion Mosaicism in Primary Immunodeficiency Diseases

Reversion mosaicism has been reported in an increasing number of genetic disorders including primary immunodeficiency diseases. Several mechanisms can mediate somatic reversion of inherited mutations. Back mutations restore wild-type sequences, whereas second-site mutations result in compensatory changes. In addition, intragenic recombination, chromosomal deletions, and copy-neutral loss of heterozygosity have been demonstrated in mosaic individuals. Revertant cells that have regained wild-type function may be associated with milder disease phenotypes in some immunodeficient patients with reversion mosaicism. Revertant cells can also be responsible for immune dysregulation. Studies identifying a large variety of genetic changes in the same individual further support a frequent occurrence of reversion mosaicism in primary immunodeficiency diseases. This phenomenon also provides unique opportunities to evaluate the biological effects of restored gene expression in different cell lineages. In this paper, we review the recent findings of reversion mosaicism in primary immunodeficiency diseases and discuss its clinical implications.

Professor Asghar Aghamohammadi (1951-2020)

Professor Asghar Aghamohammadi, the founder of the Immunology and Genetics Journal, passed away on November 14th, 2020, at the age of 69. We were terribly shocked by his death due to the Coronavirus Disease 2019 (COVID-19), while he had been working continuously and actively until late October, before his admission to the hospital because of an infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Professor Aghamohammadi was born in 1951 in Khouzestan Province, Iran. After completing his primary education in Ahvaz, he studied medicine in Mashad University of Medical Sciences and Jundishapur University of Medical Sciences. After graduating in 1978, he joined the Red Crescent Organization in Iran. Afterwards, he continued his education in pediatrics in 1984, followed by a fellowship in clinical immunology and allergy in 1988. Consequently, he became the faculty member in the Department of Pediatrics, Children’s Medical Center, Tehran University of Medical Sciences, where he dedicated all his life researching on the Primary Immunodeficiency Diseases (PIDs), by making the infrastructure for increasing the general awareness about PIDs, conducting fundamental research on PIDs, and facilitating the diagnosis and treatment of patients with PIDs. Professor Aghamohammadi established the “Iranian Association for PID Patients Support”, the “Iranian Primary Immunodeficiency Diseases Registry (IPIDR)”, “Research Center for Immunodeficiencies”, “Iranian PID Network”, and the “Immunology and Genetics Journal”. His international collaborations and hard works, along with his honesty, are some of his landmarks, which made him one of the world’s scientists top 1%. This is what the young generation should learn from him. The international PIDs communities, including the European Society for Immunodeficiencies (ESID), the Clinical Immunology Society (CIS), the International Patient Organization for Primary Immunodeficiencies (IPOPI), the Jeffrey Modell Foundation (JMF), and the J Project respect him a lot and cannot forget his amazing efforts in the field of PIDs for all these years. We all at the Research Center for Immunodeficiencies (RCID) and the Immunology and Genetics Journal (IGJ), are still in shock and cannot imagine continuing without him. We will not forget that the father of the PIDs in Iran was a remarkable scientist. He will remain in the minds and hearts of all those who were close to him. May his name be always remembered with respect and love.

Diagnostic Vaccination in Clinical Practice

Testing the antibody response to vaccination (diagnostic vaccination) is crucial in the clinical evaluation of primary immunodeficiency diseases. Guidelines from the American Academy of Allergy, Asthma & Immunology (AAAAI) provide detailed recommendations for diagnostic vaccination with pure pneumococcal polysaccharide vaccines (PPV). However, the degree of compliance with these guidelines and the utility of the guidelines in actual practice are undescribed. To address this, we systematically evaluated diagnostic vaccination in adult patients with suspected primary immunodeficiency diseases in a single tertiary center from 2011 to 2016 (n = 229). We found that full compliance with the AAAAI guidelines was achieved for only 39 patients (17%), suggesting that the guidelines are not easy to follow. Worse, interpretation according to the guidelines was heavily influenced by which serotype-specific antibodies that were used for the evaluation. We found that the arbitrary choices of serotype-specific antibodies could change the fraction of patients deemed to have ‘adequate immunity’ by a factor of four, exposing an inherent flaw in the guidelines. The flaw relates to dichotomous principles for data interpretation under the AAAAI guidelines. We therefore propose a revised protocol for diagnostic vaccination limited to PPV vaccination, subsequent antibody measurements, and data interpretation using Z-scores. The Z-score compiles multiple individual antibody levels, adjusted for different weighting, into one single continuous variable for each patient. In contrast to interpretation according to the AAAAI guidelines, the Z-scores were robust to variations in the choice of serotype-specific antibodies used for interpretation. Moreover, Z-scores revealed reduced immunity after vaccination in the patients with recurrent pneumonia (a typical symptom of antibody deficiency) compared with control patients. Assessment according to the AAAAI guidelines failed to detect this difference. We conclude that our simplified protocol and interpretation with Z-scores provides more robust clinical results and may enhance the value of diagnostic vaccination.