Manish Butte

Immunotherapy. 2022 Jan 6. doi: 10.2217/imt-2021-0313. Online ahead of print.

ABSTRACT

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.

PMID:34986666 | DOI:10.2217/imt-2021-0313

J Clin Immunol. 2022 Jan 4. doi: 10.1007/s10875-021-01182-5. Online ahead of print.

ABSTRACT

CD40 ligand (CD40L) deficiency is a rare inborn error of immunity presenting with heterogeneous clinical manifestations. While a detailed characterization of patients affected by CD40L deficiency is essential to an accurate diagnosis and management, information about this disorder in Latin American patients is limited. We retrospectively analyzed data from 50 patients collected by the Latin American Society for Immunodeficiencies registry or provided by affiliated physicians to characterize the clinical, laboratory, and molecular features of Latin American patients with CD40L deficiency. The median age at disease onset and diagnosis was 7 months and 17 months, respectively, with a median diagnosis delay of 1 year. Forty-seven patients were genetically characterized revealing 6 novel mutations in the CD40LG gene. Pneumonia was the most common first symptom reported (66%). Initial immunoglobulin levels were variable among patients. Pneumonia (86%), upper respiratory tract infections (70%), neutropenia (70%), and gastrointestinal manifestations (60%) were the most prevalent clinical symptoms throughout life. Thirty-five infectious agents were reported, five of which were not previously described in CD40L deficient patients, representing the largest number of pathogens reported to date in a cohort of CD40L deficient patients. The characterization of the largest cohort of Latin American patients with CD40L deficiency adds novel insights to the recognition of this disorder, helping to fulfill unmet needs and gaps in the diagnosis and management of patients with CD40L deficiency.

PMID:34982304 | DOI:10.1007/s10875-021-01182-5

Expert Rev Clin Immunol. 2022 Jan 3:1-15. doi: 10.1080/1744666X.2021.2008241. Online ahead of print.

ABSTRACT

INTRODUCTION: There is a wide spectrum of noninfectious gastrointestinal pathology, causing considerable morbidity and mortality in CVID, where both etiology and effective therapy are under debate.

AREAS COVERED: This review will focus on the noninfectious inflammation in the GI tract in CVID patients, covering the both the upper and lower GI tract inflammation, including the liver. The controversy of the CVID enteropathy definition and that of gluten-free diet for celiac-like disease in CVID will be discussed. Furthermore, the review will cover the link between GI inflammation and GI cancer. Finally, the role of gut microbiota, IgA, and genetics and its relationship with CVID enteropathy is scrutinized. The authors reviewed literature from PubMed.

EXPERT OPINION: The heterogeneity and the unknown mechanism behind CVID enteropathy, and thereby the lack of effective treatment, is one of the key challenges in the field of CVID. Celiac-like disease in CVID is due to immune dysregulation, and a gluten-free diet is therefore not indicated. Gut microbial dysbiosis and mucosal IgA can initiate systemic and local inflammation and is involved in the immune dysregulation in CVID. Considering the heterogeneity of CVID enteropathy, personalized medicine is probably the future for these patients.

PMID:34978241 | DOI:10.1080/1744666X.2021.2008241

Case Rep Ophthalmol Med. 2021 Dec 23;2021:6317358. doi: 10.1155/2021/6317358. eCollection 2021.

ABSTRACT

BACKGROUND: Hyperimmunoglobulin E syndrome (HIES), or Job’s syndrome, is a primary immunodeficiency disorder that is characterized by an elevated level of IgE with values reaching over 2000 IU (normal < 200 IU), eczema, and recurrent staphylococcus infection. Affected individuals are predisposed to infection, autoimmunity, and inflammation. Herein, we report a case of HIES with clinical findings of retinal occlusive vasculitis. Case Presentation. A 10-year-old boy with a known case of hyperimmunoglobulin E syndrome had exhibited loss of vision and bilateral dilated fixed pupil. Fundoscopic examination revealed peripheral retinal hemorrhaging, vascular sheathing around the retinal arteries and veins, and vascular occlusion in both eyes. A fluorescein angiography of the right eye showed hyper- and hypofluorescence in the macula and hypofluorescence in the periphery of the retina, peripheral arterial narrowing, and arterial occlusion. A fluorescein angiography of the left eye showed hyper- and hypofluorescence in the supranasal area of the optic disc. Macular optical coherence tomography of the right eye showed inner and outer retinal layer distortion. A genetic study was performed that confirmed mutations of the dedicator of cytokinesis 8 (DOCK 8). HSV polymerase chain reaction testing on aqueous humor and vitreous was negative, and finally, the patient was diagnosed with retinal occlusive vasculitis.

CONCLUSION: Occlusive retinal vasculitis should be considered as a differential diagnosis in patients with hyperimmunoglobulin E syndrome presenting with visual loss.

PMID:34976422 | PMC:PMC8718279 | DOI:10.1155/2021/6317358

Front Immunol. 2021 Dec 17;12:786516. doi: 10.3389/fimmu.2021.786516. eCollection 2021.

ABSTRACT

Predominantly antibody deficiencies (PAD) are a heterogeneous group of disorders characterized by dysfunctional antibody production, low immunoglobulin levels in serum and impaired vaccine responses. The clinical picture is variable, ranging from mild symptoms to severe complications, which may include autoimmunity, gastrointestinal disease, allergy, and malignancies. If left untreated, PAD patients are at risk of enduring disease progression, irreversible organ damage, and reduced life expectancy. A timely diagnosis has been shown to significantly improve disease prognosis. Here, we report on our experience using targeted gene panel sequencing by employing Agilent’s HaloPlex or SureSelect and Illumina’s MiSeq technologies in a cohort of 291 individuals who presented with low or absent immunoglobulin levels in combination with or without other clinical features. In total, we have detected over 57 novel or previously reported relevant mutations in ADA, ADA2, BTK, CTLA4, LRBA, NFKB1, NFKB2, PIK3CD, STAT3, and TNFRSF13B. Overall, a genetic diagnosis could be made in 24.7% of the investigated patients. The percentage of coverage for the targeted regions ranged from 90% to 98% in this study. Moreover, functional assays were performed on a defined group of the patients carrying candidate variants in CTLA4, LRBA, NFKB1 and BTK, which confirmed their deleterious effect on protein expression and/or function. This study reiterates that the immunological heterogeneity of predominantly antibody deficiencies may have a diverse genetic origin, although certain clinical features may hint towards a specific group of defects. Employing targeted sequencing panels proves to be a very time- and cost-efficient, yet reliable, method for the establishment of a genetic diagnosis in individuals with PAD. However, in case of negative panel results, or if functional testing reveals inconspicuous observations in patients with a clear indication for genetic testing, further work-up including whole exome or whole genome sequencing should be considered.

PMID:34975878 | PMC:PMC8718408 | DOI:10.3389/fimmu.2021.786516

J Clin Immunol. 2022 Jan 1. doi: 10.1007/s10875-021-01181-6. Online ahead of print.

ABSTRACT

PURPOSE: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI).

METHODS: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject’s previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured.

RESULTS: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate.

CONCLUSIONS: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI.

PMID:34973143 | DOI:10.1007/s10875-021-01181-6

J Clin Immunol. 2022 Jan 1. doi: 10.1007/s10875-021-01183-4. Online ahead of print.

ABSTRACT

PURPOSE: Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown.

METHODS: We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN’s Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype.

RESULTS: More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12-7.10, p = 0.023, urine: OR: 8.23, 95% CI: 1.06-64.11, p = 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin [Formula: see text] ng/mL, OR: 2.16, 95% CI: 1.28-3.66, p = 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 – 2.60, p = 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12-2.76, p = 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10-2.68, p = 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21-14.5, p = 0.019).

CONCLUSION: Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.

PMID:34973142 | DOI:10.1007/s10875-021-01183-4

Clin Infect Dis. 2021 Dec 31:ciab1059. doi: 10.1093/cid/ciab1059. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent COVID-19 infection, having no viable treatment options.

METHODS: A retrospective analysis of patients with primary and/or secondary immunodeficiency-associated antibody disorders who received casirivimab and imdevimab (REGEN-COV ®) under emergency compassionate use.

OBJECTIVES: describe safety and response to REGEN-COV, focusing on the subset of patients who had COVID-19 duration ≥21 days before treatment.

RESULTS: Quantitative (change in oxygenation status and/or viral load) and/or qualitative (physician-reported clinical status) patient outcomes data are reported from 64 patients who received REGEN-COV. Improvement in ≥1 outcome was observed in 90.6% of the overall patient group. Thirty-seven of these had COVID-19 duration ≥21 days before treatment; median time from diagnosis to REGEN-COV was 60.5 days. Of the 29 patients with COVID-19 duration ≥21 days before treatment and available outcome data, 96.6% showed improvement in ≥1 outcome. In the 14 patients with post-treatment RT-PCR results available, 11 (78.6%) reported a negative RT-PCR following treatment, with 5 (45.5%) reporting a negative RT-PCR within 5 days and 8 (72.7%) within 21 days of treatment. Ten of 85 patients (11.8%) experienced serious adverse events, only one was an infusion-related reaction, possibly related to REGEN-COV. Two deaths were reported, neither were attributed to REGEN-COV.

CONCLUSIONS: In this retrospective analysis of immunodeficient patients granted REGEN-COV under the compassionate use program, REGEN-COV treatment was associated with rapid viral clearance and clinical improvement in patients with long-standing COVID-19. Adverse events were consistent with COVID-19 and its associated complications, and due to patients’ concurrent medical conditions.

PMID:34971385 | DOI:10.1093/cid/ciab1059

Ann Clin Microbiol Antimicrob. 2021 Dec 30;20(1):85. doi: 10.1186/s12941-021-00491-2.

ABSTRACT

BACKGROUND: There is growing evidence that antibody responses play a role in the resolution of SARS-CoV-2 infection. Patients with primary or secondary antibody deficiency are at increased risk of persistent infection. This challenging clinical scenario is associated with adverse patient outcome and potentially creates an ecological niche for the evolution of novel SARS-CoV-2 variants with immune evasion capacity. Case reports and/or series have implied a therapeutic role for convalescent plasma (CP) to secure virological clearance, although concerns have been raised about the effectiveness of CP and its potential to drive viral evolution, and it has largely been withdrawn from clinical use in the UK.

CASE PRESENTATION: We report two cases in which persistent SARS-CoV-2 infection was cleared following administration of the monoclonal antibody combination casirivimab and imdevimab (REGN-COV2, Ronapreve). A 55-year-old male with follicular lymphoma, treated with B cell depleting therapy, developed SARS-CoV-2 infection in September 2020 which then persisted for over 200 days. He was hospitalised on four occasions with COVID-19 and suffered debilitating fatigue and malaise throughout. There was no clinical response to antiviral therapy with remdesivir or CP, and SARS-CoV-2 was consistently detected in nasopharyngeal swabs. Intrahost evolution of several spike variants of uncertain significance was identified by viral sequence analysis. Delivery of REGN-COV2, in combination with remdesivir, was associated with clinical improvement and viral clearance within 6 days, which was sustained for over 150 days despite immunotherapy for relapsed follicular lymphoma. The second case, a 68-year-old female with chronic lymphocytic leukaemia on ibrutinib, also developed persistent SARS-CoV-2 infection. Despite a lack of response to remdesivir, infection promptly cleared following REGN-COV2 in combination with remdesivir, accompanied by resolution of inflammation and full clinical recovery that has been maintained for over 290 days.

CONCLUSIONS: These cases highlight the potential benefit of REGN-COV2 as therapy for persistent SARS-CoV-2 infection in antibody deficient individuals, including after failure of CP treatment. Formal clinical studies are warranted to assess the effectiveness of REGN-COV2 in antibody-deficient patients, especially in light of the emergence of variants of concern, such as Omicron, that appear to evade REGN-COV2 neutralisation.

PMID:34969393 | DOI:10.1186/s12941-021-00491-2

Front Immunol. 2021 Dec 13;12:803459. doi: 10.3389/fimmu.2021.803459. eCollection 2021.

ABSTRACT

Primary immunodeficiency (PID) is primarily characterized by susceptibility to infectious diseases. In addition, patients with some type of PID are prone to develop autoimmune, autoinflammatory, or malignant diseases. Therefore, the term, inborn errors of immunity (IEI), has been more used rather than PID. In recent years, the number of diseases which belong to PID has been increasing. There were approximately 110 diseases in the report of International Union of Immunological Societies in 1999. Since then, the number increased to 430 diseases in the latest IUIS report in 2019. We conducted PID nationwide survey in Japan for 3 times in the last 15 years. These studies were focused on incidence and complications of PID, the clinical course of viral infection, and methods to prevent infectious diseases in PID patients. For the awareness of PID, it is essential to know the general and fundamental information of PID patients. Needless to say, we need it to offer appropriate medical services for PID patients. Moreover, chances to provide answers to the questionnaires and seeing the results of the analysis should contribute to the awareness of PID among doctors. In this review, I am going to summarize the results of 3 nationwide survey in Japan, and pick up interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency as an example for creating awareness for its appropriate management.

PMID:34966393 | PMC:PMC8710485 | DOI:10.3389/fimmu.2021.803459