Manish Butte

J Clin Immunol. 2021 Dec 10. doi: 10.1007/s10875-021-01193-2. Online ahead of print.

ABSTRACT

Patients with primary antibody deficiency are at risk for severe and in many cases for prolonged COVID-19. Convalescent plasma treatment of immunocompromised individuals could be an option especially in countries with limited access to monoclonal antibody therapies. While studies in immunocompetent COVID19 patients have demonstrated only a limited benefit, evidence for the safety, timing, and effectiveness of this treatment in antibody-deficient patients is lacking. Here, we describe 16 cases with primary antibody deficiency treated with convalescent plasma in four medical centers. In our cohort, treatment was associated with a reduction in viral load and improvement of clinical symptoms, even when applied over a week after onset of infection. There were no relevant side effects besides a short-term fever reaction in one patient. Longitudinal full-genome sequencing revealed the emergence of mutations in the viral genome, potentially conferring an antibody escape in one patient with persistent viral RNA shedding upon plasma treatment. However, he resolved the infection after a second course of plasma treatment. Thus, our data suggest a therapeutic benefit of convalescent plasma treatment in patients with primary antibody deficiency even months after infection. While it appears to be safe, PCR follow-up for SARS-CoV-2 is advisable and early re-treatment might be considered in patients with persistent viral shedding.

PMID:34893946 | DOI:10.1007/s10875-021-01193-2

J Clin Immunol. 2021 Dec 10. doi: 10.1007/s10875-021-01189-y. Online ahead of print.

ABSTRACT

PURPOSE: GATA2 deficiency is a rare primary immunodeficiency that has become increasingly recognized due to improved molecular diagnostics and clinical awareness. The only cure for GATA2 deficiency is allogeneic hematopoietic stem cell transplantation (allo-HSCT). The inconsistency of genotype-phenotype correlations makes the decision regarding “who and when” to transplant challenging. Despite considerable morbidity and mortality, the reported proportion of patients with GATA2 deficiency that has undergone allo-HSCT is low (~ 35%). The purpose of this study was to explore if detailed clinical, genetic, and bone marrow characteristics could predict end-point outcome, i.e., death and allo-HSCT.

METHODS: All medical genetics departments in Norway were contacted to identify GATA2 deficient individuals. Clinical information, genetic variants, treatment, and outcome were subsequently retrieved from the patients’ medical records.

RESULTS: Between 2013 and 2020, we identified 10 index cases or probands, four additional symptomatic patients, and no asymptomatic patients with germline GATA2 variants. These patients had a diverse clinical phenotype dominated by cytopenia (13/14), myeloid neoplasia (10/14), warts (8/14), and hearing loss (7/14). No valid genotype-phenotype correlations were found in our data set, and the phenotypes varied also within families. We found that 11/14 patients (79%), with known GATA2 deficiency, had already undergone allo-HSCT. In addition, one patient is awaiting allo-HSCT. The indications to perform allo-HSCT were myeloid neoplasia, disseminated viral infection, severe obliterating bronchiolitis, and/or HPV-associated in situ carcinoma. Two patients died, 8 months and 7 years after allo-HSCT, respectively.

CONCLUSION: Our main conclusion is that the majority of patients with symptomatic GATA2 deficiency will need allo-HSCT, and a close surveillance of these patients is important to find the “optimal window” for allo-HSCT. We advocate a more offensive approach to allo-HSCT than previously described.

PMID:34893945 | DOI:10.1007/s10875-021-01189-y

J Allergy Clin Immunol Pract. 2021 Dec 7:S2213-2198(21)01357-X. doi: 10.1016/j.jaip.2021.10.073. Online ahead of print.

ABSTRACT

Recurrent and life-threatening respiratory infections are nearly universal in patients with primary immunodeficiency diseases (PIDD). Early recognition, aggressive treatment, and prophylaxis with antimicrobials and immunoglobulin replacement have been the mainstays of management, and will be reviewed here with an emphasis on respiratory infections. Genetic discoveries have allowed direct translation of research to clinical practice – improving our understanding of clinical patterns of pathogen susceptibilities and guiding prophylaxis. The recent identification of inborn errors in type I interferon signaling as a basis for life threatening viral infections in otherwise healthy individuals suggests another targetable pathway for treatment and/or prophylaxis. The future of PIDD diagnosis will certainly involve early genetic identification by newborn screening before onset of infections, with early treatment offering the potential of preventing disease complications such as chronic lung changes. Gene editing approaches offer tremendous therapeutic potential, with rapidly emerging delivery systems. Anti-viral therapies are desperately needed and specific cellular therapies show promise in patients requiring hematopoietic stem cell transplantation. The introduction of approved therapies for clinical use in PIDD is limited by the difficulty of studying outcomes in rare patients/conditions with conventional clinical trials.

PMID:34890826 | DOI:10.1016/j.jaip.2021.10.073

Pediatrics. 2021 Dec 10:e2021052411. doi: 10.1542/peds.2021-052411. Online ahead of print.

ABSTRACT

Omenn syndrome (OS) is a rare variant of severe combined immunodeficiency characterized by susceptibility to severe opportunistic infections and peculiar manifestations, such as protein-losing erythroderma, alopecia, hepatosplenomegaly, lymphadenopathies, and severe diarrhea. The typical form of the disease is caused by hypomorphic mutation of the recombination-activating genes (RAG1 and RAG2), which are critical in initiating the molecular processes leading to lymphocyte and immunoglobulin receptor formation. Affected patients lack B cells, whereas autoreactive oligoclonal T cells infiltrate the skin, gut, spleen, and liver. In the absence of hematopoietic stem cell transplantation, patients with OS usually succumb early in life because of opportunistic infections. The incidence of OS is estimated to be <1 per 1 000 000; however, the actual frequency is difficult to ascertain. We report 2 siblings affected by OS due to a homozygous frameshift mutation (NM_000448.3:c.519delT, p.E174Sfs*26) in the RAG1 gene presenting with nonimmune hydrops fetalis (NIHF). To the best of our knowledge, this is the first reported association between OS and NIHF. NIHF specifically refers to the presence of ≥2 abnormal fluid collections in the fetus, without red blood cell alloimmunization. A broad spectrum of pathologies is associated with NIHF; however, in ∼20% of the cases, the primary cause remains unclear. Understanding the etiology of NIHF is essential for guiding clinical management, determining prognosis, and informing parents regarding recurrence risk. Our case contributes to expanding the spectrum of OS presentation and highlights the importance of a complete immunologic and genetic workup in otherwise unexplained cases of NIHF.

PMID:34889447 | DOI:10.1542/peds.2021-052411

Sultan Qaboos Univ Med J. 2021 Nov;21(4):652-656. doi: 10.18295/squmj.4.2021.047. Epub 2021 Nov 25.

ABSTRACT

Netherton syndrome (NS) is an autosomal recessive primary immunodeficiency. It is characterised by substantial skin barrier defects and is often misdiagnosed as severe atopic dermatitis or hyper-immunoglobulin E syndrome. Although more than 80 NS-associated pathogenic mutations in the serine peptidase inhibitor kazal type 5 (SPINK5) gene have been reported worldwide, only one has been reported in the Arab population to date. We report the case of a novel association between the c.1887+1G>A mutation in the SPINK5 gene and NS in an Omani-Arab patient born in 2014 who was managed at a paediatric immunology clinic in Muscat, Oman. Accurate genetic diagnosis facilitated tailored clinical management of the index patient and enabled the provision of genetic counselling and offering of future reproductive options to the individuals related to the index patient.

PMID:34888090 | PMC:PMC8631226 | DOI:10.18295/squmj.4.2021.047

Front Immunol. 2021 Nov 23;12:788278. doi: 10.3389/fimmu.2021.788278. eCollection 2021.

ABSTRACT

B-cell lymphoma/leukemia 11B (BCL11B) is a C₂H₂ zinc finger transcription factor that is critically important for regulating the development and function of a variety of systems including the central nervous system, the skin, and the immune system. Germline heterozygous variants are associated with a spectrum of clinical disorders, including severe combined immunodeficiency as well as neurological, craniofacial, and dermal defects. Of these individuals, ~50% present with severe allergic disease. Here, we report the detailed clinical and laboratory workup of one of the most severe BCL11B-dependent atopic cases to date. Leveraging a zebrafish model, we were able to confirm a strong T-cell defect in the patient. Based on these data, we classify germline BCL11B-dependent atopic disease as a novel primary atopic disorder.

PMID:34887873 | PMC:PMC8650153 | DOI:10.3389/fimmu.2021.788278

Endocr Metab Immune Disord Drug Targets. 2021 Dec 9. doi: 10.2174/1871530321666211209162834. Online ahead of print.

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiencies. LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency characterized by a CVID-like phenotype. Affected patients by LRBA and CVID present a wide range of clinical manifestations, including hypogammaglobulinemia, recurrent infections, autoimmunity, as well as T cell abnormality.

METHODS: The study population comprised of patients with CVID (n=10), LRBA deficiency (n=11), and healthy controls (n=12). CD4+ T cell frequency and CD4 MFI (mean fluorescence intensity) were evaluated using flow cytometry before and after stimulation with PMA/ION.

RESULTS: The frequencies of CD4+ T cells were significantly lower in patients with LRBA deficiency than in HCs before and after treatment. In the unstimulated state, the CD4+ T cells frequency in CVID patients was significantly lower than in HCs. There were no statistically significant differences between patients and healthy individuals in CD4+ T cell proliferation. Compared to HCs, LRBA and CVID patients showed a lower CD4 MFI in unstimulated conditions. Furthermore, CD4 MFI decreased in both patients and the control group following activation.

CONCLUSION: Despite the reported decrease in CD4+ T cell frequency in patients with CVID and LRBA deficiency, our findings demonstrated that their CD4+ T cells have a normal proliferative response to stimuli similar to healthy individuals.

PMID:34886783 | DOI:10.2174/1871530321666211209162834

ERJ Open Res. 2021 Dec 6;7(4):00467-2021. doi: 10.1183/23120541.00467-2021. eCollection 2021 Oct.

ABSTRACT

The first ever research prioritisation exercise in GLILD: this survey identified areas of interest in the diagnosis, treatment and management of GLILD, which can be used as a roadmap for future research https://bit.ly/3nVuzti.

PMID:34881327 | PMC:PMC8646000 | DOI:10.1183/23120541.00467-2021

Transplant Cell Ther. 2021 Dec 4:S2666-6367(21)01409-3. doi: 10.1016/j.jtct.2021.11.022. Online ahead of print.

ABSTRACT

We recently demonstrated that TCRαβ+/CD19+ graft depletion successfully prevents severe acute and chronic GVHD in pediatric patients with primary immunodeficiencies (PID) receiving transplants from both matched unrelated and mismatched related donors. However, in all patients, short-term post-HSCT immunosuppressive therapy (IST) was used. There are limited data on TCRαβ+/CD19+ graft depletion with no post-HSCT IST implementation. In the current study were included 74 PID patients who underwent first HSCT from matched unrelated (n=51) or mismatched related donors (n=23) with TCRαβ+/CD19+ graft depletion. All received in conditioning regimen a combination of treosulfan with fludarabine and either melphalan or thiotepa. In all, thymoglobulin 5 mg/kg (days -5, -4, -3) and rituximab at day -1 were used. In 48 patients, various approaches to short-term post-transplant IST were used and 26 patients received no post-HSCT IST. The rates of engraftment, acute and chronic GVHD, survival and mortality were similar in those who received and did not receive IST, with a slightly higher incidence of graft rejection in patients not receiving IST: 19% in the non-IST group against 13% in the IST group (p=0.41). The incidence of CMV reactivation was 50% and 39% (p=0.5) and EBV reactivation 10% and 0 (p=0.2) in the IST and non-IST groups, respectively. No grade 4 adverse events were seen in both groups, although in 19/40 (47.5%) patients receiving calcineurin inhibitors, the therapy was discontinued before day +45. More robust immune recovery with both T- and B- lymphocytes was observed in the non-IST group. To conclude, TCRαβ+/CD19+ in combination with particular serotherapy effectively prevents severe acute and chronic GVHD in PID. Regarding remaining risks of infectious complications and additional drug-related toxicity, there are no benefits to post-HSCT IST use in these patients.

PMID:34875404 | DOI:10.1016/j.jtct.2021.11.022

J Ethnopharmacol. 2021 Dec 4:114893. doi: 10.1016/j.jep.2021.114893. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: A mixture (SH003) of Astragalus membranaceus (Fisch.) Bunge, Angelica gigas Nakai, and Trichosanthes Kirilowii (Maxim.) has beneficial effects against several carcinomas. There have been few reports on an immune-enhancing activity of SH003 and its active constituent nodakenin.

AIM OF THE STUDY: This study aimed at identifying the immune-enhancing effect of SH003 and nodakenin.

MATERIALS AND METHODS: The immune-enhancing effect was evaluated using RAW264.7 macrophages, mouse primary splenocytes, and a cyclophosphamide (CP)-induced immunosuppression murine model.

RESULTS: The results show that SH003 or nodakenin stimulated the production levels of granulocyte colony-stimulating factor, IL-12, IL-2, IL-6, TNF-α, and nitric oxide (NO) and the expression levels of iNOS in RAW264.7 macrophages. SH003 or nodakenin also enhanced NF-κB p65 activation in RAW264.7 macrophages. SH003 or nodakenin stimulated the production levels of IFN-γ, IL-12, IL-2, TNF-α, and NO and the expression levels of iNOS in splenocytes. SH003 or nodakenin increased the splenic lymphocyte proliferation and splenic NK cell activity. In addition, SH003 or nodakenin increased the levels of IFN-γ, IL-12, IL-2, IL-6, and TNF-α in the serum and spleen of CP-treated mice, alleviating CP-induced immunosuppression.

CONCLUSION: Taken together, the results of this study show that SH003 improved immunosuppression through the activation of macrophages, splenocytes, and NK cells. These findings suggest that SH003 could be applied as a potential immunostimulatory agent for a variety of diseases caused or exacerbated by immunodeficiency.

PMID:34875347 | DOI:10.1016/j.jep.2021.114893