Manish Butte

Update on Immunodeficiency-Associated Vaccine-Derived Polioviruses – Worldwide, July 2018-December 2019.

MMWR Morb Mortal Wkly Rep. 2020 Jul 17;69(28):913-917

Authors: Macklin G, Diop OM, Humayun A, Shahmahmoodi S, El-Sayed ZA, Triki H, Rey G, Avagyan T, Grabovac V, Jorba J, Farag N, Mach O

Abstract
Since establishment of the Global Polio Eradication Initiative* in 1988, polio cases have declined >99.9% worldwide; extensive use of live, attenuated oral poliovirus vaccine (OPV) in routine childhood immunization programs and mass campaigns has led to eradication of two of the three wild poliovirus (WPV) serotypes (types 2 and 3) (1). Despite its safety record, OPV can lead to rare emergence of vaccine-derived polioviruses (VDPVs) when there is prolonged circulation or replication of the vaccine virus. In areas with inadequate OPV coverage, circulating VDPVs (cVDPVs) that have reverted to neurovirulence can cause outbreaks of paralytic polio (2). Immunodeficiency-associated VDPVs (iVDPVs) are isolated from persons with primary immunodeficiency (PID). Infection with iVDPV can progress to paralysis or death of patients with PID, and excretion risks seeding cVDPV outbreaks; both risks might be reduced through antiviral treatment, which is currently under development. This report updates previous reports and includes details of iVDPV cases detected during July 2018-December 2019 (3). During this time, 16 new iVDPV cases were reported from five countries (Argentina, Egypt, Iran, Philippines, and Tunisia). Alongside acute flaccid paralysis (AFP) surveillance (4), surveillance for poliovirus infections among patients with PID has identified an increased number of persons excreting iVDPVs (5). Expansion of PID surveillance will facilitate early detection and follow-up of iVDPV excretion among patients with PID to mitigate the risk for iVDPV spread. This will be critical to help identify all poliovirus excretors and thus achieve and maintain eradication of all polioviruses.

PMID: 32673297 [PubMed – as supplied by publisher]

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Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations.

J Clin Immunol. 2020 Jul 15;:

Authors: Martín-Nalda A, Fortuny C, Rey L, Bunney TD, Alsina L, Esteve-Solé A, Bull D, Anton MC, Basagaña M, Casals F, Deyá A, García-Prat M, Gimeno R, Juan M, Martinez-Banaclocha H, Martinez-Garcia JJ, Mensa-Vilaró A, Rabionet R, Martin-Begue N, Rudilla F, Yagüe J, Estivill X, García-Patos V, Pujol RM, Soler-Palacín P, Katan M, Pelegrín P, Colobran R, Vicente A, Arostegui JI

Abstract
Autoinflammatory diseases (AIDs) were first described as clinical disorders characterized by recurrent episodes of seemingly unprovoked sterile inflammation. In the past few years, the identification of novel AIDs expanded their phenotypes toward more complex clinical pictures associating vasculopathy, autoimmunity, or immunodeficiency. Herein, we describe two unrelated patients suffering since the neonatal period from a complex disease mainly characterized by severe sterile inflammation, recurrent bacterial infections, and marked humoral immunodeficiency. Whole-exome sequencing detected a novel, de novo heterozygous PLCG2 variant in each patient (p.Ala708Pro and p.Leu845_Leu848del). A clear enhanced PLCγ2 activity for both variants was demonstrated by both ex vivo calcium responses of the patient’s B cells to IgM stimulation and in vitro assessment of PLC activity. These data supported the autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) diagnosis in both patients. Immunological evaluation revealed a severe decrease of immunoglobulins and B cells, especially class-switched memory B cells, with normal T and NK cell counts. Analysis of bone marrow of one patient revealed a reduced immature B cell fraction compared with controls. Additional investigations showed that both PLCG2 variants activate the NLRP3-inflammasome through the alternative pathway instead of the canonical pathway. Collectively, the evidences here shown expand APLAID diversity toward more severe phenotypes than previously reported including dominantly inherited agammaglobulinemia, add novel data about its genetic basis, and implicate the alternative NLRP3-inflammasome activation pathway in the basis of sterile inflammation.

PMID: 32671674 [PubMed – as supplied by publisher]

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Novel pathogenic mutations identified in the first Chinese pedigree of complete C6 deficiency.

Clin Transl Immunology. 2020;9(7):e1148

Authors: Li PH, Wong WW, Leung EN, Lau CS, Au E

Abstract
Objectives: Complete C6 deficiency (C6Q0) is a rare primary immunodeficiency leading to increased susceptibility to recurrent Neisseria infections. Patients with C6Q0 have mostly been reported in individuals of African ancestry previously, but never in Chinese. We identify the first Chinese patients with C6Q0 through family screening of an index case presenting with recurrent Neisseria meningitis with septicaemia and performed extensive clinical, serological and genetic investigations.
Methods: Two variants in C6 were identified by next-generation sequencing and confirmed by Sanger sequencing in an index case of C6Q0. Immunological investigations, complement haemolytic assays (CH50/AH50), C6 gene sequencing and quantification of serum C6 levels were performed for all available members of his nonconsanguineous family.
Results: Three C6Q0 patients were identified with near-absent C6 levels, absent CH50/AH50 activity and compound heterozygous for two nonsense mutations in the C6 gene: NM_000065.4:c.1786C>T (p.Arg596Ter) and NM_000065.4:c.1816C>T (p.Arg606Ter). Neither mutations have been reported to be pathogenic previously. Two other family members who were heterozygous for either p.Arg596Ter or and p.Arg606Ter had intermediate C6 levels but preserved CH50/AH50 activity. These two loss-of-function mutations showed a strong genotype-phenotype correlation in C6 levels.
Conclusions: We report on two compound heterozygous mutations in C6, p.Arg596Ter and p.Arg606Ter inherited in three patients of the first recorded Chinese pedigree of C6Q0. Neither mutations had been reported to be pathogenic previously. We demonstrate that heterozygous family members with subtotal C6 levels had preserved complement haemolytic function and demonstrate a threshold effect of C6 protein level.

PMID: 32670577 [PubMed]

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Autologous Stem Cell Transplantation in Common Variable Immunodeficiency: A Case of Successful Treatment of Severe Refractory Autoimmune Encephalitis.

Front Immunol. 2020;11:1317

Authors: Froehlich M, Schwaneck EC, Gernert M, Gadeholt O, Strunz PP, Morbach H, Tony HP, Schmalzing M

Abstract
Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. It is associated with hypogammaglobulinemia, recurring infections and autoimmune phenomena. Treatment includes immunoglobulin substitution and immunosuppressants. Autoimmune neurological manifestations of CVID are rare and occur predominantly as granulomatous disease. We report the case of a 35-year-old woman with CVID who developed autoimmune encephalitis as demonstrated by double cerebral biopsy. Infectious or malignant causes could be excluded. Despite intensive immunosuppressive therapy with common regimens no significant improvement could be achieved. Ultimately, an autologous hematopoietic stem cell transplantation (HSCT) was performed, resulting in lasting complete remission of the encephalitis. To our knowledge, this is the first report of refractory autoimmune phenomena in CVID treated by autologous HSCT.

PMID: 32670291 [PubMed – in process]

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Lower T Regulatory and Th17 Cell Populations Predicted by RT-PCR-Amplified FOXP3 and RORγt Genes Are Not Rare in Patients With Primary Immunodeficiency Diseases.

Front Immunol. 2020;11:1111

Authors: Lee WI, Huang JL, Lin SJ, Yeh KW, Chen LC, Ou LS, Yao TC, Jaing TH, Shih YF, Wu CY

Abstract
Deficiencies in T regulatory (Treg) and Th17 cells attenuate peripheral tolerance and the IL-17 family of cytokines, contributing to autoimmune disorders and opportunistic (fungal) infections, respectively. Because of limited blood samples from patients with primary immunodeficiency diseases (PIDs), a positive correlation/linear relationship between Treg and Th17 cells and their respective expressions of transcription factors forkhead box P3 (FOXP3) and retinoic acid-related orphan receptor γ (RORγt) by real-time PCR (RT-PCR) amplification, was used to predict the percentages of Treg and Th17 cells in peripheral blood. Compared to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression, the percentages of Treg and Th17 cells were calculated as the linear relationship to the 2-ΔCT value (cycle threshold). Among 91 PIDs patients, 68 and 78 had predicted Treg and Th17 percentages below 5% of the normal ranges (0.859 and 0.734%, respectively), which expanded different categories beyond obvious T cell deficiency. Notably, FOXP3 was undetectable in one patient (CVID), RORγt was undetectable in six patients (one CVID, one CID, two neutropenia, one WAS, and one CMC), and both were undetectable in four patients (two SCID, one STAT1, and one periodic fever). In contrast, two patients with auto-IFNγ antibodies had increased susceptibility to intracellular mycobacterial infections, interrupted Th1 development and subsequent elevation in the Th17 cells. Both predicted Treg and Th17 percentages in the PIDs patients were more independent of age (months) than in the controls. The predicted Th17/Treg ratio in the PIDs patients, overall, was lower than that in the healthy controls (0.79 ± 0.075 vs. 1.16 ± 0.208; p = 0.038). In conclusion, lower predicted Treg and Th17 cell populations calculated by RT-PCR-amplified FOXP3 and RORγt in PIDs patients at diagnosis can explain the higher potential phenotypes of autoimmune disorders and opportunistic infections, although effective interventions in the early stage might have prevented such phenotypic development and caused a statistical bias in the comparisons.

PMID: 32670274 [PubMed – in process]

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Editorial: Follicular Helper T Cells in Immunity and Autoimmunity.

Front Immunol. 2020;11:1042

Authors: Cicalese MP, Salek-Ardakani S, Fousteri G

PMID: 32670272 [PubMed – in process]

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Facilitated Subcutaneous Immunoglobulin Replacement Therapy in Clinical Practice: A Two Center, Long-Term Retrospective Observation in Adults With Primary Immunodeficiencies.

Front Immunol. 2020;11:981

Authors: Wiesik-Szewczyk E, Sołdacki D, Paczek L, Jahnz-Różyk K

Abstract
Facilitated subcutaneous immunoglobulin (fSCIG) replacement therapy is the latest method of IgG administration; however, real-life data are limited. We retrospectively analyzed the everyday experience of fSCIG administration, particularly, the method used to switch from intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) to fSCIG and the dosing modifications required. Of the 39 adult patients with primary immunodeficiency (PID) who received fSCIG, 34 remained on the therapy at the end of the study. The median observation time was 18 (range, 3-24) months. Two patients were IgG-treatment-naïve; 23 had previously received IVIG and 14 had received SCIG. In 25 cases, a non-ramp-up dosing mode was used to switch to fSCIG (including two half-monthly doses given biweekly in 14 cases, and full monthly doses given in 11 cases), a ramp-up mode was used in six cases; other methods were used in eight cases. The median IgG trough level at baseline was 7.9 g/L (n = 38), 7.9 g/L (n = 32) at Month 6, 9.0 g/L (n = 30) at Month 12, 8.6 g/L (n = 22) at Month 18, and 9.0 g/L (n = 11) at Month 24. No serious bacterial infections or hospitalizations due to PID complications occurred. At the end of the study, 24 patients (71%) received fSCIG every 4 weeks, six (18%) received fSCIG every 3 weeks, and four (12%) received fSCIG biweekly. In conclusion, our study provides real-life evidence of clinical efficacy of personalized fSCIG treatment when switching from prior immunoglobulin replacement using various switching modes and dosing frequencies.

PMID: 32670265 [PubMed – in process]

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Medical and surgical treatment outcomes in patients with chronic rhinosinusitis and immunodeficiency: a systematic review.

Int Forum Allergy Rhinol. 2020 Jul 15;:

Authors: Samargandy S, Grose E, Chan Y, Monteiro E, Lee JM, Yip J

Abstract
BACKGROUND: Immunodeficiency is a risk factor for recalcitrant chronic rhinosinusitis (CRS). Currently, there is no consensus on effective treatment modalities for immunodeficient CRS patients. This review aims to evaluate the existing evidence on the treatment outcomes and its limitations in patients with CRS and immunodeficiency.
METHODS: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to April 2019 for studies reporting measurable medical or surgical treatment outcomes for adult patients with CRS and underlying primary or secondary immunodeficiency.
RESULTS: Of the 2459 articles screened, 13 studies met the inclusion criteria: 2 prospective double-blind placebo-controlled trials, 2 prospective case-control studies, 2 prospective cohort studies, and 7 case series. The high degree of study heterogeneity precluded a meta-analysis. Antibiotic monotherapy was not linked with significant improvement in clinical, radiographic, or endoscopic outcomes. Immunoglobulin replacement therapy may potentially reduce the frequency of acute or chronic sinusitis in patients with primary immunodeficiency (PID) but may not improve their sinonasal symptoms. Outcomes from endoscopic sinus surgery (ESS) were reported in 8 studies, which found that surgery was linked with improvement in symptoms, disease-specific quality of life, endoscopy scores, and radiographic scores. The average reported ESS revision rate was 14%.
CONCLUSION: Patients with CRS and immunodeficiency likely benefit from ESS based on the available evidence. Data supporting medical therapy in this targeted population is limited overall, but there may be a potential role for immunoglobulin therapy in patients with PID and CRS.

PMID: 32668102 [PubMed – as supplied by publisher]

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Novel NCF2 Mutation Causing Chronic Granulomatous Disease.

J Clin Immunol. 2020 Jul 14;:

Authors: Roth IL, Salamon P, Freund T, Gadot YB, Baron S, Hershkovitz T, Shefler I, Hanna S, Confino-Cohen R, Bentur L, Hagin D

Abstract
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder caused by defects in the NADPH oxidase complex. Mutations in NCF2 encoding the cytosolic factor p67phox result in autosomal recessive CGD. We describe three patients with a novel c.855G>C NCF2 mutation presenting with diverse clinical phenotype. Two siblings were heterozygous for the novel mutation and for a previously described exon 8-9 duplication, while a third unrelated patient was homozygous for the novel mutation. Mutation pathogenicity was confirmed by abnormal DHR123 assay and absent p67phox production and by sequencing of cDNA which showed abnormal RNA splicing. Clinically, the homozygous patient presented with suspected early onset interstitial lung disease and NCF2 mutation was found on genetic testing performed in search for surfactant-related defects. The two siblings also had variable presentation with one having history of severe pneumonia, lymphadenitis, and recurrent skin abscesses and the other presenting in his 30s with discoid lupus erythematosus and without significant infectious history. We therefore identified a novel pathogenic NCF2 mutation causing diverse and unusual clinical phenotype.

PMID: 32666379 [PubMed – as supplied by publisher]

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