Manish Butte

Primary Immunodeficiency and Rhinosinusitis.

Immunol Allergy Clin North Am. 2020 May;40(2):233-249

Authors: Huwyler C, Lin SY, Liang J

Abstract
Refractory rhinosinusitis can be related to comorbid medical conditions, including primary immunodeficiency. Given the prevalence of immunodeficiency, clinicians should have a low threshold to consider these diagnoses. This article reviews primary immunodeficiencies contributing to chronic rhinosinusitis, including a proposed diagnostic work-up and the evidence for treatment in this unique population.

PMID: 32278448 [PubMed – as supplied by publisher]

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Peripheral Blood Lymphocyte Phenotype Differentiates Secondary Antibody Deficiency in Rheumatic Disease from Primary Antibody Deficiency.

J Clin Med. 2020 Apr 07;9(4):

Authors: Jablonka A, Etemadi H, Adriawan IR, Ernst D, Jacobs R, Buyny S, Witte T, Schmidt RE, Atschekzei F, Sogkas G

Abstract
The phenotype of primary immunodeficiency disorders (PID), and especially common variable immunodeficiency (CVID), may be dominated by symptoms of autoimmune disorders. Furthermore, autoimmunity may be the first manifestation of PID, frequently preceding infections and the diagnosis of hypogammaglobulinemia, which occurs later on. In this case, distinguishing PID from hypogammaglobulinemia secondary to anti-inflammatory treatment of autoimmunity may become challenging. The aim of this study was to evaluate the diagnostic accuracy of peripheral blood lymphocyte phenotyping in resolving the diagnostic dilemma between primary and secondary hypogammaglobulinemia. Comparison of B and T cell subsets from patients with PID and patients with rheumatic disease, who developed hypogammaglobulinemia as a consequence of anti-inflammatory regimes, revealed significant differences in proportion of naïve B cells, class-switched memory B cells and CD21low B cells among B cells as well as in CD4+ memory T cells and CD4+ T follicular cells among CD4+ T cells. Identified differences in B cell and T cell subsets, and especially in the proportion of class-switched memory B cells and CD4+ T follicular cells, display a considerable diagnostic efficacy in distinguishing PID from secondary hypogammaglobulinemia due to anti-inflammatory regimens for rheumatic disease.

PMID: 32272789 [PubMed]

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Pediatric hereditary angioedema: what the otolaryngologist should know.

Curr Opin Otolaryngol Head Neck Surg. 2019 Dec;27(6):499-503

Authors: Bailey CE, Carr MM

Abstract
PURPOSE OF REVIEW: To review pediatric hereditary angioedema for otolaryngologists, with emphasis on articles within the past 12-18 months.
RECENT FINDINGS: Biologic therapies are accepted for adult hereditary angioedema (HAE), but have been studied less for pediatric HAE. Recent literature supports expanded use of biologic agents in pediatrics as acute treatment and prophylaxis. Available agents include plasma-derived C1 esterase inhibitors (C1-INH) (Berinert, Haegarda, Cinryze), recombinant C1-INH (Ruconest), bradykinin B2 receptor inhibitor (Icatibant), and kallikrein inhibitors (Ecallantide and lanadelumab). Of these, only Berinert is Food and Drug Administration (FDA) approved for acute therapy for children under 12 years of age. Ruconest is approved for treatment of acute attacks over age 13. Ecallantide also has FDA approval as acute treatment for age 12 and older, while lanadelumab and Haegarda are prophylactic agents for adolescents. Icatibant lacks FDA approval in patients under 18 years of age. Cinryze has FDA approval only for prophylaxis for children as young as 6 years old.
SUMMARY: Pediatric HAE is a potentially life-threatening disease. Targeted biologic agents have gained acceptance in treatment of acute attacks, and their use as prophylactic agents is changing the focus of management from acute intervention to preventive management. While intubation or surgical airway management may still be necessary, early intervention or prophylaxis can decrease morbidity and improve quality of life.

PMID: 31592791 [PubMed – indexed for MEDLINE]

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Excellent Outcomes Following Hematopoietic Cell Transplantation for Wiskott-Aldrich Syndrome: A PIDTC Report.

Blood. 2020 Apr 08;:

Authors: Burroughs L, Petrovic A, Brazauskas R, Liu X, Griffith LM, Ochs HD, Bleesing J, Edwards S, Dvorak CC, Chaudhury S, Prockop S, Quinones R, Goldman F, Quigg T, Chandrakasan S, Smith AR, Parikh SH, Dávila Saldaña BJ, Thakar MS, Phelan R, Shenoy S, Forbes LR, Martinez CA, Chellapandian D, Shereck E, Miller H, Kapoor N, Barnum JL, Chong H, Shyr D, Chen K, Abu-Arja RF, Shah A, Weinacht K, Moore TB, Joshi A, DeSantes K, Gillio AP, Cuvelier GDE, Keller MD, Rozmus J, Torgerson TR, Pulsipher MA, Haddad E, Sullivan K, Logan BR, Kohn DB, Puck JM, Notarangelo LD, Pai SY, Rawlings D, Cowan MJ

Abstract
Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. Here we report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers between 2005 and 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs. ≥5 years old at the time of HCT (94% vs. 66%, overall p=0.0008). OS was excellent regardless of donor type even in cord blood recipients (90%). Conditioning intensity did not impact OS, but was associated with donor T-cell and myeloid engraftment post-HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early post-HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) versus low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005 compared to prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution following either myeloablative or busulfan-containing reduced intensity conditioning. (www.clinicaltrials.gov NCT02064933.).

PMID: 32268350 [PubMed – as supplied by publisher]

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Primary immunodeficiency testing in a Massachusetts tertiary care NICU: persistent challenges in the extremely premature population.

Pediatr Res. 2020 Apr 08;:

Authors: Frazer LC, O’Connell AE

Abstract
BACKGROUND: Prematurity presents a diagnostic challenge in interpreting primary immunodeficiency (PID) testing.
METHODS: We retrospectively reviewed the charts of all infants in our level IV referral neonatal intensive care unit (NICU) in Massachusetts, with immunologic testing performed done from 2006 to 2018.
RESULTS: The overall rate of PID testing was enriched in our population, with 1% of admitted patients having extended immunologic testing. The addition of TREC (T cell receptor excision circle) newborn screening in Massachusetts in 2009 increased the proportion of infants tested for PID in our NICU by 3-fold (1.21% post-newborn screening (NBS) vs. 0.46% pre-NBS). A majority of the term and late preterm (≥34 weeks) infants (31 of 41, 76%), as well as very premature (29-33 weeks) infants (12 of 17, 71%), who had immune testing, had a genetic diagnosis associated with secondary immunodeficiency or a PID. Most infants who were born extremely premature (EP, <29 weeks) (25 of 29, 86%) had no identifiable cause of immunodeficiency besides prematurity, despite a mean postmenstrual age of 40.1 weeks at the time of testing.
CONCLUSIONS: Persistent immune derangements were present within a subgroup of the EP population through term postmenstrual age. EP infants with significant infectious history and abnormal immune testing at term-corrected age should be considered for genetic testing.
IMPACT: The role of immunologic testing in the premature population is unclear, we therefore reviewed the records of all infants in our NICU who had immunologic testing, to rule out immunodeficiency, done from 2006 to 2018.The addition of newborn screening for SCID in 2009 doubled the number of infants who had immune investigations.The extremely premature cohort included many infants with persistent immune derangements through term-corrected gestational age, suggesting a persistent effect of prematurity on immune development and potential function.We propose that former premature infants with clinical evidence of immunodeficiency and sustained immune abnormalities by term-corrected age undergo genetic testing for immunodeficiency.

PMID: 32268342 [PubMed – as supplied by publisher]

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Perianal Disease and Granulomas: Think Out of the Box….

GE Port J Gastroenterol. 2020 Feb;27(2):119-123

Authors: Reis-Melo A, Espinheira MDC, Pinto-Pais I, Bonito Vitor A, Bustamante J, Trindade E

Abstract
Background: Chronic granulomatous disease (CGD) is a primary immunodeficiency due to a malfunction of NADPH oxidase. It is characterized by recurrent and severe infections caused by catalase-positive microorganisms and autoinflammatory manifestations. Recently, there has been described an NCF4 gene variant that causes a deficiency of p40^phox, a subunit of NADPH oxidase. Patients with this deficiency appear to have a less severe clinical form as compared to classic CGD.
Case: A 15-year-old girl with vulvar lichen planus since she was 2 years old and suspected Crohn’s disease (CD) was first seen at our hospital. At the age of 12 years, she had been submitted to sacrococcygeal cyst exeresis, without cicatrization of the surgical wound and extension of the lesion to the perianal area. The diagnosis of CD was questioned, and the patient underwent an endoscopic and radiologic assessment, which was normal. A skin biopsy from the perianal area revealed a granuloma; thus, CD with isolated perianal disease was assumed. After several different treatments including antibiotics, infliximab, and adalimumab, the perianal lesion persisted, with no associated gastrointestinal symptoms. Therefore, the hypothesis of an immunodeficiency was considered. An immunologic and genetic study revealed reduced oxidative burst in the phorbol myristate acetate test, with diminished reactive oxygen species production and a homozygous mutation in the NCF4 gene. The adolescent started prophylactic trimethoprim-sulfamethoxazole and became asymptomatic.
Conclusions: The present case highlights that alternative diagnoses to CD must be considered in the presence of isolated perianal disease with granulomatous inflammation, especially when the disease is refractory to conventional CD therapy.

PMID: 32266309 [PubMed]

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Activated phosphoinositide 3-kinase delta syndrome 1 and 2 (APDS 1 and APDS 2): similarities and differences based on clinical presentation in two boys.

Allergy Asthma Clin Immunol. 2020;16:22

Authors: Ewertowska M, Grześk E, Urbańczyk A, Dąbrowska A, Bąbol-Pokora K, Łęcka M, Kołtan S

Abstract
Background: Activated PI3K delta syndrome (APDS) belongs to the heterogeneous group of primary immunodeficiency disorders (PIDs). Progress in next-generation sequencing (NGS) enabled identification of gain-of-function mutations in phosphoinositide 3-kinase (PI3K) genes. Depending on the type of causative mutation, APDS is classified into two types: APDS 1 and APDS 2. To date, less than 100 cases of APDS have been reported. Clinical symptoms of APDS result from impaired immune regulation and are clinically manifested by recurrent infections, allergies, lymphoproliferation and autoimmunity. They show similarity to other PIDs. Therefore, many patients were diagnosed incorrectly. The availability of genetic testing has allowed establishing the correct diagnosis in increasing number of patients suffering from APDS.
Case presentations: The first male patient presented in infancy with recurrent infections. Subsequently he was found to suffer from hepatosplenomegaly, early portal hypertension, massive lymphoproliferation and hypogammaglobulinemia. The common E1021K mutation in the PI3KCD gene was identified. The patient underwent successful hematopoietic stem cell transplantation with resolution of most symptoms. The second patient suffered from persistent growth retardation since early life, facial dysmorphism and recurrent respiratory infections from early childhood. He was found to have systemic lympho-proliferation, panhypoglobulinemia and impaired antibody responses to vaccines. The introduction of NGS in Poland enabled rapid identification of a mutation in the PI3KR1 gene. Growth hormone administration seemed to have worsened the lymphoproliferation.
Conclusions: Patients with suspected common variable immunodeficiency (CVID) and additional symptoms, such as allergy, facial dysmorphia, short stature, enhanced lymphoproliferation and lack of adequate response to human immunoglobulin replacement therapy, should be considered for NGS-based genetic testing. It may substantially shorten the time needed to establish the correct diagnosis, direct appropriate treatment and avoid potentially harmful therapies. To date, few cases of APDS have been described. It is important to report each of them to establish clinical indices and laboratory biomarkers of APDS 1 and APDS 2, to develop the standards of care in these conditions.

PMID: 32265996 [PubMed]

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Editorial: Application of Cytometry in Primary Immunodeficiencies.

Front Immunol. 2020;11:463

Authors: Kalina T, Abraham RS, Rizzi M, van der Burg M

PMID: 32265921 [PubMed – in process]

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EuroFlow Standardized Approach to Diagnostic Immunopheneotyping of Severe PID in Newborns and Young Children.

Front Immunol. 2020;11:371

Authors: Kalina T, Bakardjieva M, Blom M, Perez-Andres M, Barendregt B, Kanderová V, Bonroy C, Philippé J, Blanco E, Pico-Knijnenburg I, Paping JHMP, Wolska-Kuśnierz B, Pac M, Tkazcyk J, Haerynck F, Akar HH, Formánková R, Freiberger T, Svatoň M, Šedivá A, Arriba-Méndez S, Orfao A, van Dongen JJM, van der Burg M

Abstract
The EuroFlow PID consortium developed a set of flow cytometry tests for evaluation of patients with suspicion of primary immunodeficiency (PID). In this technical report we evaluate the performance of the SCID-RTE tube that explores the presence of recent thymic emigrants (RTE) together with T-cell activation status and maturation stages and discuss its applicability in the context of the broader EuroFlow PID flow cytometry testing algorithm for diagnostic orientation of PID of the lymphoid system. We have analyzed peripheral blood cells of 26 patients diagnosed between birth and 2 years of age with a genetically defined primary immunodeficiency disorder: 15 severe combined immunodeficiency (SCID) patients had disease-causing mutations in RAG1 or RAG2 (n = 4, two of them presented with Omenn syndrome), IL2RG (n = 4, one of them with confirmed maternal engraftment), NHEJ1 (n = 1), CD3E (n = 1), ADA (n = 1), JAK3 (n = 3, two of them with maternal engraftment) and DCLRE1C (n = 1) and 11 other PID patients had diverse molecular defects [ZAP70 (n = 1), WAS (n = 2), PNP (n = 1), FOXP3 (n = 1), del22q11.2 (DiGeorge n = 4), CDC42 (n = 1) and FAS (n = 1)]. In addition, 44 healthy controls in the same age group were analyzed using the SCID-RTE tube in four EuroFlow laboratories using a standardized 8-color approach. RTE were defined as CD62L+CD45RO-HLA-DR-CD31+ and the activation status was assessed by the expression of HLA-DR+. Naïve CD8+ T-lymphocytes and naïve CD4+ T-lymphocytes were defined as CD62L+CD45RO-HLA-DR-. With the SCID-RTE tube, we identified patients with PID by low levels or absence of RTE in comparison to controls as well as low levels of naïve CD4+ and naïve CD8+ lymphocytes. These parameters yielded 100% sensitivity for SCID. All SCID patients had absence of RTE, including the patients with confirmed maternal engraftment or oligoclonally expanded T-cells characteristic for Omenn syndrome. Another dominant finding was the increased numbers of activated CD4+HLA-DR+ and CD8+HLA-DR+ lymphocytes. Therefore, the EuroFlow SCID-RTE tube together with the previously published PIDOT tube form a sensitive and complete cytometric diagnostic test suitable for patients suspected of severe PID (SCID or CID) as well as for children identified via newborn screening programs for SCID with low or absent T-cell receptor excision circles (TRECs).

PMID: 32265901 [PubMed – in process]

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Visualizing Association of the Retroviral Gag Protein with Unspliced Viral RNA in the Nucleus.

mBio. 2020 Apr 07;11(2):

Authors: Maldonado RJK, Rice B, Chen EC, Tuffy KM, Chiari EF, Fahrbach KM, Hope TJ, Parent LJ

Abstract
Packaging of genomic RNA (gRNA) by retroviruses is essential for infectivity, yet the subcellular site of the initial interaction between the Gag polyprotein and gRNA remains poorly defined. Because retroviral particles are released from the plasma membrane, it was previously thought that Gag proteins initially bound to gRNA in the cytoplasm or at the plasma membrane. However, the Gag protein of the avian retrovirus Rous sarcoma virus (RSV) undergoes active nuclear trafficking, which is required for efficient gRNA encapsidation (L. Z. Scheifele, R. A. Garbitt, J. D. Rhoads, and L. J. Parent, Proc Natl Acad Sci U S A 99:3944-3949, 2002, https://doi.org/10.1073/pnas.062652199; R. Garbitt-Hirst, S. P. Kenney, and L. J. Parent, J Virol 83:6790-6797, 2009, https://doi.org/10.1128/JVI.00101-09). These results raise the intriguing possibility that the primary contact between Gag and gRNA might occur in the nucleus. To examine this possibility, we created a RSV proviral construct that includes 24 tandem repeats of MS2 RNA stem-loops, making it possible to track RSV viral RNA (vRNA) in live cells in which a fluorophore-conjugated MS2 coat protein is coexpressed. Using confocal microscopy, we observed that both wild-type Gag and a nuclear export mutant (Gag.L219A) colocalized with vRNA in the nucleus. In live-cell time-lapse images, the wild-type Gag protein trafficked together with vRNA as a single ribonucleoprotein (RNP) complex in the nucleoplasm near the nuclear periphery, appearing to traverse the nuclear envelope into the cytoplasm. Furthermore, biophysical imaging methods suggest that Gag and the unspliced vRNA physically interact in the nucleus. Taken together, these data suggest that RSV Gag binds unspliced vRNA to export it from the nucleus, possibly for packaging into virions as the viral genome.IMPORTANCE Retroviruses cause severe diseases in animals and humans, including cancer and acquired immunodeficiency syndromes. To propagate infection, retroviruses assemble new virus particles that contain viral proteins and unspliced vRNA to use as gRNA. Despite the critical requirement for gRNA packaging, the molecular mechanisms governing the identification and selection of gRNA by the Gag protein remain poorly understood. In this report, we demonstrate that the Rous sarcoma virus (RSV) Gag protein colocalizes with unspliced vRNA in the nucleus in the interchromatin space. Using live-cell confocal imaging, RSV Gag and unspliced vRNA were observed to move together from inside the nucleus across the nuclear envelope, suggesting that the Gag-gRNA complex initially forms in the nucleus and undergoes nuclear export into the cytoplasm as a viral ribonucleoprotein (vRNP) complex.

PMID: 32265329 [PubMed – in process]

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