Manish Butte

Otitis Media and Inborn Errors of Immunity.

Curr Allergy Asthma Rep. 2020 Jul 11;20(10):59

Authors: Bardou MLD, Pontarolli D, Grumach AS

Abstract
PURPOSE OF REVIEW: The aim of this review is as follows: (1) to present the role of otitis as a warning sign for inborn errors of immunity (IEI), (2) to establish which patients presenting otitis should be investigated for IEI, (3) to review data about main IEI associated with otitis-prone patients.
RECENT FINDINGS: Otitis media is a very common infection in general population. The concept of otitis-prone children established a certain frequency of the infections in order to look for conditions leading to them. The confirmation of middle ear impairment by specialists has demonstrated better confiability. The hallmarks for immunologic evaluation are the presence of complications as mastoiditis and membrane perforation, failure to thrive, and additional respiratory symptoms. Humoral immunodeficiencies have been more frequently described in association with otitis-prone patients, for example, hypogammaglobulinemia, MBL deficiency, and IEI associated with major syndromes. Most of the patients with confirmed IEI present otitis as one of the recurrent infections. It is suggested the investigation of immune defects in patients with otitis, and the following warning signs are suggested: Otitis evolving with mastoiditis, abscesses, or systemic infections; no response to appropriate antibiotic therapy; otitis media associated with other infections; recurrent otitis leading to failure to thrive and general developmental delay; and family history of primary immunodeficiency and/or consanguinity.

PMID: 32654069 [PubMed – as supplied by publisher]

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Outcomes after Haploidentical Stem Cell Transplantation with Post-Transplantation Cyclophosphamide in Patients with Primary Immunodeficiency Diseases.

Biol Blood Marrow Transplant. 2020 Jul 09;:

Authors: Fernandes JF, Nichele S, Arcuri LJ, Ribeiro L, Netto GZ, Loth G, Rodrigues ALM, Kuwahara C, Koliski A, Trennepohl J, Garcia JL, Daudt LE, Seber A, Gomes AA, Fasth A, Pasquini R, Hamerschlak N, Rocha V, Bonfim C

Abstract
Allogeneic hematopoietic stem cell transplantation(HCT) can cure primary immunodeficiency diseases(PID). When a HLA-matched donor is not available haploidentical family donor may be considered. The use of T-cell replete haploidentical HCT with post-transplant cyclophosphamide(Haplo-PTCy) in children with PID has been described in few case-series. Donor is readily available and Haplo-PTCy can be used in urgent cases. We studied outcomes of 73 patients with PID who underwent Haplo- PTCy: 55 patients as a first and 18 as salvage transplant after graft failure of previous HCT. Median age was 1.6 years. Most children were male(n=54); had active infection at the time of transplant(n=50) and 10 had severe organ damage. Diagnosis was SCID in 34 patients and non-SCID in 39(Wiskott-Aldrich Syndrome;n=14, chronic granulomatous disease;n=10 and other PID;n=15). Median follow-up of survivors was 2 years. Cumulative incidence(CI) of neutrophil recovery was 88% in the SCID group and 84% in non-SCID group and it was 81% for first transplants and 83% after a salvage graft. At 100-days, CI of acute GVHD(II-IV) and(III-IV) were 33% and 14%, respectively. The majority of patients reached 200/ μL CD4+ and 1000/ μL CD3+ cell counts between 3-6 months. Estimated 2-year overall survival was 66%; It was 64% for SCID and 65% for non-SCID patients and it was 63% for first and 77% for salvage transplants. Twenty-five patients died, most of them due to infection early after transplant(before 100 days). In conclusion, Haplo-PTCy is a feasible procedure, can cure 2/3 of PID children and can be used as rescue for previous graft failure.

PMID: 32653621 [PubMed – as supplied by publisher]

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Update on DNA-Double Strand Break Repair Defects in Combined Primary Immunodeficiency.

Curr Allergy Asthma Rep. 2020 Jul 09;20(10):57

Authors: Slatter MA, Gennery AR

Abstract
PURPOSE OF REVIEW: The most serious DNA damage, DNA double strand breaks (DNA-dsb), leads to mutagenesis, carcinogenesis or apoptosis if left unrepaired. Non-homologous end joining (NHEJ) is the principle repair pathway employed by mammalian cells to repair DNA-dsb. Several proteins are involved in this pathway, defects in which can lead to human disease. This review updates on the most recent information available for the specific diseases associated with the pathway.
RECENT FINDINGS: A new member of the NHEJ pathway, PAXX, has been identified, although no human disease has been associated with it. The clinical phenotypes of Artemis, DNA ligase 4, Cernunnos-XLF and DNA-PKcs deficiency have been extended. The role of haematopoietic stem cell transplantation, following reduced intensity conditioning chemotherapy, for many of these diseases is being advanced. In the era of newborn screening, urgent genetic diagnosis is necessary to correctly target appropriate treatment for patients with DNA-dsb repair disorders.

PMID: 32648006 [PubMed – in process]

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Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation.

Ann Rheum Dis. 2020 Jul 09;:

Authors: Matsuda T, Kambe N, Ueki Y, Kanazawa N, Izawa K, Honda Y, Kawakami A, Takei S, Tonomura K, Inoue M, Kobayashi H, Okafuji I, Sakurai Y, Kato N, Maruyama Y, Inoue Y, Otsubo Y, Makino T, Okada S, Kobayashi I, Yashiro M, Ito S, Fujii H, Kondo Y, Okamoto N, Ito S, Iwata N, Kaneko U, Doi M, Hosokawa J, Ohara O, Saito MK, Nishikomori R, PIDJ members in the JSIAD, PIDJ (Primary Immunodeficiency and Autoinflammatory Diseases Database Project) members in the JSIAD (Japanese Society for Immunodeficiency and Autoinflammatory Diseases)

Abstract
OBJECTIVES: To collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis.
METHODS: Fifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians.
RESULTS: The study population comprised 26 males and 24 females aged 0-61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment.
CONCLUSIONS: In patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.

PMID: 32647028 [PubMed – as supplied by publisher]

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Nivolumab for Treatment of Progressive Multifocal Leukoencephalopathy in Sézary Syndrome.

Eur J Neurol. 2020 Jul 09;:

Authors: Grassl N, Bunse L, Beutel T, Klockziem M, Gass A, Platten M, Eisele P

Abstract
Progressive multifocal leukoencephalopathy (PML) is a rare but severe opportunistic CNS infection caused by JC polyomavirus in immunosuppressed patients. Immune checkpoint blockade stimulates immune function and has been suggested to reinvigorate viral clearance in PML patients by expanding JCV-specific T cells1 . Among the first 13 published PML patients treated with programmed cell death 1 inhibitors (PD1I) 8 showed a mild to marked treatment response2-7 . The underlying conditions ranged from chronic lymphocytic leukemia, AIDS, Non-Hodgkin lymphoma, idiopathic lymphopenia, variable immune deficiency, Hodgkin lymphoma, B-cell lymphoma to primary and combined immunodeficiency. Here, we present a patient with Sézary syndrome (SS) who developed PML and did not benefit from treatment with nivolumab.

PMID: 32644207 [PubMed – as supplied by publisher]

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[Chronic Granulomatous Disease: A Rare Differential Diagnosis in Recurrent Pulmonary Infections in Adults].

Pneumologie. 2020 Jul 08;:

Authors: Kleymann J, Schütz C, Körholz J, Taube F, Vogler M, Halank M, Kolditz M, Langner S, Geberzahn L, Holotiuk O, Roesler J, Koschel D

Abstract
Chronic granulomatous disease (CGD) should be considered as a differential diagnosis in children and adolescents with frequent infections, especially when caused by certain specific pathogens.This case report describes a 64-year-old female with multiple recurrent and complicated bronchopulmonary infections, caused by common, but also rare pathogens, autoimmune phenomena, malignancies and recurrent organizing pneumonia (OP) with granulomas. Finally, the patient was diagnosed with p47phox-deficient chronic granulomatous disease (CGD).Individuals with a primary immunodeficiency may survive multiple complications and may be diagnosed at an advanced age especially if the affected structure shows residual activity. When confronted with patients with recurrent bronchopulmonary infections, especially with certain specific rare pathogens, in combination with organizing pulmonary granulomas as well as autoimmune phenomena, CGD should be considered even in elderly patients. Delayed diagnosis significantly increases mortality and morbidity in such cases.

PMID: 32643764 [PubMed – as supplied by publisher]

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Progress in treating chronic granulomatous disease.

Br J Haematol. 2020 Jul 08;:

Authors: Gennery AR

Abstract
Chronic granulomatous disease is a primary immunodeficiency due to a defect in one of six subunits that make up the nicotinamide adenine dinucleotide phosphate oxidase complex. The most commonly defective protein, gp91phox , is inherited in an X-linked fashion; other defects have autosomal recessive inheritance. Bacterial and fungal infections are common presentations, although inflammatory complications are increasingly recognized as a significant cause of morbidity and are challenging to treat. Haematopoietic stem cell transplantation offers cure from the disease with improved quality of life; overall survival in the current era is around 85%, with most achieving long-term cure free of medication. More recently, gene therapy is emerging as an alternative approach. Results using gammaretroviral vectors were disappointing with genotoxicity and loss of efficacy, but preliminary results using lentiviral vectors are extremely encouraging.

PMID: 32643199 [PubMed – as supplied by publisher]

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Primary immunodeficiencies in cytosolic pattern-recognition receptor pathways: Toward host-directed treatment strategies.

Immunol Rev. 2020 Jul 08;:

Authors: van der Made CI, Hoischen A, Netea MG, van de Veerdonk FL

Abstract
In the last decade, the paradigm of primary immunodeficiencies (PIDs) as rare recessive familial diseases that lead to broad, severe, and early-onset immunological defects has shifted toward collectively more common, but sporadic autosomal dominantly inherited isolated defects in the immune response. Patients with PIDs constitute a formidable area of research to study the genetics and the molecular mechanisms of complex immunological pathways. A significant subset of PIDs affect the innate immune response, which is a crucial initial host defense mechanism equipped with pattern-recognition receptors. These receptors recognize pathogen- and damage-associated molecular patterns in both the extracellular and intracellular space. In this review, we will focus on primary immunodeficiencies caused by genetic defects in cytosolic pattern-recognition receptor pathways. We discuss these PIDs organized according to their mutational mechanisms and consequences for the innate host response. The advanced understanding of these pathways obtained by the study of PIDs creates the opportunity for the development of new host-directed treatment strategies.

PMID: 32640080 [PubMed – as supplied by publisher]

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Primary Pneumococcal Peritonitis can be the first presentation of a familial complement factor I deficiency.

Clin Exp Immunol. 2020 Jul 08;:

Authors: Ugrinovic S, Firth H, Kavanagh D, Gouliouris T, Gurugama P, Baxendale H, Lachmann PJ, Kumararatne D, Gkrania-Klotsas E

Abstract
Primary pneumococcal peritonitis is a rare infection that has been described in women but has not been previously linked with immunodeficiency. The complement system plays a central role in immune defense against Streptococcus pneumoniae and, in order to evade complement attack, pneumococci have evolved a large number of mechanisms that limit complement mediated opsonization and subsequent phagocytosis.We investigated an apparently immunocompetent woman with primary pneumococcal peritonitis and identified a family with deficiency for complement factor I. Primary pneumococcal peritonitis should be considered a possible primary immunodeficiency presentation.

PMID: 32640035 [PubMed – as supplied by publisher]

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