Manish Butte

Immunological Features of Neuroblastoma Amplified Sequence Deficiency: Report of the First Case Identified Through Newborn Screening for Primary Immunodeficiency and Review of the Literature.

Front Immunol. 2019;10:1955

Authors: Ricci S, Lodi L, Serranti D, Moroni M, Belli G, Mancano G, La Barbera A, Forzano G, Mangone G, Indolfi G, Azzari C

Abstract
This is the first case of NBAS disease detected by NBS for primary immunodeficiency. NBS with KRECs is revealing unknown potentialities detecting conditions that benefit from early recognition like NBAS deficiency. Immune phenotyping should be mandatory in patients with NBAS deficiency since they can exhibit severe immunodeficiency with hypogammaglobulinemia as the most frequent finding. Fever during infections is a known trigger of acute liver failure in this syndrome, so immune dysfunction, should never go unnoticed in NBAS deficiency in order to start adequate therapy and prophylaxis.

PMID: 31507590 [PubMed – in process]

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Dilemmas in diagnosis and management of hemophagocytic lymphohistiocytosis in children.

World J Pediatr. 2019 Sep 10;:

Authors: Xu XJ, Tang YM

Abstract
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening entity which is characterized by severe hyperinflammation. Now the HLH-2004 protocol has been widely accepted and clinically used; however, many questions still remain in clinical practice. In this review, we discuss the dilemmas in the diagnosis and treatment of HLH in children.
DATA SOURCES: Original research for articles and literature reviews published in PubMed was carried out using the key term “hemophagocytic lymphohistiocytosis”.
RESULTS: As the gene sequencing technology progresses, the range of causal mutations and primary HLH has been redefined. The monoallelic variants may contribute to the pathogenesis of the disease. Many conditions without defective cytotoxicity of T or NK cells may lead to HLH, such as primary immunodeficiency (PID) and dysregulated immune activation or proliferation (DIAP). HLH shares overlapping clinical and laboratory characteristics with severe sepsis, but usually the single values are more pronounced in HLH than sepsis. H score is another approach to help the diagnosis of secondary HLH. Specific Th1/Th2 cytokine patterns are very helpful tools to differentiate HLH (reactivation of HLH) from sepsis. Moreover, it also has been used successfully to stratify the therapy intensity. The treatment of HLH should consider underlying diseases, triggers and severity. HLH-94 is recommended for patients who need etoposide-based therapy.
CONCLUSIONS: Dramatic progress has been made during the past decades in understanding the pathophysiology of HLH. However, diagnosis and treatment of HLH remain with many dilemmas because of the heterogeneous nature of the disease. Better understanding new gene defects and more effective diagnostic approaches and salvage regimens are goals for the future.

PMID: 31506890 [PubMed – as supplied by publisher]

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A Novel Splice Site Mutation in IFNGR2 in Patients With Primary Immunodeficiency Exhibiting Susceptibility to Mycobacterial Diseases.

Front Immunol. 2019;10:1964

Authors: Bandari AK, Muthusamy B, Bhat S, Govindaraj P, Rajagopalan P, Dalvi A, Shankar S, Raja R, Reddy KS, Madkaikar M, Pandey A

Abstract
Primary immunodeficiency (PID) refers to a group of heterogeneous genetic disorders with a weakened immune system. Mendelian susceptibility to mycobacterial disease (MSMD) is a subset of PID in which patients exhibit defects in intrinsic and innate immunity. It is a rare congenital disorder characterized by severe and recurrent infections caused by weakly virulent mycobacteria or other environmental mycobacteria. Any delay in definitive diagnosis poses a major concern due to the confounding nature of infections and immune deficiencies. Here, we report the clinical, immunological, and genetic characteristics of two siblings (infants) with recurrent infections. There was a history of death of two other siblings in the family after BCG vaccination. Whole exome sequencing of the two affected surviving infants along with their consanguineous parents identified a novel, homozygous single nucleotide splice acceptor site variant in intron 2 of the interferon gamma receptor 2 (IFNGR2) gene. Sanger sequencing of DNA obtained from blood and fibroblasts confirmed the variant. The patients underwent bone marrow transplantation from their father as a donor. RT-PCR and Sanger sequencing of the cDNA of patients from blood samples after transplantation showed the expression of both wild type and mutant transcript expression of IFNGR2. To assess partial or complete expression of IFNGR2 mutant transcripts, fibroblasts were cultured from skin biopsies. RT-PCR and Sanger sequencing of cDNA obtained from patient fibroblasts revealed complete expression of mutant allele and acquisition of a cryptic splice acceptor site in exon 3 that resulted in deletion of 9 nucleotides in exon 3. This led to an in-frame deletion of three amino acids p.(Thr70-Ser72) located in a fibronectin type III (FN3) domain in the extracellular region of IFNGR2. This illustrates individualized medicine enabled by next generation sequencing as identification of this mutation helped in the clinical diagnosis of MSMD in the infants as well as in choosing the most appropriate therapeutic option.

PMID: 31497017 [PubMed – in process]

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Prospective study of a novel, radiation-free, reduced-intensity bone marrow transplantation platform for primary immunodeficiency diseases.

Biol Blood Marrow Transplant. 2019 Sep 04;:

Authors: Dimitrova D, Gea-Banacloche J, Steinberg SM, Sadler JL, Hicks SN, Carroll E, Wilder JS, Parta M, Skeffington L, Hughes TE, Blau JE, Broadney MM, Rose JJ, Hsu AP, Fletcher R, Nunes NS, Yan XY, Telford WG, Kapoor V, Cohen JI, Freeman AF, Garabedian E, Holland SM, Lisco A, Malech HL, Notarangelo LD, Sereti I, Shah NN, Uzel G, Zerbe CS, Fowler DH, Gress RE, Kanakry CG, Kanakry JA

Abstract
Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, utilize alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with median hematopoietic cell transplantation-comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III-IV acute GVHD-free, graft failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells which gradually increased by day +60. The cumulative incidences of grade II-IV and grade III-IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid-responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (n=2) or with unknown underlying genetic defect (n=3). All six patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients.

PMID: 31493539 [PubMed – as supplied by publisher]

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Nonsevere combined immunodeficiency T-cell lymphopenia identified through newborn screening.

Curr Opin Allergy Clin Immunol. 2019 Sep 03;:

Authors: Patrawala M, Kobrynski L

Abstract
PURPOSE OF REVIEW: Although severe combined immunodeficiency (SCID) is the primary target condition for newborn screening (NBS), over 25 secondary targets, conditions other than SCID, have been identified. There is no standard method for evaluating neonates with non-SCID T-cell lymphopenia (TCL) and no standard approaches to treatment. We will describe these conditions and discuss recommendations for evaluating and follow-up of non-SCID TCL detected by NBS.
RECENT FINDINGS: The birth prevalence of non-SCID TCL detected through SCID NBS is higher than SCID and can be a burden on NBS programs. We will present some publications discussing outcomes and comorbidities in these patients.
SUMMARY: NBS for SCID has been very successful in identifying infants with SCID at birth to institute early life saving therapies. TCL due to other conditions can cause significant immune deficiency and treatment is dependent on the cause of the defect, as well as the magnitude of the immunodeficiency. Data collection from NBS programs should include assessment of various therapies and clinical outcomes. Better systems for recording long-term outcomes of SCID NBS including both SCID and non-SCID conditions should become a priority for NBS programs. This will help to advance the goal of NBS programs: improve outcomes in the most cost-effective manner.

PMID: 31490207 [PubMed – as supplied by publisher]

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Nebulised hypertonic saline in moderate-to-severe bronchiolitis: a randomised clinical trial.

Arch Dis Child. 2019 Sep 05;:

Authors: Jaquet-Pilloud R, Verga ME, Russo M, Gehri M, Pauchard JY

Abstract
OBJECTIVES: To investigate whether nebulised hypertonic saline (HS) treatment would decrease length of hospital stay (LOS) among infants with moderate-to severe-bronchiolitis compared with standard supportive care (SC).
METHODS: We conducted an open, multicentre, randomised clinical trial from 1 April 2013 to 31 March 2016, in Swiss children’s hospitals. Patients aged 6 weeks to 24 months with a primary diagnosis of moderate or severe bronchiolitis were included. Children with previous episodes of wheezing, cardiac disease, chronic respiratory disease, immunodeficiency, prematurity (gestational age <34 weeks), corticotherapy in the preceding 2 weeks or inhaled bronchodilators within 24 hours before presentation were excluded. Patients were randomised to receive standard SC with nebulisation of 4 mL of 3% sodium chloride every 6 hours versus SSC. Main outcomes and measures were LOS duration of oxygen therapy, transfer to intensive care unit (ICU), readmission within 7 days following discharge and adverse events.
RESULTS: 121 children were randomised. No statistically significant differences were found between treatment groups at baseline (age, Wang Score, atopic history, smoking exposure). Children in the HS group had a non-significant difference in length of stay -2.8 hours (-10; 16) compared with the SC group. There were no differences in oxygen therapy duration, transfer to ICU, readmission rate or adverse events. The intervention was discontinued at the parents’ request in 16% of the cases.
CONCLUSION: Our study does not support the use of HS nebulisation in children with moderate to severe bronchiolitis.
TRIAL REGISTRATION NUMBER: NCT01812525.

PMID: 31488402 [PubMed – as supplied by publisher]

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Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis.

Proc Natl Acad Sci U S A. 2019 Sep 04;:

Authors: Drutman SB, Haerynck F, Zhong FL, Hum D, Hernandez NJ, Belkaya S, Rapaport F, de Jong SJ, Creytens D, Tavernier SJ, Bonte K, De Schepper S, van der Werff Ten Bosch J, Lorenzo-Diaz L, Wullaert A, Bossuyt X, Orth G, Bonagura VR, Béziat V, Abel L, Jouanguy E, Reversade B, Laurent-Casanova J

Abstract
Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.

PMID: 31484767 [PubMed – as supplied by publisher]

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A Novel BTK Gene Mutation in a Child With Atypical X-Linked Agammaglobulinemia and Recurrent Hemophagocytosis: A Case Report.

Front Immunol. 2019;10:1953

Authors: Han SP, Lin YF, Weng HY, Tsai SF, Fu LS

Abstract
X-linked agammaglobulinemia (XLA), caused by a mutation in the Bruton’s tyrosine kinase (BTK) gene, is rarely reported in patients with recurrent hemophagocytic lymphohistiocytosis (HLH). This mutation leads to significantly reduced numbers of circulatory B cells and serum immunoglobulins in patients. Therefore, they exhibit repetitive bacterial infections since infancy, and immunoglobulin (Ig) replacement therapy is the primary treatment. HLH is a life-threatening condition with manifestations of non-remitting fever, hepatosplenomegaly, cytopenias, coagulopathy, lipid disorder, and multiple organ failure. It is caused by the immune dysregulation between cytotoxic T cells, NK cells, and histiocytes. The treatment is based on HLH-2004 protocol including immunotherapy, chemotherapy, supportive therapy, and stem cell transplantation. However, as we know more about the classification and pathophysiology of HLH, the treatment is modified. T-cell-directed immunotherapy is effective in patients with primary HLH, and strong immunosuppression is contraindicated in patients with severe ongoing infections or some primary immunodeficiency diseases (PIDs). Here, we report the case of a 7-year-old boy who presented with ecthyma gangrenosum and several episodes of pyogenic infections during childhood. At the age of 5 years, he exhibited cyclic HLH every 2-3 months. The remission of HLH episodes finally achieved after he received monthly Ig replacement therapy (400 mg/kg) at the 4th HLH. However, transient elevation of IgM was incidentally discovered after 6 cycles of monthly Ig replacement therapy. IgM-secreting multiple myeloma, Waldenström’s macroglobulinemia, and lymphoma were excluded. The IgM levels then declined and returned to the normal range within a year. The patient and his parents received whole-genome sequencing analysis. It revealed a novel hemizygous c.1632-1G>A mutation in the BTK gene and XLA was diagnosed. XLA exhibits a spectrum of clinical and immunological presentations in patients. The identification of the mutation in the BTK gene contribute to an accurate diagnosis. Ig replacement therapy is the primary treatment for HLH in patients with XLA.

PMID: 31481959 [PubMed – in process]

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