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The immunologic features of patients with early-onset and polyautoimmunity.

December 16, 2019 By Manish Butte

The immunologic features of patients with early-onset and polyautoimmunity.

Clin Immunol. 2019 Dec 12;:108326

Authors: Hoyt KJ, Chatila TA, Notarangelo LD, Hazen MM, Janssen E, Henderson LA

Abstract
Inflammatory conditions are increasingly described in patients with primary immunodeficiencies; however, little is known about the prevalence of immune defects in patients who present first with autoimmunity. We describe the immunologic features of children with early-onset/polyautoimmunity followed in the Multiple Autoimmunity and Immunodeficiency (MAID) Clinic, where patients are co-managed by rheumatologists and immunologists. The most common autoimmune manifestations were cytopenias, lymphoproliferation, and colitis. Recurrent infections were noted in 65% of patients. Abnormalities in lymphocyte subsets and immunoglobulins were common. A pathogenic variant was identified in 19% of patients, and 2 novel inherited disorders were discovered. Additionally, 42% of patients had treatment changes implemented in the MAID clinic. By evaluating this unique cohort of patients, we report on the immunologic underpinning of early-onset/polyautoimmunity. The high rate of genetic diagnoses and treatment interventions in this population highlights the value of collaboration between rheumatologists and immunologists in the care of these complex patients.

PMID: 31838215 [PubMed – as supplied by publisher]

In case of recurrent wheezing and bronchiolitis: Think again, it may be a primary immunodeficiency.

December 15, 2019 By Manish Butte

In case of recurrent wheezing and bronchiolitis: Think again, it may be a primary immunodeficiency.

Asian Pac J Allergy Immunol. 2019 Dec 14;:

Authors: Ozbek B, Ayvaz DÇ, Esenboga S, Halaçlι SO, Aytekin ES, Yaz I, Tan Ç, Tezcan I

Abstract
BACKGROUND: Wheezing, starting early in life, is a heterogeneous medical condition caused by airway obstruction due to different underlying mechanisms. Primary immunodeficiencies are also among the risk factors that cause wheezing and recurrent bronchiolitis. ADA deficiency is a primary immunodeficiency, also a rare metabolic disease associated with multisystemic clinical findings.
OBJECTIVE: This report will be helpful for adressing the importance of thinking primary immunodeficiency in case of wheezing and recurret bronchiolitis.
METHODS: The patient was diagnosed by using a targeted next generation sequencing PID panel. Lymphocyte subsets were measured by flow-cytometry.
RESULTS: Here we present an infant with ADA deficiency who admitted with wheezing and recurrent bronchiolitis as the first presentation. He was found to have wheezing, relative CD4+ T cell deficiency, and prolonged neutropenia.
CONCLUSION: Primary immunodeficiencies including ADA deficiency should be considered in infants with wheezing, recurrent bronchiolitis, lymphopenia and neutropenia.

PMID: 31837214 [PubMed – as supplied by publisher]

Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2.

December 15, 2019 By Manish Butte

Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2.

Sci Immunol. 2019 Dec 13;4(42):

Authors: Duncan CJA, Thompson BJ, Chen R, Rice GI, Gothe F, Young DF, Lovell SC, Shuttleworth VG, Brocklebank V, Corner B, Skelton AJ, Bondet V, Coxhead J, Duffy D, Fourrage C, Livingston JH, Pavaine J, Cheesman E, Bitetti S, Grainger A, Acres M, Innes BA, Mikulasova A, Sun R, Hussain R, Wright R, Wynn R, Zarhrate M, Zeef LAH, Wood K, Hughes SM, Harris CL, Engelhardt KR, Crow YJ, Randall RE, Kavanagh D, Hambleton S, Briggs TA

Abstract
Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

PMID: 31836668 [PubMed – in process]

Bronchiectasis in common variable immunodeficiency: A systematic review and meta-analysis.

December 14, 2019 By Manish Butte

Bronchiectasis in common variable immunodeficiency: A systematic review and meta-analysis.

Pediatr Pulmonol. 2019 Dec 13;:

Authors: Ramzi N, Jamee M, Bakhtiyari M, Rafiemanesh H, Zainaldain H, Tavakol M, Rezaei A, Kalvandi M, Zian Z, Mohammadi H, Jadidi-Niaragh F, Yazdani R, Abolhassani H, Aghamohammadi A, Azizi G

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency disorder characterized by infectious and noninfectious complications. Bronchiectasis continues to be a common respiratory problem and therapeutic challenge in CVID. The aim of this study is to estimate the overall prevalence of bronchiectasis and its associated phenotype in patients with CVID.
METHODS: A systematic literature search was performed in Web of Science, PubMed, and Scopus from the earliest available date to February 2019 with standard keywords. All pooled analyses of bronchiectasis prevalence and the corresponding 95% confidence intervals (CIs) were based on random-effects models.
RESULTS: Fifty-five studies comprising 8535 patients with CVID were included in the meta-analysis. Overall prevalence of bronchiectasis was 34% (95% CI: 30-38; I2 = 90.19%). CVID patients with bronchiectasis had significantly lower serum immunoglobulin A (IgA) and IgM levels at the time of diagnosis compared with those without bronchiectasis. Among the clinical features, the frequencies of splenomegaly, pneumonia, otitis media, and lymphocytic interstitial pneumonia were significantly higher in CVID patients with bronchiectasis compared with those without bronchiectasis, respectively.
CONCLUSION: A higher prevalence of bronchiectasis in patients with CVID should be managed by controlling recurrent and severe pneumonia episodes which are immune dysregulation since this complication is associated with poor prognosis in these patients.

PMID: 31833673 [PubMed – as supplied by publisher]

A novel mutation in NCF2 resulting in very-early-onset colitis and juvenile idiopathic arthritis in a patient with chronic granulomatous disease.

December 14, 2019 By Manish Butte

A novel mutation in NCF2 resulting in very-early-onset colitis and juvenile idiopathic arthritis in a patient with chronic granulomatous disease.

Allergy Asthma Clin Immunol. 2019;15:68

Authors: AlKhater S

Abstract
Background: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder caused by a defect in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The disease primarily presents with recurrent infections, and patients may also present with inflammatory conditions, including noninfectious colitis, and an increased frequency of autoimmunity. We report here a patient with CGD in whom the presentation, unlike the classical presentation of CGD, was predominantly of an inflammatory and autoimmune phenotype.
Case presentation: A 3-year-old Pakistani female presented with bloody diarrhea since the age of 7 days, followed by the development of perianal abscesses and fistula. There was no other history of recurrent infections. The patient subsequently developed joint pain and stiffness with persistently elevated inflammatory markers and elevated anti-cyclic citrullinate peptide (anti-CCP) antibody titer. She was diagnosed with oligoarticular juvenile idiopathic arthritis and colitis. The diagnosis of CGD was later made and was based on the absence of NADPH oxidase activity in the patient’s neutrophils upon phorbol myristate acetate (PMA) stimulation using the dihydrorhodamine-1,2,3 (DHR) flow cytometry test. Targeted next-generation sequencing revealed an unreported deletion mutation in exon 10 as a homozygous loss-of-function variant of the human neutrophil oxidase factor 2 (NCF2) (NCF2: NM_001190789, nucleotide change: c.855_856del:p.T285fs). The gene encodes a protein subunit, p67phox, in the NADPH enzyme complex.
Conclusions: The case emphasizes the importance of maintaining high clinical suspicion of immunodeficiency and CGD in patients with very-early-onset colitis and autoimmune disorders. This case is important due to its rarity and because it might represent a previously undiscovered mutation, which is possibly more common in the patient’s ethnic group. Other mutations in NCF2 have been linked to inflammatory bowel disease and autoimmunity, but without CGD, suggesting similarities in the pathogenesis.

PMID: 31832070 [PubMed]

Immune Cellular Evaluation Following Newborn Screening For Severe T and B Cell Lymphopenia.

December 14, 2019 By Manish Butte

Immune Cellular Evaluation Following Newborn Screening For Severe T and B Cell Lymphopenia.

EJIFCC. 2019 Nov;30(4):396-406

Authors: Wolf J, Dahlenburg K, Borte S

Abstract
Newborn screening (NBS) for severe T and/or B cell lymphopenia to identify neonates with severe combined immunodeficiencies (SCID) or agammaglobulinemia rapidly after birth has paved its way into clinical practice. Debate exists on the concept and strategy for rapid verification and stratification of the cellular immune status of positively screened infants. We provide impulses for harmonization of flow cytometric approaches to allow rapid integration in the growing number of immunological laboratories involved in follow-up and subdivision of SCID and non-SCID entities.

PMID: 31832054 [PubMed]

Delayed diagnosis of X-linked agammaglobulinaemia in a boy with recurrent meningitis.

December 14, 2019 By Manish Butte

Delayed diagnosis of X-linked agammaglobulinaemia in a boy with recurrent meningitis.

BMC Neurol. 2019 Dec 12;19(1):320

Authors: Zhang YN, Gao YY, Yang SD, Cao BB, Zheng KL, Wei P, Chen LF, Chen WX

Abstract
BACKGROUND: X-linked agammaglobulinaemia (XLA) is a rare inherited primary immunodeficiency disease characterized by the B cell developmental defect, caused by mutations in the gene coding for Bruton’s tyrosine kinase (BTK), which may cause serious recurrent infections. The diagnosis of XLA is sometimes challenging because a few number of patients have higher levels of serum immunoglobulins than expected. In this study, we reported an atypical case with recurrent meningitis, delayed diagnosis with XLA by genetic analysis at the second episode of meningitis at the age of 8 years.
CASE REPORT: An 8-year-old Chinese boy presented with fever, dizziness and recurrent vomiting for 3 days. The cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) results were suggestive of bacterial meningoencephalitis, despite the negative gram staining and cultures of the CSF. The patient was treated with broad-spectrum antibiotics and responded well to the treatment. He had history of another episode of acute pneumococci meningitis 4 years before. The respective level of Immunoglobulin G (IgG), Immunoglobulin A (IgA) and Immunoglobulin M (IgM) was 4.85 g/L, 0.93 g/L and 0.1 g/L at 1st episode, whereas 1.9 g/L, 0.27 g/L and 0 g/L at second episode. The B lymphocytes were 0.21 and 0.06% of peripheral blood lymphocytes at first and second episode respectively. Sequencing of the BTK coding regions showed that the patient had a point mutation in the intron 14, hemizyous c.1349 + 5G > A, while his mother had a heterozygous mutation. It was a splice site mutation predicted to lead to exon skipping and cause a truncated BTK protein.
CONCLUSION: Immunity function should be routinely checked in patients with severe intracranial bacterial infection. Absence of B cells even with normal level of serum immunoglobulin suggests the possibility of XLA, although this happens only in rare instances. Mutational analysis of BTK gene is crucial for accurate diagnosis to atypical patients with XLA.

PMID: 31830942 [PubMed – in process]

Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway.

December 13, 2019 By Manish Butte

Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway.

J Clin Immunol. 2019 Dec 11;:

Authors: García-Laorden MI, Hernández-Brito E, Muñoz-Almagro C, Pavlovic-Nesic S, Rúa-Figueroa I, Briones ML, Rajas O, Borderías L, Payeras A, Lorente L, Freixinet J, Ferreres J, Obando I, González-Quevedo N, Rodríguez de Castro F, Solé-Violán J, Rodríguez-Gallego C

Abstract
Mannose-binding lectin (MBL)-associated serine protease-2 (MASP-2) is an indispensable enzyme for the activation of the lectin pathway of complement. Its deficiency is classified as a primary immunodeficiency associated to pyogenic bacterial infections, inflammatory lung disease, and autoimmunity. In Europeans, MASP-2 deficiency, due to homozygosity for c.359A > G (p.D120G), occurs in 7 to 14/10,000 individuals. We analyzed the presence of the p.D120G mutation in adults (increasing the sample size of our previous studies) and children. Different groups of patients (1495 adults hospitalized with community-acquired pneumonia, 186 adults with systemic lupus erythematosus, 103 pediatric patients with invasive pneumococcal disease) and control individuals (1119 healthy adult volunteers, 520 adult patients without history of relevant infectious diseases, and a pediatric control group of 311 individuals) were studied. Besides our previously reported MASP-2-deficient healthy adults, we found a new p.D120G homozygous individual from the pediatric control group. We also reviewed p.D120G homozygous individuals reported so far: a total of eleven patients with a highly heterogeneous range of disorders and nine healthy controls (including our four MASP-2-deficient individuals) have been identified by chance in association studies. Individuals with complete deficiencies of several pattern recognition molecules of the lectin pathway (MBL, collectin-10 and collectin-11, and ficolin-3) as well as of MASP-1 and MASP-3 have also been reviewed. Cumulative evidence suggests that MASP-2, and even other components of the LP, are largely redundant in human defenses and that individuals with MASP-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases.

PMID: 31828694 [PubMed – as supplied by publisher]

The critical role of histology in distinguishing sarcoidosis from common variable immunodeficiency disorder (CVID) in a patient with hypogammaglobulinemia.

December 13, 2019 By Manish Butte

The critical role of histology in distinguishing sarcoidosis from common variable immunodeficiency disorder (CVID) in a patient with hypogammaglobulinemia.

Allergy Asthma Clin Immunol. 2019;15:78

Authors: Ameratunga R, Ahn Y, Tse D, Woon ST, Pereira J, McCarthy S, Blacklock H

Abstract
Background: Common variable immunodeficiency disorders (CVID) are a rare group of primary immune defects, where the underlying cause is unknown. Approximately 10-20% of patients with typical CVID have a granulomatous variant, which has closely overlapping features with sarcoidosis.
Case presentation: Here we describe a young man who sequentially developed refractory Evans syndrome, cauda equina syndrome and most recently renal impairment. Following immunosuppression, he has made a recovery from all three life-threatening autoimmune disorders. As the patient was hypogammaglobulinemic for most of the time while on immunosuppression, vaccine challenges and other tests were not possible. Histological features were in keeping with sarcoidosis rather than the granulomatous variant of CVID. In the brief period when immunosuppression was lifted between the cauda equina syndrome and renal impairment, he normalised his immunoglobulins, confirming sarcoidosis rather than CVID was the underlying cause.
Conclusion: We discuss diagnostic difficulties distinguishing the two conditions, and the value of histological features in our diagnostic criteria for CVID in identifying sarcoidosis, while the patient was hypogammaglobulinemic. The key message from this case report is that the characteristic histological features of CVID can be very helpful in making (or excluding) the diagnosis, particularly when other tests are not possible.

PMID: 31827542 [PubMed]

Successful Use of Cidofovir in an Immunocompetent Child With Severe Adenoviral Sepsis.

December 13, 2019 By Manish Butte

Successful Use of Cidofovir in an Immunocompetent Child With Severe Adenoviral Sepsis.

Pediatrics. 2019 Dec 11;:

Authors: Alcamo AM, Wolf MS, Alessi LJ, Chong HJ, Green M, Williams JV, Simon DW

Abstract
Adenovirus infection is common in childhood and is generally associated with self-limited disease. Cidofovir, a viral DNA polymerase inhibitor, is used to treat adenovirus infection in select populations but is not often recommended for immunocompetent patients because of limited antiviral activity and nephrotoxicity. Here, we report a case of fulminant adenovirus infection associated with lymphopenia and multiple organ failure requiring extracorporeal membrane oxygenation support in a previously healthy child. After 1 week of supportive therapy, the patient had persistent organ failure and continued to have adenoviremia of >560 000 copies per mL. Weekly doses of cidofovir with concurrent probenecid for renal protection was initiated. Adenovirus blood load declined after the first cidofovir dose, becoming undetectable after 3 doses. The patient was successfully decannulated from extracorporeal membrane oxygenation, extubated, and eventually discharged at his functional baseline without need for ongoing respiratory support. Lymphopenia improved after viremia resolved, and a subsequent immunologic workup revealed no evidence of primary immunodeficiency. The viral isolate was genotyped as adenovirus type 7. This case reveals the successful use of cidofovir for management of severe adenovirus infection in a previously healthy child. To date, there are no universally accepted recommendations for the use of cidofovir in this population. Further study is warranted to determine the potential role of cidofovir in treating severe adenovirus infections in immunocompetent children.

PMID: 31826930 [PubMed – as supplied by publisher]