Manish Butte

Etanercept for the Treatment of Chronic Arthritis Related to Chronic Granulomatous Disease: A Case.

Pediatr Allergy Immunol Pulmonol. 2019 Sep 01;32(3):131-134

Authors: Balcı S, Kışla Ekinci RM, Serbes M, Doğruel D, Altıntaş DU, Yılmaz M

Abstract
Introduction: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency, in which infections are the main presenting symptoms. Moreover, patients may also experience inflammatory and autoimmune manifestations. With proper management of infections, patients now survive to adulthood, and inflammatory manifestations have become more prominent problems. Treatment of the inflammatory manifestations in CGD is challenging and requires a multidisciplinary approach. Since tumor necrosis factor (TNF)-α has been cited as having a possible role on inflammatory conditions in CGD, etanercept, an anti-TNF agent, may represent a major advance in the management of inflammatory manifestations. Case Presentation: In this report, we described a 15-year-old boy, suffering concurrently both from human leukocyte antigen (HLA)-B27-positive chronic arthritis and CGD, whose arthritis did not respond to treatment with methotrexate and ibuprofen. Remission was achieved 6 months after etanercept initiation and during the next 18 months on medication, we did not encounter any signs of severe infections. Conclusion: Treatment of inflammatory conditions in CGD patients is still challenging in view of the lack of evidence-based therapeutic options. In this study, we report the first pediatric CGD case, in which chronic arthritis was successfully treated with etanercept.

PMID: 32140283 [PubMed]

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Whole exome sequencing (WES) approach for diagnosing primary immunodeficiencies (PIDs) in a highly consanguineous community.

Clin Immunol. 2020 Mar 02;:108376

Authors: Simon AJ, Golan AC, Lev A, Stauber T, Barel O, Somekh I, Klein C, AbuZaitun O, Eyal E, Kol N, Unal E, Amariglio N, Rechavi G, Somech R

Abstract
Primary immunodeficiencies (PIDs) are a heterogeneous group of monogenic inborn errors of immunity. The genetic causes of these diseases can be identified using whole exome sequencing (WES). Here, DNA samples from 106 patients with a clinical suspicion of PID were subjected to WES in order to test the diagnostic yield of this test in a highly consanguineous community. A likely genetic diagnosis was achieved in 70% of patients. Several factors were considered to possibly influence the diagnostic rate of WES among our cohort including early age, presence of consanguinity, family history suggestive of PID, the number of family members who underwent WES and the clinical phenotype of the patient. The highest diagnostic rate was in patients with combined immunodeficiency with and/or without a syndrome. Notably, WES findings altered the clinical management in 39% (41/106) of patients in our cohort. Our findings support the use of WES as an important diagnostic tool in patients with suspected PID, especially in highly consanguineous communities.

PMID: 32135276 [PubMed – as supplied by publisher]

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The case for severe combined immunodeficiency (SCID) and T cell lymphopenia newborn screening: saving lives…one at a time.

Immunol Res. 2020 Mar 04;:

Authors: Quinn J, Orange JS, Modell V, Modell F

Abstract
Severe combined immunodeficiency (SCID) is a group of syndromes resulting from genetic defects causing severe deficiency in T cell and B cell function. These conditions are life-threatening and result in susceptibility to serious infections. SCID is often fatal in the first year of life if not detected and properly treated. SCID and related T cell lymphopenias can be detected in newborns by a simple screening test, the T cell receptor excision circle (TREC) assay, using the same dried blood spot samples already collected from newborns to screen for other genetic disorders. The TREC assay facilitates the earliest possible identification of cases of SCID before opportunistic infections, irreversible organ damage, or death, thus allowing for the possibility of curative treatment through hematopoietic stem cell transplant and gene therapy. Infants receiving hematopoietic stem cell transplant in the first few months of life, after being identified through screening, have a high probability of survival (95-100%), along with lower morbidity. The TREC assay has proven to have outstanding specificity and sensitivity to accurately identify almost all infants with SCID (the primary targets) as well as additional infants having other select immunologic abnormalities (secondary targets). The TREC assay is inexpensive and has been effectively integrated into many public health programs. Without timely treatment, SCID is a fatal disease that causes accrual of exorbitant healthcare costs even in just 1 year of life. The cost of care for just one infant with SCID, not diagnosed through newborn screening, could be more than the cost of screening for an entire state or regional population. Continued implementation of TREC screening will undoubtedly enhance early diagnosis, application of treatment, and healthcare cost savings. The Jeffrey Modell Foundation helped initiate newborn screening for SCID in the USA in 2008 and continues its efforts to advocate for SCID screening worldwide. Today, all 50 states and Puerto Rico are screening for SCID and T cell lymphopenia, with 27 million newborns screened to date, and hundreds diagnosed and treated. Additionally, there are at least 20 countries around the world currently conducting screening for SCID at various stages. Newborn screening for SCID and related T cell lymphopenia is cost-effective, and most importantly, it is lifesaving and allows children with SCID the opportunity to live a healthy life.

PMID: 32128663 [PubMed – as supplied by publisher]

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MKL1 deficiency results in a severe neutrophil motility defect due to impaired actin polymerization.

Blood. 2020 Mar 03;:

Authors: Sprenkeler EGG, Henriet S, Tool A, Kreft IC, van der Bijl I, Aarts CCEM, van Houdt M, Verkuijlen P, van Aerde K, Jaspers G, van Heijst A, Koole W, Gardeitchik T, Geissler J, de Boer M, Tol S, Bruggeman CW, van Alphen F, Verhagen HJ, van den Akker E, Janssen H, van Bruggen R, van den Berg TK, Liem KD, Kuijpers TW

Abstract
Megakaryoblastic leukemia 1 (MKL1) promotes the regulation of essential cell processes, including actin cytoskeletal dynamics by co-activating serum response factor. Recently, the first human case with MKL1 deficiency, leading to a novel primary immunodeficiency, was identified. We report a second family with two siblings with a homozygous frameshift mutation in MKL1. The index case deceased as an infant from progressive and severe pneumonia by Pseudomonas aeruginosa and poor wound healing. The younger sib was preemptively transplanted shortly after birth. The immunodeficiency was marked by a pronounced actin polymerization defect and a strongly reduced motility and chemotactic response by MKL1-deficient neutrophils. Apart from the lack of MKL1, subsequent proteomic and transcriptomic analyses of patient neutrophils revealed actin and several actin-related proteins to be downregulated, confirming a role for MKL1 as transcriptional co-regulator. Degranulation was enhanced upon suboptimal neutrophil activation, while production of reactive oxygen species was normal. Neutrophil adhesion was intact but without proper spreading. The latter could explain the observed failure in firm adherence and transendothelial migration under flow conditions. No apparent defect in phagocytosis and bacterial killing was found. Also monocyte-derived macrophages showed intact phagocytosis; lymphocyte counts and proliferative capacity were normal. Non-hematopoietic primary patient fibroblasts demonstrated defective differentiation into myofibroblasts but normal migration and filamentous actin (F-actin) content, most probably due to compensatory mechanisms of MKL2, which is not expressed in neutrophils. Our findings extend current insight into the severe immune dysfunction in MKL1 deficiency, with cytoskeletal dysfunction and defective extravasation of neutrophils as most prominent features.

PMID: 32128589 [PubMed – as supplied by publisher]

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Clinical Practice Experience with HyQvia in Adults Using Alternative Dosing Regimens and Pediatric Patients: A Retrospective Study.

Adv Ther. 2020 Mar 02;:

Authors: Wasserman RL, HyQvia Experience Study Group

Abstract
INTRODUCTION: HyQvia (Immune Globulin Infusion 10% [Human] with Recombinant Human Hyaluronidase) was developed to combine the advantages of intravenous and subcutaneous immune globulin (SCIG), allowing administration of larger volumes at a single subcutaneous site with less frequent dosing when compared to other SCIG products. Current US prescribing guidelines for HyQvia are limited to adults and do not encompass the flexibility required to achieve success in all patients with primary immunodeficiency (PID).
METHODS: This retrospective study was designed to evaluate the clinical experience of treating patients with PID with HyQvia regimens outside of package insert recommendations as well as in pediatric patients. Data were abstracted from 38 patient records (317 HyQvia infusions), including five patients less than 16 years of age, from seven US immunology clinics.
RESULTS: Among 37 patients receiving HyQvia regimens differing from prescribing guidelines, the most notable variations included shorter ramp-up periods, use of two rather than one infusion site, and slower than maximal infusion rates to mitigate local adverse events (AEs). The medication volume infused for single site doses ranged from 75 to 200 mL and doses split between two sites ranged from 100 to 750 mL. The most common type of regimen variation was a condensed ramp-up phase (shorter schedule, higher doses), and 96% (24/25) of patients managed in this way completed ramp-up. The most common ramp-up schedule was three infusions (one at 25-45%, another at 50-75%, and the final at 100% of target dose) spread over 2-4 weeks.
CONCLUSIONS: A shorter ramp-up schedule did not appear to increase the number of AEs compared to standard ramp-up schedules. For patients with AEs, slower infusion rates and the use of two sites may improve medication tolerability. Four of five pediatric patients reported no AEs, and only one discontinued, stating a fear of needles. HyQvia may be tailored to adults requiring alternative rates, ramp-up, and/or dosing regimens and may be especially well-suited to children.

PMID: 32124273 [PubMed – as supplied by publisher]

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A late preterm infant with lymphopenia.

Allergy Asthma Proc. 2020 Mar 01;41(2):141-143

Authors: Lutfeali S, Khan DA, Wysocki C

Abstract
The newborn screen for severe combined immunodeficiency (SCID) uses real-time quantitative polymerase chain reaction for T-cell receptor excision circles and is highly sensitive for SCID. However, T-cell lymphopenia from other primary and secondary causes, such as DiGeorge syndrome, prematurity, thymic involution from stress, and thymectomy during cardiac surgery, is also detected. We present a newborn girl with T-cell lymphopenia of unknown etiology detected via abnormal newborn screen.

PMID: 32122450 [PubMed – in process]

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Impact of mannose-binding lectin 2 gene polymorphisms on disease severity in noncystic fibrosis bronchiectasis in children.

Pediatr Pulmonol. 2020 Mar 02;:

Authors: Dogru D, Polat SE, Tan Ç, Tezcan İ, Yalçın SS, Utine E, Oğuz B, Yaz İ, Emiralioğlu N, Hızal M, Yalçın E, Özçelik U, Çağdaş D, Kiper N

Abstract
BACKGROUND: Mannose-binding lectin (MBL) is a complement protein involved in the innate immune system, and is associated with some chronic respiratory diseases including noncystic fibrosis (non-CF) bronchiectasis in adults. The aim of this study was to investigate the frequency of MBL2 gene polymorphisms in children with non-CF bronchiectasis, and the effect of MBL deficiency on disease severity.
METHODS: Fifty children with non-CF bronchiectasis (bronchiectasis group) and 50 healthy controls (control group) were included. The demographic findings, number of acute pulmonary exacerbations in the previous year, airway cultures, pulmonary function tests, and radiologic scores of the bronchiectasis group were recorded. DNA extraction was performed in both groups and MBL2 gene polymorphisms in codons 52, 54, 57 in exon 1 and H/L, Y/X in the promoter region were studied using real-time polymerase chain reaction. Haplotypes were made by genotypes, and MBL serum expression was classified according to the genotypes in the literature.
RESULTS: The bronchiectasis group consisted of 23 (46%) patients with primary ciliary dyskinesia, 5 (10%) with primary immunodeficiency diseases, and 22 (44%) with idiopathic bronchiectasis. There were no statistically significant differences between the bronchiectasis and control groups in terms of allele and genotype frequencies of polymorphisms in codons 52, 54, 57 in exon 1 and promoter H/L. However, the YX heterozygote genotype was more frequent in the control group (82%) compared with the bronchiectasis group (50%) (P = .002). The frequency of patients with intermediate serum MBL expression genotype was higher in the bronchiectasis group (20%) than in the control group (0%) (P = .001). In the bronchiectasis group, there were no significant differences in growth, annual pulmonary exacerbation rates in the last year, pulmonary function tests, radiologic scores, and microbiologic findings between low, intermediate, and high-expressing genotypes.
CONCLUSIONS: In children with non-CF bronchiectasis, MBL genotype was different from healthy controls. MBL deficiency associated only with MBL genotype was not related to disease severity in this group of patients.

PMID: 32119194 [PubMed – as supplied by publisher]

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A case report of sinusoidal diffuse large B-cell lymphoma in a STK4 deficient patient.

Medicine (Baltimore). 2020 Feb;99(9):e18601

Authors: Ashrafi F, Klein C, Poorpooneh M, Sherkat R, Khoshnevisan R

Abstract
INTRODUCTION: Primary immunodeficiency diseases (PIDs), a rare group of gene defects with different manifestations, are at great risk of malignancy. The incidence of diffuse large B-cell lymphoma in the sinusoidal tract is quite rare with nasal congestion, stuffiness, and pain in maxillary sinus manifestation. Human serine-threonine kinase 4 (STK4) deficiency affects the immune system with recurrent bacterial and viral infections, mucocutaneous candidiasis, cutaneous warts, skin abscesses, T- and B-cell lymphopenia, and neutropenia.
PATIENT CONCERN: In this study we describe the infrequent incidence and successful treatment of sinusoidal diffuse large B-cell lymphoma in a STK4 deficient patient with clinical manifestation of severe intractable headaches, unilateral swelling of her face, nasal congestion, stuffiness, and pain in maxillary.
DIAGNOSIS: Clinical data including headaches, unilateral swelling of face, nasal congestion, stuffiness and pain in maxillary sinus with confirmed histopathology and magnetic resonance imaging finding confirmed sinusoidal diffuse large B cell lymphoma in a STK4 deficient patient.
INTERVENTION: Six cycles of R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone) were administered and after each cycle, G-CSF support was used. Chemotherapeutic drugs were administered with standard dose and no dose reduction was done during the treatment. IVIG treatment continued during the courses of chemotherapy.
OUTCOME: The index patient achieved complete response at the end of chemotherapy courses and was in remission for about 8 months afterward, prior to the date of the present report.
CONCLUSION: PID patient are often at increased risk of malignancies. Sinusoidal diffuse large B-cell lymphoma is quite rare and prognosis is variable. Early attention to patient’s manifestation, suitable treatment, and monitoring manifestations caused by PID are critical.

PMID: 32118703 [PubMed – as supplied by publisher]

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