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Clinical characteristics and etiologies of bronchiectasis in Korean children: A multicenter retrospective study.

April 10, 2019 By Manish Butte

Clinical characteristics and etiologies of bronchiectasis in Korean children: A multicenter retrospective study.

Respir Med. 2019 Apr;150:8-14

Authors: Lee E, Shim JY, Kim HY, Suh DI, Choi YJ, Han MY, Baek KS, Kwon JW, Cho J, Jung M, Kim YS, Sol IS, Kim BS, Chung EH, Lee S, Jeong K, Jang YY, Jang GC, Hyun MC, Yang HJ, Shin M, Kim JT, Kim JH, Hwang YH, Ahn JY, Seo JH, Jung JA, Kim HS, Oh MY, Park Y, Lee MH, Lee SY, Jung S, Hong SJ, Ahn YM, on the behalf of Pediatric Respiratory and Diseases Study Party

Abstract
BACKGROUND: Bronchiectasis is a chronic pulmonary disease characterized by progressive and irreversible bronchial dilatation. The aim of the present study was to investigate the etiologies and clinical features of bronchiectasis in Korean children.
METHODS: We performed a retrospective review of the medical records for children diagnosed with bronchiectasis between 2000 and 2017 at 28 secondary or tertiary hospitals in South Korea.
RESULTS: A total of 387 cases were enrolled. The mean age at diagnosis was 9.2 ± 5.1 years and 53.5% of the patients were boys. The most common underlying cause of bronchiectasis was preexisting respiratory infection (55.3%), post-infectious bronchiolitis obliterans (14.3%), pulmonary tuberculosis (12.3%), and heart diseases (5.6%). Common initial presenting symptoms included chronic cough (68.0%), recurrent pneumonia (36.4%), fever (31.1%), and dyspnea (19.7%). The most predominantly involved lesions were left lower lobe (53.9%), right lower lobe (47.1%) and right middle lobe (40.2%). No significant difference was observed in the distribution of these involved lesions by etiology. The forced expiratory volume in 1 s (FEV1) levels were lowest in cases with interstitial lung disease-associated bronchiectasis, followed by those with recurrent aspiration and primary immunodeficiency.
CONCLUSIONS: Bronchiectasis should be strongly considered in children with chronic cough and recurrent pneumonia. Long-term follow-up studies on pediatric bronchiectasis are needed to further clarify the prognosis and reduce the disease burden in these patients.

PMID: 30961955 [PubMed – in process]

Autoimmune Lymphoproliferative Syndrome: An Overview.

April 9, 2019 By Manish Butte

Autoimmune Lymphoproliferative Syndrome: An Overview.

Arch Pathol Lab Med. 2019 Apr 08;:

Authors: Matson DR, Yang DT

Abstract
Autoimmune lymphoproliferative syndrome (ALPS) is an inherited nonmalignant lymphoproliferative disorder characterized by heterozygous mutations within the first apoptosis signal receptor (FAS) signaling pathway. Defects in FAS-mediated apoptosis cause an expansion and accumulation of autoreactive CD4- and CD8- (double-negative) T cells, leading to cytopenias, splenomegaly, lymphadenopathy, autoimmune disorders, and a greatly increased lifetime risk of lymphoma. The differential diagnosis of ALPS includes infection, other inherited immunodeficiency disorders, primary and secondary autoimmune syndromes, and lymphoma. The most consistent pathologic feature is a florid paracortical expansion of double-negative T cells in lymph nodes. A presumptive clinical diagnosis can be made from symptoms and a constellation of laboratory test results. However, a definitive diagnosis requires ancillary testing and enables disease subclassification. Recognition of ALPS is critical, as treatment with immunosuppressive therapies can effectively reduce or ameliorate symptoms for most patients.

PMID: 30958694 [PubMed – as supplied by publisher]

Inherited Classical and Alternative Pathway Complement Deficiencies in Children: A Single Center Experience.

April 9, 2019 By Manish Butte

Inherited Classical and Alternative Pathway Complement Deficiencies in Children: A Single Center Experience.

Iran J Immunol. 2018 Dec;15(4):309-320

Authors: Genel F, Erdem SB, Gülez N, Karaman S, Nacaroglu HT, Skattum L, Truedsson L

Abstract
BACKGROUND: Primary complement deficiencies are rare diseases.
OBJECTIVE: To retrospectively evaluate the clinical and laboratory findings and complications of patients to increase awareness of pediatricians about complement deficiencies, which are rarely encountered.
METHODS: In this study, the clinical and immunological characteristics of 21 patients who consulted the Immunology Department of our hospital between 2003 and 2017 and were diagnosed with classical or alternative pathway complement deficiency were obtained from the file records.
RESULTS: Ten patients with C1 inhibitor deficiency, four patients with factor I deficiency, three patients with properdin deficiency, two patients with C8 deficiency, one patient with C1q deficiency, and one patient with C4B deficiency were assessed. The mean age of the patients at diagnosis was 11.4±4.7 years, the age of onset of symptoms was 7.9±3.9 years, and the follow-up period was 6.7±3.9 years. Fourteen cases had a similar medical history in the family. All patients with C1q, factor I, properdin, C8, and C4B deficiencies presented with an infection, and vasculitic rash was present in two patients with factor I deficiency. In addition, immune complex glomerulonephritis was present in one patient with factor I deficiency. Meningococcal, Haemophilus influenzae type B, and pneumococcal vaccines were administered and prophylactic antibiotic treatment was initiated in all patients except patients with C1 inhibitor deficiency.
CONCLUSIONS: Early diagnosis of complement deficiencies can facilitate prevention of life-threatening complications such as severe bacterial infections by considering prophylactic antibiotics and vaccines. In patients with C1 inhibitor deficiency, achieving an acurate early diagnosis will assist in the management and timely treatment of life-threatening attacks such as upper airway obstruction and improve outcomes.

PMID: 30593745 [PubMed – indexed for MEDLINE]

[Common variable immune deficiency in adults: focus on pulmonary complications].

April 9, 2019 By Manish Butte

[Common variable immune deficiency in adults: focus on pulmonary complications].

Ter Arkh. 2017;89(12. Vyp. 2):211-215

Authors: Fomina DS, Bobrikova EN, Sinyavkin DO, Parshin VV

Abstract
Common variable immune deficiency is the most common form of a group of primary immunodeficiencies in adult patients. Pulmonary complications occupy leading positions. It is the development of recurrent bronchopulmonary inflammatory diseases that is considered to be one of the main causes of death and disability in patients with this disease. By presenting two clinical cases with long diagnostic delays, the authors try to attract the attention of specialists of related professions, which will minimize the development of irreversible complications in the patients.

PMID: 29488483 [PubMed – indexed for MEDLINE]

Costs associated with treatment of severe combined immunodeficiency-rationale for newborn screening in Sweden.

April 9, 2019 By Manish Butte

Costs associated with treatment of severe combined immunodeficiency-rationale for newborn screening in Sweden.

J Allergy Clin Immunol. 2017 05;139(5):1713-1716.e6

Authors: Gardulf A, Winiarski J, Thorin M, Heibert Arnlind M, von Döbeln U, Hammarström L

PMID: 28012934 [PubMed – indexed for MEDLINE]

Population pharmacokinetic modeling and simulation of immunoglobulin exposure with varying dosing intervals of subcutaneous immunoglobulin 20% (Ig20Gly) in patients with primary immunodeficiency diseases.

April 6, 2019 By Manish Butte

Population pharmacokinetic modeling and simulation of immunoglobulin exposure with varying dosing intervals of subcutaneous immunoglobulin 20% (Ig20Gly) in patients with primary immunodeficiency diseases.

Int Immunopharmacol. 2019 Apr 02;71:404-410

Authors: Dumas T, Berry NS, Wolfsegger M, Jolles S, McCoy B, Yel L

Abstract
BACKGROUND: Immunoglobulin (IG) replacement therapy in patients with primary immunodeficiency diseases (PID) can be administered daily to every 2 weeks subcutaneously (SCIG) or every 3 or 4 weeks intravenously (IVIG).
OBJECTIVES: Develop a population pharmacokinetic (PK) model simulating IG exposure with Ig20Gly, a 20% SCIG; determine the dose adjustment factor for Ig20Gly relative to IVIG.
METHODS: Data from patients with PID treated with Ig20Gly and IVIG 10% were used to characterize IG population PK by nonlinear mixed-effects modeling and validated using data splitting and a visual predictive check. IG profiles were simulated for 1000 patients/interval treated with Ig20Gly (daily, every 2 days, every 3 days, twice weekly, weekly, every 2 weeks). An Ig20Gly adjustment factor of 130% was used to simulate Ig20Gly to IVIG AUC ratios for weekly or every 2 weeks Ig20Gly dosing intervals and a monthly IVIG dosing interval.
RESULTS: A 1-compartment model, using weight as a covariate on clearance, derived from an index modeling dataset (n = 81) demonstrated predictability for a validation dataset (n = 21). The model estimate of bioavailability was 73.9%. Simulations for 6 dosing intervals showed similar mean profiles with overlapping prediction intervals. Mean AUC ratios of Ig20Gly to IVIG with a dose adjustment factor of 1.30:1 were 98.7% for weekly and 97.7% for twice-weekly administration demonstrating comparable exposure.
CONCLUSION: Ig20Gly exposures from daily to up to every 2 weeks appeared equivalent. A 1.30 conversion factor provided coverage comparable to IVIG when Ig20Gly is administered daily to every 2 weeks.

PMID: 30952104 [PubMed – as supplied by publisher]

Successful liver transplantation in common variable immune deficiency with reversal of hepatopulmonary syndrome.

April 6, 2019 By Manish Butte

Successful liver transplantation in common variable immune deficiency with reversal of hepatopulmonary syndrome.

BMJ Case Rep. 2019 Apr 03;12(4):

Authors: Apostolov R, Sinclair M, Lokan J, Angus P

Abstract
Common variable immune deficiency (CVID) is a primary immunodeficiency disorder that is associated with abnormal liver function tests, however advanced liver disease is uncommon. Hepatopulmonary syndrome (HPS) is a rare but debilitating complication of CVID-associated liver disease. We report a case of CVID complicated by HPS that was successfully treated with orthotopic liver transplant, with the patient recovering to normal hepatic function and successfully weaning off domiciliary oxygen post-transplantation.

PMID: 30948390 [PubMed – in process]

Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.

April 6, 2019 By Manish Butte

Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.

Nat Commun. 2019 03 19;10(1):1252

Authors: Kaasinen E, Kuismin O, Rajamäki K, Ristolainen H, Aavikko M, Kondelin J, Saarinen S, Berta DG, Katainen R, Hirvonen EAM, Karhu A, Taira A, Tanskanen T, Alkodsi A, Taipale M, Morgunova E, Franssila K, Lehtonen R, Mäkinen M, Aittomäki K, Palotie A, Kurki MI, Pietiläinen O, Hilpert M, Saarentaus E, Niinimäki J, Junttila J, Kaikkonen K, Vahteristo P, Skoda RC, Seppänen MRJ, Eklund KK, Taipale J, Kilpivaara O, Aaltonen LA

Abstract
Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.

PMID: 30890702 [PubMed – indexed for MEDLINE]

Severe Facial Herpes Vegetans and Viremia in NFKB2-Deficient Common Variable Immunodeficiency.

April 4, 2019 By Manish Butte

Severe Facial Herpes Vegetans and Viremia in NFKB2-Deficient Common Variable Immunodeficiency.

Front Pediatr. 2019;7:61

Authors: Parsons K, Cipriano SD, Rosen LB, Browne SK, Walter JE, Stone BL, Keeshin S, Chen K

Abstract
With the accessibility of next-generation sequencing modalities, an increasing number of primary immunodeficiency disorders (PIDDs) such as common variable immunodeficiency (CVID) have gained improved understanding of molecular pathogenesis and disease phenotype with the identification of a genetic etiology. We report a patient with early-onset CVID due to an autosomal dominant loss-of-function mutation in NFKB2 who developed a severe herpes vegetans cutaneous infection as well as concurrent herpes simplex virus viremia. The case highlights features of CVID, unique aspects of NF-κB2 deficiency including susceptibility to herpesvirus infections, the detection of neutralizing anticytokine antibodies, and the complexity of medical management of patients with a PIDD that can be aided by a known genetic diagnosis.

PMID: 30941333 [PubMed]

Real World Experience of Chronic Hepatitis C Retreatment with Genotype Specific Regimens in Nonresponders to Previous Interferon-Free Therapy.

April 4, 2019 By Manish Butte

Real World Experience of Chronic Hepatitis C Retreatment with Genotype Specific Regimens in Nonresponders to Previous Interferon-Free Therapy.

Can J Gastroenterol Hepatol. 2019;2019:4029541

Authors: Zarębska-Michaluk D, Buczyńska I, Simon K, Tudrujek-Zdunek M, Janczewska E, Dybowska D, Sitko M, Dobracka B, Jaroszewicz J, Pabjan P, Klapaczyński J, Laurans Ł, Mazur W, Socha Ł, Tronina O, Parczewski M, Flisiak R

Abstract
Background and Aim: The development of interferon- (IFN-) free regimens substantially improved efficacy of treatment for HCV, but despite excellent effectiveness the failures still occur. The aim of our study was to evaluate the efficacy of retreatment with genotype specific direct acting antivirals- (DAA-) based regimens in nonresponders to previous IFN-free therapy.
Materials and Methods: Analysed population consisted of 31 nonresponders to IFN-free regimen, which received second IFN-free rescue therapy, selected from 6228 patients included in a national database EpiTer-2.
Results: Age and gender distribution were similar, whereas proportion of genotype 1b was slightly higher and genotype 4 lower in the whole population compared to studied one. Patients included in the study demonstrated much more advanced fibrosis. Primary therapy was discontinued in 12 patients, which were recognized as failures due to nonvirologic reason, whereas virologic reason of therapeutic failure was recognized in 19 patients which completed therapy. Overall sustained virologic response (SVR) rate was 81% and 86% in intent-to-treat (ITT) and modified ITT analysis, respectively (74% and 78% in virologic failures, 92% and 100% in nonvirologic failures). Resistance-associated substitutions (RAS) testing was carried out in 8 patients from the group of completed primary therapy and three of them had potential risk for failure of rescue therapy due to NS5A association, while two of them achieved SVR.
Conclusions: We demonstrated moderate effectiveness of genotype specific rescue therapy in failures due to virologic reason and high in those who discontinued primary therapy. Therefore rescue therapy with genotype specific regimens should be considered always if more potent regimens are not available.

PMID: 30941326 [PubMed – in process]