Manish Butte

Incomplete penetrance in primary immunodeficiency: a skeleton in the closet.

Hum Genet. 2020 Feb 17;:

Authors: Gruber C, Bogunovic D

Abstract
Primary immunodeficiencies (PIDs) comprise a diverse group of over 400 genetic disorders that result in clinically apparent immune dysfunction. Although PIDs are classically considered as Mendelian disorders with complete penetrance, we now understand that absent or partial clinical disease is often noted in individuals harboring disease-causing genotypes. Despite the frequency of incomplete penetrance in PID, no conceptual framework exists to categorize and explain these occurrences. Here, by reviewing decades of reports on incomplete penetrance in PID we identify four recurrent themes of incomplete penetrance, namely genotype quality, (epi)genetic modification, environmental influence, and mosaicism. For each of these principles, we review what is known, underscore what remains unknown, and propose future experimental approaches to fill the gaps in our understanding. Although the content herein relates specifically to inborn errors of immunity, the concepts are generalizable across genetic diseases.

PMID: 32067110 [PubMed – as supplied by publisher]

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European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline: Deficiencies, Diagnosis, and Management.

J Clin Immunol. 2020 Feb 17;:

Authors: Brodszki N, Frazer-Abel A, Grumach AS, Kirschfink M, Litzman J, Perez E, Seppänen MRJ, Sullivan KE, Jolles S

Abstract
This guideline aims to describe the complement system and the functions of the constituent pathways, with particular focus on primary immunodeficiencies (PIDs) and their diagnosis and management. The complement system is a crucial part of the innate immune system, with multiple membrane-bound and soluble components. There are three distinct enzymatic cascade pathways within the complement system, the classical, alternative and lectin pathways, which converge with the cleavage of central C3. Complement deficiencies account for ~5% of PIDs. The clinical consequences of inherited defects in the complement system are protean and include increased susceptibility to infection, autoimmune diseases (e.g., systemic lupus erythematosus), age-related macular degeneration, renal disorders (e.g., atypical hemolytic uremic syndrome) and angioedema. Modern complement analysis allows an in-depth insight into the functional and molecular basis of nearly all complement deficiencies. However, therapeutic options remain relatively limited for the majority of complement deficiencies with the exception of hereditary angioedema and inhibition of an overactivated complement system in regulation defects. Current management strategies for complement disorders associated with infection include education, family testing, vaccinations, antibiotics and emergency planning.

PMID: 32064578 [PubMed – as supplied by publisher]

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Genetically Determined Height and Risk of Non-hodgkin Lymphoma.

Front Oncol. 2019;9:1539

Authors: Moore A, Kane E, Wang Z, Panagiotou OA, Teras LR, Monnereau A, Wong Doo N, Machiela MJ, Skibola CF, Slager SL, Salles G, Camp NJ, Bracci PM, Nieters A, Vermeulen RCH, Vijai J, Smedby KE, Zhang Y, Vajdic CM, Cozen W, Spinelli JJ, Hjalgrim H, Giles GG, Link BK, Clavel J, Arslan AA, Purdue MP, Tinker LF, Albanes D, Ferri GM, Habermann TM, Adami HO, Becker N, Benavente Y, Bisanzi S, Boffetta P, Brennan P, Brooks-Wilson AR, Canzian F, Conde L, Cox DG, Curtin K, Foretova L, Gapstur SM, Ghesquières H, Glenn M, Glimelius B, Jackson RD, Lan Q, Liebow M, Maynadie M, McKay J, Melbye M, Miligi L, Milne RL, Molina TJ, Morton LM, North KE, Offit K, Padoan M, Patel AV, Piro S, Ravichandran V, Riboli E, de Sanjose S, Severson RK, Southey MC, Staines A, Stewart C, Travis RC, Weiderpass E, Weinstein S, Zheng T, Chanock SJ, Chatterjee N, Rothman N, Birmann BM, Cerhan JR, Berndt SI

Abstract
Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00-1.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01-1.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.

PMID: 32064237 [PubMed]

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Multiple Listeria Abscesses in an Immunocompetent Patient.

Cureus. 2020 Jan 13;12(1):e6642

Authors: Frade HC, Pingili C, Nattanamai P

Abstract
Listeria monocytogenes is a ubiquitous organism that can potentially cause gastroenteritis and, less commonly, central nervous system infections. Brain abscess is rare and often associated with immunocompromised status. We report a case of multiple abscesses caused by Listeria in a previously immunocompetent elderly patient who developed a headache and left-sided hemiparesis over the course of days. Neuroimaging studies revealed multiple ring-enhancing lesions in the brain and midbrain territories. Blood culture, brain tissue aspirate, and cerebrospinal fluid nucleic acid amplification test were positive for Listeria. Extensive immunologic workup revealed no primary or secondary immunodeficiency disorders. After the initiation of antibiotics, the patient showed gradual clinical improvement and went to a skilled nursing facility after two weeks.

PMID: 32064214 [PubMed]

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The evaluation of malignancies in Turkish PID patients; a multicenter study.

Pediatr Allergy Immunol. 2020 Feb 14;:

Authors: Cekic S, Metin A, Aytekin C, Karaca NE, Baris S, Karali Y, Kiykim A, Karakoc Aydıner E, Ozen A, Aslan T, Sevinir B, Aksu G, Kutukculer N, Kilic SS

Abstract
BACKGROUND: There is no data regarding the prevalence of malignancies in patients with primary immunodeficiency (PID) in Turkey. Along with the prevalence of malignancy, we aimed to present the types of malignancy and define the underlying immune deficiency of the patients.
METHOD: Between the years 1992 and 2018 years, from 5 tertiary immunology clinics, fifty-nine patients with PID who developed malignancy were included. All patients were evaluated for demographics, clinical features, and prognosis.
RESULTS: The prevalence of malignancy in our cohort was detected as 0.9% (59/6392). The male to female ratio was 1.8 (38/21), and the median age of patients was 14 years (range: 1.5 – 51). The median age at diagnosis of malignancy was 10 years (range: 1.5 – 51). Ataxia-telangiectasia was the most frequent PID in patients with malignancy (n= 19, 32.2%), and non-Hodgkin lymphoma was the most common malignancy (n= 32, 51.6%). The rate of malignancy in DOCK8 deficiency (n=7/43, 16.3%) was higher than AT (n=19/193, 9.8%), WAS (n=2/22, 9.1%) and CVID (n=11/205, 5.4%). EBV quantitative PCR was positive in 16 out of 53 patients (30.2%). Three patients had secondary malignancies. Remission was achieved in 26 patients (44.1%). However, 31 patients (52.5%) died. Two patients (3.4%) are still on chemotherapy.
CONCLUSION: This study is the largest cohort investigating the association of malignancy in patients with PID in Turkey. While lymphoid malignancies were the most common malignancy and observed more frequently in AT patients, the risk for malignancy was higher in patients with DOCK8 deficiency then AT.

PMID: 32060950 [PubMed – as supplied by publisher]

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Evaluation of Respiratory Complications in Patients with X-Linked and Autosomal Recessive Agammaglobulinemia.

Pediatr Allergy Immunol. 2020 Feb 14;:

Authors: Fekrvand S, Yazdani R, Olbrich P, Azizi G, Shirzadi R, Modaresi M, Sohani M, Delavari S, Kalantari A, Shariat M, Shafiei A, Lu N, Hassanpour G, Rahimi Hajiabadi M, Ashournia P, Razaghian A, Asgharyan M, Shahraki-Ghadimi Z, Rouhani R, Hoda Fallah F, Rezaei N, Abolhassani H, Aghamohammadi A

Abstract
BACKGROUND: Congenital agammaglobulinemia is the first primary immunodeficiency disorder characterized by a defect in B lymphocytes development, and subsequently decreased immunoglobulin levels. These patients are prone to suffer from recurrent infections mostly involving the respiratory tract. In this study, we aimed to describe in detail respiratory tract complications as the most prominent clinical feature among agammaglobulinemic patients.
METHODS: A total number of 115 patients were included. Demographic, clinical and genetic data were collected from the patients’ medical records. Among the available patients, pulmonary function tests (PFTs) and/or high-resolution computed tomography (HRCT) were performed.
RESULTS: Respiratory tract complications (85.2%) especially pneumonia (62.6%) were the most prominent clinical features in our cohort. Among patients with abnormal PFT results (N=19), a mixed respiratory pattern was observed in 36.8%. HRCT was carried out in 29 patients; Bhalla scoring-based evaluation of these patients indicated excellent (44.8%), followed by good (34.5%) and mild (20.7%) results. Bronchiectasis was found in 13 patients undergoing HRCT (44.8%). We found significant inverse correlations between the Bhalla score and incidence rate of pneumonia, as well as the presence of bronchiectasis. Patients with abnormal PFT results had statistically significant higher bronchiectasis frequency and lower Bhalla scores compared to those with normal results. Forty-one patients were deceased and here respiratory failure was the most common cause of death (45.5%).
CONCLUSION: High prevalence of respiratory tract infections among agammaglobulinemic patients and subsequent progression to permanent lung damage highlights the importance of implementing respiratory evaluation as part of routine follow-up program of agammaglobulinemic patients. Physicians should be aware of this and regularly monitor the respiratory function of these patients to allow for timely diagnosis and treatment initiation aiming to improve patients’ prognosis and quality of life.

PMID: 32058651 [PubMed – as supplied by publisher]

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Lymphocyte Subgroups and KREC Numbers in Common Variable Immunodeficiency: A Single Center Study.

J Clin Immunol. 2020 Feb 14;:

Authors: Yaz I, Ozbek B, Ng YY, Cetinkaya PG, Halacli SO, Tan C, Kasikci M, Kosukcu C, Tezcan I, Cagdas D

Abstract
Common variable immunodeficiency (CVID) results in defective B cell differentiation and impaired antibody production and is the most common symptomatic primary immunodeficiency. Our aim was to evaluate the correlation among B cell subgroups, κ-deleting recombination excision circle (KREC) copy numbers, and clinical and immunological data of the patients with CVID, and evaluate the patients according to classifications currently available to define the role of KREC copy numbers in the diagnosis of CVID. KREC analysis was performed using a quantitative real-time polymerase chain reaction assay, and B cell subgroups were measured by flow cytometry. The median age of the patients (n = 30) was 25 (6-69) years. Parental consanguinity ratio was 33%. The median age at diagnosis was 15 (4-59), and follow-up period was 6 (1-37) years. CD19+ and CD4+ cell counts at the time of diagnosis were low in 66.7% and 46.7% of the patients, respectively. CD19+ cell counts were positively correlated with KREC copy numbers in patients and healthy controls. CD19+ cell counts and KREC copy numbers were significantly reduced in CVID patients compared to healthy controls as expected. KRECs are quantitative markers for B cell defects. We found low CD4+ cell numbers, recent thymic emigrants, and lymphopenia in some of the patients at diagnosis, which reminds the heterogeneity of CVID’s etiology. In this study, a positive correlation was shown between CD19+ cell counts and KREC copy numbers. Low KREC copy numbers indicated B cell deficiency; however, high KREC copy numbers were not sufficient to rule out CVID.

PMID: 32056073 [PubMed – as supplied by publisher]

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