Manish Butte

Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.

J Clin Immunol. 2020 Aug 27;:

Authors: Aljohani AH, Al-Mousa H, Arnaout R, Al-Dhekri H, Mohammed R, Alsum Z, Nicolas-Jilwan M, Alrogi F, Al-Muhsen S, Alazami AM, Al-Saud B

Abstract
PURPOSE: Combined immunodeficiency (CID), due to mutations in TFRC gene that encodes the transferrin receptors (TfR1), is a rare monogenic disorder. In this study, we further characterize the clinical and immunological phenotypes in a cohort of eight patients.
METHODS: A retrospective review of clinical and immunological features of patients diagnosed with a TFRC gene mutation between 2015 and 2019 in three tertiary centers.
RESULTS: Eight patients from six unrelated families were enrolled. The patients had a median age of 7 years (4-32 years). All patients presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life. Less common features were skin abscesses, conjunctivitis, global developmental delay, optic nerve atrophy, vitiligo, multinodular goiter, and hemophagocytic lymphohistiocytosis-like symptoms. All patients had intermittent neutropenia and 87% of the patients had recurrent thrombocytopenia. Anemia was found in 62%. All patients had hypogammaglobinemia and one had a persistent high IgM level. All patients had impaired function of T cells. The same homozygous missense mutation c.58T>C:p.Y20H, in the TFRC gene, was detected in all patients. Stem cell transplantation from matched donors was successful in two patients. Five patients did not receive stem cell transplantation, and they are on prophylactic treatment. One patient died due to severe sepsis and neurological complications.
CONCLUSION: This report provides a large cohort with a long follow up of patients with this disease. Our cohort showed variable disease severity.

PMID: 32851577 [PubMed – as supplied by publisher]

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Serum Free Immunoglobulins Light Chains: A Common Feature of Common Variable Immunodeficiency?

Front Immunol. 2020;11:2004

Authors: Guevara-Hoyer K, Ochoa-Grullón J, Fernández-Arquero M, Cárdenas M, Pérez de Diego R, Sánchez-Ramón S

Abstract
Serum free light chain (sFLC) is a recently proposed biomarker for CVID diagnosis. Most CVID patients present low or undetectable sFLC up to 10-fold lower compared to other primary antibody deficiencies. Given that κ and λ light chains are normally secreted in excess with respect to immunoglobulins, this finding points to an intrinsic defect of B cell differentiation in CVID. sFLC levels were prospectively evaluated in a cohort of 100 primary immunodeficiency (PID) patients and in 49 patients with secondary immunodeficiency to haematological malignancy (SID). CVID patients had significantly lower κ and/or λ values (mean: κ: 1.39 ± 1.7 mg/L and λ: 1.97 ± 2.24 mg/L) compared to “other PIDs” (κ: 13.97 ± 5.88 mg/L and λ: 12.92 ± 7.4 mg/L, respectively, p < 0.001 both), and SID (κ 20.9 ± 22.8 mg/L and λ 12.8 ± 8.7 mg/L, respectively, p < 0.001 both). The sum of kappa and lambda (sum κ + λ) in CVID patients (7.25 ± 7.90 mg/L) was significantly lower respect to other PIDs (26.44 ± 13.25 mg/L, p < 0.0001), and to SID patients (28.25 ± 26.24 mg/L, p = 0.0002). ROC analysis of the sum κ + λ disclosed an area under the curve (AUC) of 0.894 for CVID diagnosis (SD 0.031; 95% CI: 0.83-0.95, p < 0.0001), with optimal cut-off of 16.7 mg/L, giving the highest combination of sensitivity (92%), specificity (75%) and NPV (98%). The Relative Risk (RR) for patients presenting a sum κ + λ below 16.7 mg/L was 20.35-fold higher (95%, CI: 5.630-75.93) for CVID than below this threshold. A similar behavior of the sFLC in our CVID cohort with respect to previously published studies was observed. We propose a cut-off of sum κ + λ 16.7 with diagnostic application in CVID patients, and discuss potential specific defects converging in low or undetectable sFLC.

PMID: 32849664 [PubMed – in process]

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CD70 Deficiency Associated With Chronic Epstein-Barr Virus Infection, Recurrent Airway Infections and Severe Gingivitis in a 24-Year-Old Woman.

Front Immunol. 2020;11:1593

Authors: Krüger R, Martin E, Dmytrus J, Feiterna-Sperling C, Meisel C, Unterwalder N, Kölsch U, Wahn V, Hofmann J, Korn P, Latour S, Boztug K, von Bernuth H

Abstract
Most of the few patients with homozygous CD70 deficiency described to date suffered from EBV-related malignancies in early childhood. We present a woman with CD70 deficiency diagnosed in adulthood. She presented in childhood with recurrent airway infections due to encapsulated bacteria, herpes zoster and a fulminant EBV infection followed by chronic EBV infection with mild lymphoproliferation and severe gingivitis/periodontal disease with high EBV viral load in saliva and gingival plaques as an adult. Up to the age of 24 years she developed no malignancy despite constant EBV viremia since primary EBV infection 15 years previously. Immunologic evaluation in childhood showed hypogammaglobulinemia with impaired polysaccharide responsiveness. She has been stable on immunoglobulin substitution with no further severe viral infections and no bacterial airway infections in adulthood. Targeted panel sequencing at the age of 20 years revealed a homozygous CD70 missense mutation (ENST00000245903.3:c.2T>C). CD70 deficiency was confirmed by absent CD70 expression of B cells and activated T cell blasts. The patient finished high school, persues an academic career and has rarely sick days at college. The clinical course of our patient may help to counsel parents of CD70-deficient patients with regard to prognosis and therapeutic options including haematopoetic stem cell transplantation.

PMID: 32849540 [PubMed – in process]

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Primary Immunodeficiencies in Russia: Data From the National Registry.

Front Immunol. 2020;11:1491

Authors: Mukhina AA, Kuzmenko NB, Rodina YA, Kondratenko IV, Bologov AA, Latysheva TV, Prodeus AP, Pampura AN, Balashov DN, Ilyina NI, Latysheva EA, Deordieva EA, Shvets OA, Deripapa EV, Abramova IN, Pashenko OE, Vahlyarskaya SS, Zinovyeva NV, Zimin SB, Skorobogatova EV, Machneva EB, Fomina DS, Ipatova MG, Barycheva LY, Khachirova LS, Tuzankina IA, Bolkov MA, Shakhova NV, Kamaltynova EM, Sibgatullina FI, Guseva MN, Kuznetsova RN, Milichkina AM, Totolian AA, Kalinina NM, Goltsman EA, Sulima EI, Kutlyanceva AY, Moiseeva AA, Khoreva AL, Nesterenko Z, Tymofeeva EV, Ermakova A, Proligina DD, Kalmetieva LR, Davletbaieva GA, Mirsayapova IA, Richkova OA, Kuzmicheva KP, Grakhova MA, Yudina NB, Orlova EA, Selezneva OS, Piskunova SG, Samofalova TV, Bukina TV, Pechkurova AD, Migacheva N, Zhestkov A, Barmina EV, Parfenova NA, Isakova SN, Averina EV, Sazonova IV, Starikova SY, Shilova TV, Asekretova TV, Suprun RN, Kleshchenko EI, Lebedev VV, Demikhova EV, Demikhov VG, Kalinkina VA, Gorenkova AV, Duryagina SN, Pavlova TB, Shinkareva VM, Smoleva IV, Aleksandrova TP, Bambaeva ZV, Philippova MA, Gracheva EM, Tcyvkina GI, Efremenkov AV, Mashkovskaya D, Yarovaya IV, Alekseenko VA, Fisyun IV, Molokova GV, Troitskya EV, Piatkina LI, Vlasova EV, Ukhanova O, Chernishova EG, Vasilieva M, Laba OM, Volodina E, Safonova EV, Voronin KA, Gurkina MV, Rumyantsev AG, Novichkova GA, Shcherbina AY

Abstract
Introduction: Primary immunodeficiencies (PID) are a group of rare genetic disorders with a multitude of clinical symptoms. Characterization of epidemiological and clinical data via national registries has proven to be a valuable tool of studying these diseases. Materials and Methods: The Russian PID registry was set up in 2017, by the National Association of Experts in PID (NAEPID). It is a secure, internet-based database that includes detailed clinical, laboratory, and therapeutic data on PID patients of all ages. Results: The registry contained information on 2,728 patients (60% males, 40% females), from all Federal Districts of the Russian Federation. 1,851/2,728 (68%) were alive, 1,426/1,851 (77%) were children and 425/1,851 (23%) were adults. PID was diagnosed before the age of 18 in 2,192 patients (88%). Antibody defects (699; 26%) and syndromic PID (591; 22%) were the most common groups of PID. The minimum overall PID prevalence in the Russian population was 1.3:100,000 people; the estimated PID birth rate is 5.7 per 100,000 live births. The number of newly diagnosed patients per year increased dramatically, reaching the maximum of 331 patients in 2018. The overall mortality rate was 9.8%. Genetic testing has been performed in 1,740 patients and genetic defects were identified in 1,344 of them (77.2%). The median diagnostic delay was 2 years; this varied from 4 months to 11 years, depending on the PID category. The shortest time to diagnosis was noted in the combined PIDs-in WAS, DGS, and CGD. The longest delay was observed in AT, NBS, and in the most prevalent adult PID: HAE and CVID. Of the patients, 1,622 had symptomatic treatment information: 843 (52%) received IG treatment, mainly IVIG (96%), and 414 (25%) patients were treated with biological drugs. HSCT has been performed in 342/2,728 (16%) patients, of whom 67% are currently alive, 17% deceased, and 16% lost to follow-up. Three patients underwent gene therapy for WAS; all are currently alive. Conclusions: Here, we describe our first analysis of the epidemiological features of PID in Russia, allowing us to highlight the main challenges around PID diagnosis and treatment.

PMID: 32849507 [PubMed – in process]

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When Actin is Not Actin’ Like It Should: A New Category of Distinct Primary Immunodeficiency Disorders.

J Innate Immun. 2020 Aug 26;:1-23

Authors: Sprenkeler EGG, Webbers SDS, Kuijpers TW

Abstract
An increasing number of primary immunodeficiencies (PIDs) have been identified over the last decade, which are caused by deleterious mutations in genes encoding for proteins involved in actin cytoskeleton regulation. These mutations primarily affect hematopoietic cells and lead to defective function of immune cells, such as impaired motility, signaling, proliferative capacity, and defective antimicrobial host defense. Here, we review several of these immunological “actinopathies” and cover both clinical aspects, as well as cellular mechanisms of these PIDs. We focus in particular on the effect of these mutations on human neutrophil function.

PMID: 32846417 [PubMed – as supplied by publisher]

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Treatment and management of primary antibody deficiency: German interdisciplinary evidence-based consensus guideline.

Eur J Immunol. 2020 Aug 26;:

Authors: Hanitsch L, Baumann U, Boztug K, Burkhard-Meier U, Fasshauer M, Habermehl P, Hauck F, Klock G, Liese J, Meyer O, Müller R, Pachlopnik-Schmid J, Pfeiffer-Kascha D, Warnatz K, Wehr C, Wittke K, Niehues T, von Bernuth H

Abstract
This evidence-based clinical guideline provides consensus-recommendations for the treatment and care of patients with primary antibody deficiencies (PADs). The guideline group comprised 20 clinical and scientific expert associations of the German, Swiss and Austrian healthcare system and representatives of patients. Recommendations were based on results of a systematic literature search, data extraction, evaluation of methodology and study quality in combination with the clinical expertise of the respective representatives. Consensus-based recommendations were determined via nominal group technique. PADs are the largest clinically relevant group of primary immunodeficiencies. Most patients with PADs present with increased susceptibility to infections, however immune dysregulation,autoimmunity and cancer affect a significant number of patients and may precede infections. This guideline therefore covers interdisciplinary clinical and therapeutic aspects of infectious (e.g. antibiotic prophylaxis, management of bronchiectasis) and non-infectious manifestations (e.g. management of granulomatous disease, immune cytopenia). PADs are grouped into disease entities with definitive, probable, possible or unlikely benefit of IgG-replacement therapy. Summary and consensus-recommendations are provided for treatment indication, dosing, application forms and adverse events of IgG-replacement therapy. Special aspects of concomitant impaired T-cell function are highlighted as well as clinical data on selected monogenetic inborn errors of immunity formerly classified into PADs (APDS, CTLA-4- and LRBA-deficiency). This article is protected by copyright. All rights reserved.

PMID: 32845010 [PubMed – as supplied by publisher]

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Increased respiratory viral detection and symptom burden among patients with primary antibody deficiency: results from the BIPAD study.

J Allergy Clin Immunol Pract. 2020 Aug 22;:

Authors: Ponsford M, Price C, Farewell D, Greene G, Moore C, Perry M, Price N, Cottrell S, Steven R, El-Shanawany T, Carne E, Cousins R, Williams P, Schaub A, Vonarburg C, Jolles S

Abstract
BACKGROUND: Patients with primary antibody deficiency (PAD) are at increased risk of respiratory tract infections but our understanding of their nature and consequences remains limited.
OBJECTIVE: To define the symptomatic and microbial burden of upper airway infection in adults with PAD relative to age-matched controls.
METHODS: Prospective 12-month observational study consisting of a daily upper and lower airway symptom score alongside fortnightly nasal swab with molecular detection of 19 pathogen targets.
RESULTS: 44 patients and 42 controls (including 34 household pairs) were recruited, providing over 22,500 days of symptom scores and 1,496 nasal swabs. Swab and questionnaire compliance exceeded 70%. At enrolment, 64% of patients received prophylactic antibiotics with a 34% prevalence of bronchiectasis. On average, PAD patients experienced symptomatic respiratory exacerbations every 6 days compared to 6 weeks for controls, associated with significant impairment of respiratory-specific quality of life scores. Viral detections were associated with worsening of symptom scores from a participant’s baseline. PAD patients had increased odds ratio (OR) for pathogen detection, particularly viral (OR 2.73; 95% CI: 2.09 to 3.57), specifically human rhinovirus HRV (OR 3.60; 2.53-5.13), and parainfluenza (OR 3.06; 1.25-7.50). H. influenzae and S. pneumonia were also more frequent in PAD. Young child exposure, IgM deficiency, and presence of bronchiectasis were independent risk factors for viral detection. Prophylactic antibiotic use was associated with a lower risk of bacterial detection by PCR.
CONCLUSION: PAD patients have a significant respiratory symptom burden associated with increased viral infection frequency despite immunoglobulin replacement and prophylactic antibiotic use. This highlights a clear need for future therapeutic trials in the PAD-population, and informs future study design.

PMID: 32841749 [PubMed – as supplied by publisher]

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Successful long-term outcome after combined hematopoietic stem cell transplantation and small bowel transplantation: A case report and review of the literature.

Pediatr Transplant. 2019 11;23(7):e13563

Authors: Na S, Saldana BD, Peredo-Pinto H, Gonzalez CE, Kroemer AH, Hawksworth J, Matsumoto CS, Yazigi N, Kaufman S, Fishbein TM, Khan K

Abstract
Combining HSCT with SOT is an unusual and challenging undertaking given the complexities of immune modulation, the need to balance comorbidities, and the cumulative potential for complications. Early life-threatening complications include infections and related effects, graft rejection, and GVHD can be expected to be increased especially if the HSCT is indicated for high-risk cases such as individuals with severe combined immune deficiency and SOT that includes an intestine graft. Herein, we report such a case. Our patient is unique as a long-term survivor. We review the literature and the features of our case, especially the timing of transplants and human leukocyte antigen matching for HSCT that resulted in a successful outcome and discuss how this may be applied to others in the future.

PMID: 31471935 [PubMed – indexed for MEDLINE]

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Allogeneic hematopoietic stem cell and liver transplantation in a young girl with dedicator of cytokinesis 8 protein deficiency.

Pediatr Transplant. 2019 11;23(7):e13545

Authors: Kuloglu Z, Balcı D, Haskoloğlu ZŞ, Kendirli T, Bingöl-Koloğlu M, Tuna-Kırsaçlıoğlu C, Bal S, Selbuz S, Kırımker O, Savaş B, Altuntaş C, Güner ŞN, Can ÖS, Karayalçın K, Doğu F, Kansu Tanca A, İkincioğulları A

Abstract
DOCK8 deficiency is a rare inherited combined immunodeficiency, caused by mutations in the DOCK8 gene. We describe a case with DOCK8 deficiency associated with severe CLD in whom orthotopic LT was performed successfully after allogeneic HSCT. A 5 year-old girl with DOCK8 deficiency presented with mild direct hyperbilirubinemia and abnormal GGT level and without a previous history of jaundice. She had severe growth retardation, hepatosplenomegaly and generalized eczema. Progressive worsening of CLD was observed within 4 months. Investigations for etiology of liver disease were negative. Liver biopsy showed bridging necrosis, cholestasis and, cirrhosis. Recurrent immune hemolytic crisis and several viral infections developed in follow-up. She underwent whole cadaveric LT for end-stage liver disease (ESLD) 1 year after allogenic HSCT from a full matched related donor. The postoperative course was uneventful. The patient is alive with normal liver function and moderate skin graft versus host disease for 36 months after LT. In conclusion DOCK8 deficiency can be associated with severe CLD. Successful LT following HSCT is possible in patients with ESLD in DOCK8 deficiency. The timing of LT is challenging in patients requiring both HSCT and LT since conditioning regimens for HSCT can be highly hepatotoxic and the patients with suboptimal liver function can become decompensated during HSCT.

PMID: 31297914 [PubMed – indexed for MEDLINE]

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