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Health-Related Quality of Life and Emotional Difficulties in Chronic Granulomatous Disease: Data on Adult and Pediatric Patients from Italian Network for Primary Immunodeficiency (IPINet).

J Clin Immunol. 2019 Dec 20;:

Authors: Pulvirenti F, Sangerardi M, Plebani A, Soresina A, Finocchi A, Pignata C, Cirillo E, Trizzino A, Aiuti A, Migliavacca M, Locatelli F, Bertaina A, Naviglio S, Carrabba M, De Carli M, Barbaro MGF, Gattorno M, Quinti I, Martire B

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections, inflammation, and autoimmunity with an impact on health-related quality of life (HRQoL). Few data are available for children, whereas no study has been conducted in adults. Here, we investigated HRQoL and emotional functioning of 19 children and 28 adults enrolled in Italian registry for CGD. PEDsQL and SDQ were used for children and their caregivers, and adults completed the SF-12 questionnaire. Mean scores were compared with norms and with patients affected by chronic diseases. Comparisons were made for CGD patients who underwent or not hematopoietic stem cell transplantation (HSCT). When compared with norms, CGD children exhibited higher difficulties in social/school areas, peer relationship, and conduct/emotional problems (< 5 years of age), as scored by proxies. Differently, CGD adults reported higher difficulties both in mental and physical area than norms. Only for children, clinical status had a damaging effect on psychosocial and school dimensions, whereas age had a negative impact on social areas. No significant difference was observed between patients treated or not with HSCT. When compared with patients affected by chronic diseases, CGD children and adults both displayed fewer physical disabilities. Differently, in mental scale adults scored lower than those with rheumatology diseases and had similar impairment in comparison with patients with diabetes mellitus and cancer. This study emphasized the impact of CGD on HRQoL since infancy and its decline in adulthood, with emotional difficulties occurring early. HRQoL impairment should be considered in clinical picture of CGD and pro-actively assessed and managed by clinicians.

PMID: 31863244 [PubMed – as supplied by publisher]

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Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B cell activation.

J Allergy Clin Immunol. 2019 Dec 17;:

Authors: Chou J, Alazami AM, Jaber F, Hoyos-Bachiloglu R, Jones J, Weeks S, Alosaimi MF, Bainter W, Cangemi B, Badran YR, Mohammed R, Alroqi F, Almutairi A, Al-Onazi N, AlAjaji S, Al-Saud B, Arnaout R, Elkins M, Devana S, Imperial J, Li B, Drexhage L, Abdel Rahman AM, Jacob M, Haddad H, Hanna-Wakim R, Dbaibo G, Massaad MJ, Dasouki M, Mikhael R, Baz Z, Geha RS, Al-Mousa H

Abstract
BACKGROUND: AK2 encodes the phosphotransferase adenylate kinase 2 (AK2). Human variants in AK2 cause reticular dysgenesis, a severe combined immunodeficiency with agranulocytosis, lymphopenia, and sensorineural deafness that requires hematopoietic stem cell transplantation for survival.
OBJECTIVE: We investigated the mechanisms underlying recurrent sino-pulmonary infections and hypogammaglobulinemia in 15 patients, ranging from three to 34 years of age, from nine kindreds. Only two patients, both of whom had mildly impaired T cell proliferation, each had a single clinically significant opportunistic infection.
METHODS: Patient cells were studied with next-generation DNA sequencing, tandem mass spectrometry, and assays of lymphocyte and mitochondrial function.
RESULTS: We identified two different homozygous variants in AK2. AK2G100S and AK2A182D permit residual protein expression, enzymatic activity, and normal numbers of neutrophils and lymphocytes. All but one patient have intact hearing. The patients’ B cells had severely impaired proliferation and in vitro immunoglobulin secretion. With activation, the patients’ B cells exhibit defective mitochondrial respiration and impaired regulation of mitochondrial membrane potential and quality. Although activated T cells from the patients with opportunistic infections demonstrated impaired mitochondrial function, the mitochondrial quality in T cells was preserved. Consistent with the capacity of activated T cells to utilize non-mitochondrial metabolism, these findings reveal a less strict cellular dependence of T cell function on AK2 activity. Chemical inhibition of ATP synthesis in control T and B cells similarly demonstrated the greater dependency of B cells on mitochondrial function.
CONCLUSIONS: Our patients demonstrate the in vivo sequelae of the cell-specific requirements for the functions of AK2 and mitochondria, particularly in B cell activation and antibody production.

PMID: 31862378 [PubMed – as supplied by publisher]

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The influence of clinical features mimicking primary immunodeficiency diseases (mPID) on children with Langerhans cell histiocytosis (LCH) – Four with mPID among 39 LCH children from one referral center during 18-year period.

Immunobiology. 2019 Nov 27;:151877

Authors: Lin SC, Lee WI, Jaing TH, Yang CP, Hung IJ, Chang TY, Huang JL, Chen LC, Ou LS, Yao TC, Chen SH

Abstract
BACKGROUND: Recurrent or refractory infections can be a warning sign of primary immunodeficiency diseases (PID). Such mimicking PID (mPID) can occur in patients with Langerhans cell histiocytosis (LCH). Because some cases with refractory molluscum contagiosum-like lesions and persistent otorrhea are finally diagnosed with LCH, we wondered whether such mPID can occur in LCH children and affect on their prognosis.
METHODS: We retrospectively reviewed all children with LCH at our institute from 2001 to 2018. A complete medical review of sex, age, symptoms, treatment course, and outcome comparison was performed.
RESULTS: Of 39 enrolled LCH patients, three had persistent otorrhea and one had refractory molluscum contagiosum-like lesions despite aggressive antibiotic therapy. These four cases with mPID had significantly higher rates of multi-system involvement, recurrence and 5-month more lag time, but no risk organ (liver, spleen and bone marrow) involvement compared to those without mPID, although bone and skin were the most involved in both groups. Overall, the lag-time in multi-system was longer than that in single-system involvement (median 2.5 vs. 1.0 months; p = 0.003). The diagnosis-age of risk organ involvement was younger than those without (median 8 vs. 43 months; p = 0.004). There were no significant differences in diagnosis-age, single/multi-system and risk organ involvement between remission and recurrence groups. All were alive excluding four who were lost to follow-up.
CONCLUSIONS: The LCH children with mPID had greater lag time, multi-system involvement, recurrence and more refractory treatment including transplantation despite the ratio of bone and skin lesions equal to those without mPID.

PMID: 31862125 [PubMed – as supplied by publisher]

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Herpes simplex virus type 2 meningitis as a manifestation of Good’s syndrome.

J Neurovirol. 2019 Dec 19;:

Authors: Matta L, Ramírez-Velasco MC, Zea-Vera AF

Abstract
Good’s syndrome is a primary immunodeficiency phenocopy characterized for thymoma and immunodeficiency. The most frequent clinical presentation is recurrent or opportunistic infections, hematological alterations, and chronic diarrhea. We treated a 66-year-old man who consulted for 5 days of headache and diplopia with right sixth cranial nerve palsy at examination. Patient reported chronic diarrhea and prolonged febrile syndrome accompanied by weight loss of 23 kg in the last year. Exhaustive evaluation revealed Herpes simplex virus (HSV) type 2 meningitis, eosinophilic colitis, and type A thymoma. Severe antibody deficiency (hypogammaglobulinemia) associated with thymoma confirmed the diagnosis of Good’s syndrome.

PMID: 31858482 [PubMed – as supplied by publisher]

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Expanding Clinical Phenotype and Novel Insights into the Pathogenesis of ICOS Deficiency.

J Clin Immunol. 2019 Dec 20;:

Authors: Abolhassani H, El-Sherbiny YM, Arumugakani G, Carter C, Richards S, Lawless D, Wood P, Buckland M, Heydarzadeh M, Aghamohammadi A, Hambleton S, Hammarström L, Burns SO, Doffinger R, Savic S

Abstract
BACKGROUND: Inducible T cell co-stimulator (ICOS) deficiency has been categorized as a combined immunodeficiency often complicated by enteropathies, autoimmunity, lymphoproliferation, and malignancy. We report seven new patients and four novel ICOS mutations resulting in a common variable immunodeficiency (CVID)-like phenotype and show that dysregulated IL-12 release, reduced cytotoxic T lymphocyte-associated protein 4 (CTLA4) expression, and skewing towards a Th1-dominant phenotype are all associated with inflammatory complications in this condition.
METHODS: A combination of whole exome and Sanger sequencing was used to identify novel mutations. Standard clinical and immunological evaluation was performed. FACS and ELISA-based assays were used to study cytokine responses and ICOS/ICOSL/CTLA4 expression following stimulation of whole blood and PBMCs with multiple TLR ligands, anti-CD3, and PHA.
RESULTS: Four novel ICOS mutations included homozygous c.323_332del, homozygous c.451C>G, and compound heterozygous c.58+1G>A/c.356T>C. The predominant clinical phenotype was that of antibody deficiency associated with inflammatory complications in 4/7 patients. Six out of seven patients were treated with immunoglobulin replacement and one patient died from salmonella sepsis. All patients who were tested showed reduced IL-10 and IL-17 cytokine responses, normal IL-1β, IL6, and TNF release following LPS stimulation and highly elevated IL-12 production in response to combined LPS/IFNγ stimulation. This was associated with skewing of CD4+ T cells towards Th1 phenotype and increased expression of ICOSL on monocytes. Lastly, reduced CTLA4 expression was found in 2 patients. One patient treated with ustekinumab for pancytopenia due to granulomatous bone marrow infiltration failed to respond to this targeted therapy.
CONCLUSIONS: ICOS deficiency is associated with defective T cell activation, with simultaneously enhanced stimulation of monocytes. The latter is likely to result from a lack of ICOS/ICOSL interaction which might be necessary to provide negative feedback which limits monocytes activation.

PMID: 31858365 [PubMed – as supplied by publisher]

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Structural non-infectious manifestations of the central nervous system in common variable immunodeficiency disorders.

J Allergy Clin Immunol Pract. 2019 Dec 16;:

Authors: van de Ven A, Mader I, Wolff D, Goldacker S, Fuhrer H, Rauer S, Grimbacher B, Warnatz K

Abstract
BACKGROUND: Central nervous system (CNS) disease in adult common variable immunodeficiency (CVID) is rare and therefore diagnostic and therapeutic protocols are lacking.
OBJECTIVE: To provide clinical information aiming to establish awareness and first experience-based recommendations.
METHODS: We reviewed clinical manifestations, genetic and immunological characteristics, diagnostic evaluation and treatment of CVID patients with abnormal magnetic resonance imaging (MRI) of the CNS disease in our cohort.
RESULTS: Seventeen patients with CNS manifestation and a previous diagnosis of CVID were identified. Presenting symptoms of the CNS disease included loss of sensory or motoric function, headache or epilepsy. Contrast-enhancing lesions of the brain or solely the spinal cord were the most common findings on MRI. The prevalence of splenomegaly, lymphadenopathy, interstitial lung disease and autoimmune cytopenia was significantly increased compared to control CVID patients. In eight patients, a molecular defect was identified, including mutations in CTLA4, NFKB1 and CECR1. CVID patients with CNS involvement generally displayed lymphopenia, skewed CD4+ T-cell subsets and increased proportions of CD21low B cells in the peripheral blood. CNS involvement usually responded well to high-dose steroids, but regularly required maintenance therapy in order to prevent relapse.
CONCLUSION: CNS disease is a severe but rare complication in CVID disorders, particularly affecting patients with other non-infectious disease symptoms. Diagnostic evaluation needs to rule out infectious causes by all means; a genetic evaluation is recommended given the high probability of an underlying monogenic disorder. Possible treatment consists of steroids with yet to be determined optimal maintenance therapy in case of relapse.

PMID: 31857261 [PubMed – as supplied by publisher]

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Erythropoiesis defect observed in STAT3 GOF patients with severe anaemia.

J Allergy Clin Immunol. 2019 Dec 16;:

Authors: Mauracher AA, Eekels JJ, Woytschak J, van Drogen A, Bosch A, Prader S, Felber M, Heeg M, Opitz L, Trück J, Schroeder S, Adank E, Klocperk A, Haralambieva E, Zimmermann D, Tantou S, Kotsonis K, Stergiou A, Kanariou MG, Ehl S, Boyman O, Sediva A, Renella R, Schmugge M, Vavassori S, Schmid JP

Abstract
STAT3 mediates inflammation and modulates immunity. We found that in addition to its role in autoimmunity, over-activated STAT3 interferes in early erythro-myeloid precursor development and reduces commitment towards the erythroid lineage by interfering with the erythropoietin-STAT5 signalling pathway.

PMID: 31857100 [PubMed – as supplied by publisher]

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Tuberculous Meningitis: Immunocompetence, Secondary Immunodeficiency, or Adult Onset Primary Immunodeficiency?

Am J Trop Med Hyg. 2019 Nov;101(5):1183

Authors: Zea-Vera AF

PMID: 31854958 [PubMed – as supplied by publisher]

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