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Epstein-Barr Virus-Positive Primary Central Nervous System Lymphoma in a 40-Year-Old Immunocompetent Patient.

February 23, 2021 By Manish Butte

Epstein-Barr Virus-Positive Primary Central Nervous System Lymphoma in a 40-Year-Old Immunocompetent Patient.

Cureus. 2021 Jan 17;13(1):e12754

Authors: Hajtovic S, Liu C, Diefenbach CM, Placantonakis DG

Abstract
Epstein-Barr virus-positive (EBV+) primary central nervous system lymphoma (PCNSL) is a clinical entity rarely reported in young immunocompetent patients. Here, we present the case of a 40-year-old female with no history of immunosuppression or immunodeficiency, who presented with a ring-enhancing lesion in the right basal ganglia. The tumor generated significant vasogenic edema and mass effect, causing midline shift, symptoms of increased intracranial pressure, and rapidly progressive neurologic dysfunction. She underwent gross total resection of the tumor through a tubular retractor. Her tumor was of the diffuse large B cell lymphoma (DLBCL) subtype of PCNSL and was positive for EBV. No immunodeficiency or extracranial disease was identified. After adjuvant therapy with high-dose methotrexate, rituximab, and temozolomide, she remains disease-free two years after initial presentation. EBV+ PCNSL, although rare in young immunocompetent adults, poses unique clinical challenges and may require surgical intervention in the acute setting in some cases.

PMID: 33614348 [PubMed]

B Cell Dysregulation in Common Variable Immunodeficiency Interstitial Lung Disease.

February 23, 2021 By Manish Butte

B Cell Dysregulation in Common Variable Immunodeficiency Interstitial Lung Disease.

Front Immunol. 2020;11:622114

Authors: Matson EM, Abyazi ML, Bell KA, Hayes KM, Maglione PJ

Abstract
Common variable immunodeficiency (CVID) is the most frequently diagnosed primary antibody deficiency. About half of CVID patients develop chronic non-infectious complications thought to be due to intrinsic immune dysregulation, including autoimmunity, gastrointestinal disease, and interstitial lung disease (ILD). Multiple studies have found ILD to be a significant cause of morbidity and mortality in CVID. Yet, the precise mechanisms underlying this complication in CVID are poorly understood. CVID ILD is marked by profound pulmonary infiltration of both T and B cells as well as granulomatous inflammation in many cases. B cell depletive therapy, whether done as a monotherapy or in combination with another immunosuppressive agent, has become a standard of therapy for CVID ILD. However, CVID is a heterogeneous disorder, as is its lung pathology, and the precise patients that would benefit from B cell depletive therapy, when it should administered, and how long it should be repeated all remain gaps in our knowledge. Moreover, some have ILD recurrence after B cell depletive therapy and the relative importance of B cell biology remains incompletely defined. Developmental and functional abnormalities of B cell compartments observed in CVID ILD and related conditions suggest that imbalance of B cell signaling networks may promote lung disease. Included within these potential mechanisms of disease is B cell activating factor (BAFF), a cytokine that is upregulated by the interferon gamma (IFN-γ):STAT1 signaling axis to potently influence B cell activation and survival. B cell responses to BAFF are shaped by the divergent effects and expression patterns of its three receptors: BAFF receptor (BAFF-R), transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA). Moreover, soluble forms of BAFF-R, TACI, and BCMA exist and may further influence the pathogenesis of ILD. Continued efforts to understand how dysregulated B cell biology promotes ILD development and progression will help close the gap in our understanding of how to best diagnose, define, and manage ILD in CVID.

PMID: 33613556 [PubMed – in process]

Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease.

February 23, 2021 By Manish Butte

Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease.

Front Immunol. 2020;11:574569

Authors: Rozmus J

Abstract
Chronic graft-versus-host disease (GvHD) has become a leading cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT) and can burden patients with devastating and lifelong health effects. Our understanding of the pathogenic mechanisms underlying chronic GvHD remains incomplete and this lack of understanding is reflected by lack of clear therapeutic approaches to steroid refractory disease. Observations predominantly from mouse models and human correlative studies currently support a three phase model for the initiation and development of chronic GvHD: 1) early inflammation and tissue damage triggers the innate immune system. This leads to inflammatory cytokine/chemokine patterns that recruit effector immune cell populations; 2) chronic inflammation causes the loss of central and peripheral tolerance mechanisms leading to emergence of pathogenic B and T cell populations that promote autoimmune and alloimmune reactions; 3) the dysregulated immunity causes altered macrophage polarization, aberrant tissue repair leading to scarring and end organ fibrosis. This model has led to the evaluation of many new therapies aimed at limiting inflammation, targeting dysregulated signaling pathways and restoring tolerance mechanisms. However, chronic GvHD is a multisystem disease with complex clinical phenotypes and it remains unclear as to which cluster of patients will respond best to specific therapeutic strategies. However, it is possible to gain novel insights from immune-related monogenic diseases. These diseases either share common clinical manifestations, replicate steps from the three phase chronic GvHD model or serve as surrogates for perfectly targeted drugs being investigated in chronic GvHD therapy. In this review, we will summarize the evidence from these monogenic immune related diseases that provide insight into pathogenic pathways in chronic GvHD, rationales for current therapies and novel directions for future drug discovery.

PMID: 33613511 [PubMed – in process]

[Acquired angioedema due to C1-inhibitor deficiency: CREAK recommendations for diagnosis and treatment].

February 23, 2021 By Manish Butte

[Acquired angioedema due to C1-inhibitor deficiency: CREAK recommendations for diagnosis and treatment].

Rev Med Interne. 2020 Dec;41(12):838-842

Authors: Gobert D, Bouillet L, Armengol G, Coppo P, Defendi F, Du-Thanh A, Hardy G, Javaud N, Jeandel PY, Launay D, Panayotopoulos V, Pelletier F, Boccon-Gibod I, Fain O

Abstract
Acquired angioedema with C1-inhibitor deficiency is a rare and peculiar entity belonging to the spectrum of bradykinin angioedemas. It usually occurs in subjects over 60 years old, and is mostly associated with a B-cell lymphoid hemopathy or a monoclonal gammopathy. The diagnosis relies on at least one angioedema episode, lasting more than 24 h, and on the decrease of functional C1-inhibitor. Low C1q is observed in 90% of patients, and an anti C1-inhibitor antibody is found in 50% of patients. The treatment of severe attacks relies on icatibant or C1-inhibitor perfusions. Long term prophylaxis in patients with frequent attacks requires treatment of the associated hemopathy if so. In case of idiopathic angioedema, tranexamic acid and danazol may be used, provided that there is-no thrombophilia; as well as rituximab as second-line treatment. Inhibitors of kallikrein still need to be evaluated in this therapeutic indication.

PMID: 32753245 [PubMed – indexed for MEDLINE]

Examining the utility of extended laboratory panel testing in the emergency department for risk stratification of patients with COVID-19: a single-centre retrospective service evaluation.

February 21, 2021 By Manish Butte

Examining the utility of extended laboratory panel testing in the emergency department for risk stratification of patients with COVID-19: a single-centre retrospective service evaluation.

J Clin Pathol. 2021 Feb 19;:

Authors: Ponsford MJ, Burton RJ, Smith L, Khan PY, Andrews R, Cuff S, Tan L, Eberl M, Humphreys IR, Babolhavaeji F, Artemiou A, Pandey M, Jolles SRA, Underwood J

Abstract
BACKGROUND: The role of specific blood tests to predict poor prognosis in patients admitted with infection from SARS-CoV-2 remains uncertain. During the first wave of the global pandemic, an extended laboratory testing panel was integrated into the local pathway to guide triage and healthcare resource utilisation for emergency admissions. We conducted a retrospective service evaluation to determine the utility of extended tests (D-dimer, ferritin, high-sensitivity troponin I, lactate dehydrogenase and procalcitonin) compared with the core panel (full blood count, urea and electrolytes, liver function tests and C reactive protein).
METHODS: Clinical outcomes for adult patients with laboratory-confirmed COVID-19 admitted between 17 March and 30 June 2020 were extracted, alongside costs estimates for individual tests. Prognostic performance was assessed using multivariable logistic regression analysis with 28-day mortality used as the primary endpoint and a composite of 28-day intensive care escalation or mortality for secondary analysis.
RESULTS: From 13 500 emergency attendances, we identified 391 unique adults admitted with COVID-19. Of these, 113 died (29%) and 151 (39%) reached the composite endpoint. ‘Core’ test variables adjusted for age, gender and index of deprivation had a prognostic area under the curve of 0.79 (95% CI 0.67 to 0.91) for mortality and 0.70 (95% CI 0.56 to 0.84) for the composite endpoint. Addition of ‘extended’ test components did not improve on this.
CONCLUSION: Our findings suggest use of the extended laboratory testing panel to risk stratify community-acquired COVID-19 positive patients on admission adds limited prognostic value. We suggest laboratory requesting should be targeted to patients with specific clinical indications.

PMID: 33608408 [PubMed – as supplied by publisher]

PROGRESSION OF PRIMARY SELECTIVE IgM DEFICIENCY TO COMMON VARIABLE IMMUNODEFICIENCY.

February 20, 2021 By Manish Butte

PROGRESSION OF PRIMARY SELECTIVE IgM DEFICIENCY TO COMMON VARIABLE IMMUNODEFICIENCY.

Ann Allergy Asthma Immunol. 2021 Feb 16;:

Authors: Narsai T, Gupta S

PMID: 33607249 [PubMed – as supplied by publisher]

Identification of hub genes and therapeutic drugs in rheumatoid arthritis patients.

February 20, 2021 By Manish Butte

Identification of hub genes and therapeutic drugs in rheumatoid arthritis patients.

Clin Rheumatol. 2021 Feb 18;:

Authors: Wu B, He Y, Yang D, Liu RX

Abstract
OBJECTIVES: Rheumatoid arthritis (RA) is considered a chronic autoimmune inflammatory disease that causes great morbidity and shortens life expectancy; however, the precise pathogenesis of RA remains unclear. This study aimed to select hub genes correlated with the development of RA.
METHODS: Two gene expression profiles, GSE55235 and GSE12021, obtained from the Gene Expression Omnibus (GEO) were used to identify differentially expressed genes (DEGs) in control and RA samples using GEO2R, followed by other bioinformatics methods, including functional enrichment analysis, protein-protein interaction (PPI) networks, miRNA-hub gene network, and drug-hub gene interactions. In addition, qRT-PCR was finally conducted to confirm the reliability and validity of the expression level of the novel DEGs via freshly collected heparinized blood samples of healthy controls and RA patients.
RESULTS: A sum of 136 upregulated and 37 downregulated DEGs were selected. Functional enrichment analysis indicated that all the upregulated DEGs were correlated with immune response, B cell receptor signalling pathway, and adaptive immune response. KEGG pathway enrichment analysis revealed that the upregulated DEGs were mostly related to cytokine-cytokine receptor interaction, primary immunodeficiency, chemokine signalling pathways, and cell adhesion molecules (CAMs). In total, 12 hub genes (IL15, KLRK1, GZMA, CXCR6, IGHV4-38-2, IGLL5, CXCL13, CXCL11, MS4A1, SDC1, SLAMF1, and PDCD1LG2) were identified and all these hub genes were upregulated, of which IGLL5 and IGHV4-38-2 were first reported to be correlated with the pathogenic mechanism and prognosis of RA. Furthermore, we also used qRT-PCR to validate the overexpression of IGLL5 and IGHV4-38-2 in RA patients compared to the healthy controls. In the miRNA-hub gene network, hsa-miR-1185-5p and hsa-miR-3679-5p might inhibit the expression of IGLL5 during the progression of RA. The 15 most promising candidate drugs, which were all approved by the Food and Drug Administration, may assist with the treatment of RA.
CONCLUSIONS: Overall, these findings may assist with developing diagnostic, prognostic, and therapeutic biomarkers for RA. Key Points • IGLL5 and IGHV4-38-2 were first reported to be correlated with the pathogenic mechanism and prognosis of RA. • Besides, hsa-miR-1185-5p and hsa-miR-3679-5p may inhibit the expression of IGLL5 during the progression of RA.

PMID: 33604823 [PubMed – as supplied by publisher]

Primary immunodeficiency from B-cell defect: a case series of 6 patients seen in a national tertiary hospital in the Philippines.

February 20, 2021 By Manish Butte

Primary immunodeficiency from B-cell defect: a case series of 6 patients seen in a national tertiary hospital in the Philippines.

Asia Pac Allergy. 2021 Jan;11(1):e7

Authors: Tan-Lim CSC, Castor MAR

Abstract
Primary immunodeficiency disorders, although rare, pose a significant burden in the quality of life of afflicted patients and their families. The most common of these disorders are caused by B-cell defects. A total of 6 patients were seen and diagnosed in a national tertiary hospital in the Philippines from 1996 to 2018. These patients were admitted due to various infections, and were subsequently diagnosed to have B-cell defects. Four out of the 6 patients have genetic studies confirming the diagnosis of X-linked agammaglobulinemia. One patient succumbed to sepsis at 10 years of age, while the rest are on follow-up at the Philippine General Hospital for intravenous immunoglobulin infusion.

PMID: 33604277 [PubMed]

SARS-CoV-2 infection associated with hepatitis in an infant with X-linked severe combined immunodeficiency.

February 20, 2021 By Manish Butte

SARS-CoV-2 infection associated with hepatitis in an infant with X-linked severe combined immunodeficiency.

Clin Immunol. 2021 03;224:108662

Authors: van Oers NSC, Hanners NW, Sue PK, Aquino V, Li QZ, Schoggins JW, Wysocki CA

Abstract
X-linked severe combined immunodeficiency (X-SCID) is a disorder of adaptive immunity caused by mutations in the IL-2 receptor common gamma chain gene resulting in deficiencies of T and natural killer cells, coupled with severe dysfunction in B cells. X-SCID is lethal without allogeneic stem cell transplant or gene therapy due to opportunistic infections. An infant with X-SCID became infected with SARS-CoV-2 while awaiting transplant. The patient developed severe hepatitis without the respiratory symptoms typical of COVID-19. He was treated with convalescent plasma, and thereafter was confirmed to have SARS-CoV-2 specific antibodies, as detected with a microfluidic antigen array. After resolution of the hepatitis, he received a haploidentical CD34 selected stem cell transplant, without conditioning, from his father who had recovered from COVID-19. SARS CoV-2 was detected via RT-PCR on nasopharyngeal swabs until 61 days post transplantation. He successfully engrafted donor T and NK cells, and continues to do well clinically.

PMID: 33412294 [PubMed – indexed for MEDLINE]

Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia.

February 20, 2021 By Manish Butte

Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia.

Int J Mol Sci. 2020 Aug 08;21(16):

Authors: Milanesi S, Locati M, Borroni EM

Abstract
Given its pleiotropic functions, including its prominent role in inflammation, immune responses and cancer, the C-X-C chemokine receptor type 4 (CXCR4) has gained significant attention in recent years and has become a relevant target in drug development. Although the signaling properties of CXCR4 have been extensively studied, several aspects deserve deeper investigations. Mutations in the C-term tail of the CXCR4 gene cause WHIM syndrome, a rare congenital immunodeficiency associated by chronic leukopenia. Similar mutations have also been recently identified in 30% of patients affected by Waldenstrom’s macroglobulinaemia, a B-cell neoplasia with bone marrow accumulation of malignant cells. An ample body of work has been generated to define the impact of WHIM mutations on CXCR4 signaling properties and evaluate their role on pathogenesis, diagnosis, and response to therapy, although the identity of disease-causing signaling pathways and their relevance for disease development in different genetic variants are still open questions. This review discusses the current knowledge on biochemical properties of CXCR4 mutations to identify their prototypic signaling profile potentially useful to highlighting novel opportunities for therapeutic intervention.

PMID: 32784523 [PubMed – indexed for MEDLINE]