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Primary Immunodeficiency Disorders Among North Indian Children.

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Primary Immunodeficiency Disorders Among North Indian Children.

Indian J Pediatr. 2019 Jun 08;:

Authors: Gupta D, Thakral D, Kumar P, Kabra SK, Lodha R, Kumari R, Mohanty SK, Chakraborty S, Bagri N, Mitra DK

Abstract
OBJECTIVES: To report the distribution pattern of various categories of primary immunodeficiency disorders (PIDs) in children from North India, frequency of warning signs and critical parameters for evaluation.
METHODS: In this retrospective study, 528 children below 18 y of age after clinical assessment and presentation suggestive of PID were further screened by immunophenotyping for immune cell markers by flow cytometry.
RESULTS: A total of 120 (23%) children were diagnosed with PID with median age at diagnosis being 2.5 y in males and 3.5 y in females and an average delay in diagnosis from onset of symptoms being approximately 5 y. Chronic lower respiratory tract infections, gastrointestinal symptoms like persistent diarrhea and failure to thrive were amongst the most common warning signs in these patients. PIDs were classified according to the International Union of Immunological Societies’ (IUIS) criteria. The diagnosis of index study subjects included combined humoral and cellular immunodeficiency (29%), phagocytic defects (29%), followed by predominantly antibody deficiency (18%), innate immunity and dysregulation (17%) and other well-defined syndromes (7%). A family history of PID (23%), consanguineous marriage (8%) and previous sibling death (23%) were observed as major clinical predictors/clues for underlying PID. All children received prophylactic antibiotics and/or antifungals in addition to specific therapy for underlying immune deficiency.
CONCLUSIONS: The field of PIDs in India remains largely unexplored and we are faced with various challenges in the diagnosis of PIDs due to lack of awareness as well as absence of equipped immunological laboratory support. The authors propose a methodical step-wise laboratory diagnostic approach that can facilitate early diagnosis and timely intervention of these mis/underdiagnosed disorders.

PMID: 31177511 [PubMed – as supplied by publisher]

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Juvenile-Onset Immunodeficiency Secondary to Anti-Interferon-Gamma Autoantibodies.

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Juvenile-Onset Immunodeficiency Secondary to Anti-Interferon-Gamma Autoantibodies.

J Clin Immunol. 2019 Jun 08;:

Authors: Liew WK, Thoon KC, Chong CY, Tan NWH, Cheng DT, Chan BSW, Ng MSY, Das L, Arkachaisri T, Huang CH, Kuan JL, Chai LYA, Koh MJA

Abstract
Immunodeficiency secondary to anti-interferon-gamma (anti-IFN-γ) autoantibodies was first described in 2004 as an acquired defect in the IFN-γ pathway leading to susceptibility to multiple opportunistic infections, including dimorphic fungi, parasites, and bacteria, especially tuberculosis and non-tuberculous mycobacterium (NTM) species. It has so far only been described in adult patients. We present 2 cases of disseminated NTM infections in otherwise immunocompetent children. A 16-year-old girl with Sweet’s syndrome-like neutrophilic dermatosis developed recurrent fever and cervical lymphadenitis secondary to Mycobacterium abscessus. A 10-year-old boy with a history of prolonged fever, aseptic meningitis, aortitis, and arteritis in multiple blood vessels developed thoracic vertebral osteomyelitis secondary to Mycobacterium avium complex. Both patients were found to have positive serum neutralizing anti-IFNγ autoantibodies. Testing for anti-IFNγ autoantibodies should be considered in otherwise healthy immunocompetent hosts with recurrent or disseminated NTM infection. This represents a phenocopy of primary immunodeficiency which has been recently described only in adults. We report the first two cases of this phenomenon to affect children.

PMID: 31177358 [PubMed – as supplied by publisher]

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Immunomodulatory Effect of G2013 (α-L-Guluronic Acid) on the TLR2 and TLR4 in Human Mononuclear Cells.

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Icon for Bentham Science Publishers Ltd. Icon for Bentham Science Publishers Ltd. Related Articles

Immunomodulatory Effect of G2013 (α-L-Guluronic Acid) on the TLR2 and TLR4 in Human Mononuclear Cells.

Curr Drug Discov Technol. 2018;15(2):123-131

Authors: Sharifi L, Mohsenzadegan M, Aghamohammadi A, Rezaei N, Zavareh FT, Bokaie S, Moshiri M, Aghazadeh Z, Norouzbabaie Z, Azizi G, Mirshafiey A

Abstract
BACKGROUND: Inhibition of Toll-like receptors (TLRs) signaling has been established as a new method for the development of anti-inflammatory drugs instead of NSAIDs (non-steroid anti-inflammatory drugs). Since the immunomodulatory role of G2013 (α-L-Guluronic acid) was reported in some recent experiments, we decided to assess the effects of G2013 on the protein expression of TLR2 and TLR4, their downstream signaling cascade, and the secretion of pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs).
METHODS: After blood sampling from 16 healthy donors, PBMCs were isolated and treated with/without lipopolysaccharide (LPS), lipopolyteichoic acid (LTA), and G2013. Flow cytometry was done for detecting the protein expression of TLR2 and TLR4. MyD88, IκB, Tollip, and NF-κB mRNA expression were assessed by realtime PCR. ELISA was performed for assessing the concentration of IL-1β and IL-6.
RESULTS: G2013 at a concentration of 25 µg/mL (high dose) significantly downregulated NF-κB, IκB and MyD88 mRNA expression and suppressed the secretion of IL-1β by PBMCs. The findings indicate that G2013 may exert its regulatory effect under normal condition via Tollip in a dose dependence pathway. Our results demonstrated that G2013 had no profound impact on the protein expression of TLR2 and TLR4.
CONCLUSION: In conclusion, our findings point to the immunomodulatory effect of G2013 on the TLR2 and TLR4 signaling cascade and cytokine production by PBMCs. These findings could lead to an establishment of new safe anti-inflammatory drugs in the future.

PMID: 28578651 [PubMed – indexed for MEDLINE]

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A First Unexplained Invasive Encapsulated Bacterial Infection in Young Adults is Associated with High Mortality and Readmission Rates.

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A First Unexplained Invasive Encapsulated Bacterial Infection in Young Adults is Associated with High Mortality and Readmission Rates.

Clin Infect Dis. 2019 Jun 03;:

Authors: Jackson N, Sutton T, Bedford L, Ugrinovic S, Kumararatne D, Gkrania-Klotsas E

Abstract
We find that patients under the age of 40 with a first invasive encapsulated bacterial infection have a high likelihood of death or readmission in the following 23 months. It is imperative to highlight these individuals for immunological screening to enable initiation of risk-reducing prophylactic interventions and treatment.

PMID: 31157862 [PubMed – as supplied by publisher]

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Liver stiffness assessment by transient elastography suggests high prevalence of liver involvement in common variable immunodeficiency.

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Liver stiffness assessment by transient elastography suggests high prevalence of liver involvement in common variable immunodeficiency.

Dig Liver Dis. 2019 May 30;:

Authors: Crescenzi L, Pecoraro A, Fiorentino A, Poto R, Varricchi G, Rispo A, Morisco F, Spadaro G

Abstract
BACKGROUND: Up to 50% of patients with common variable immunodeficiency (CVID) present persistently increased serum levels of liver enzymes and/or mild hepatomegaly. Ultrasound-based transient elastography (TE) is largely used for early detection of the progression of chronic liver diseases, but has never been employed in CVID. We performed a cross-sectional study to evaluate TE values in a cohort of adult CVID-patients.
METHODS: Full blood count, liver function test, liver and spleen sonogram and ultrasound-based TE were performed in 77 adult CVID patients. Demographic and clinical data were retrospectively collected from medical files.
RESULTS: 33.8% (26/77) patients presented increased TE values ranging from moderate fibrosis to cirrhosis. TE values were positively correlated with ALP, γGT, spleen longitudinal diameter and peripheral blood counts (no significant correlation with BMI, AST, ALT, total proteins, albumin, bilirubin and hemoglobin). Moreover, liver stiffness was higher in patients with the clinical phenotypes polyclonal lymphoproliferation and enteropathy, and patients with both these complications had an increased risk (OR: 7.14) of presenting pathologic TE values compared with those without anyone of these.
CONCLUSIONS: Transient elastography is a useful tool to be used alongside clinical and laboratory data to assess liver involvement in CVID.

PMID: 31155490 [PubMed – as supplied by publisher]

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Targeted screening for primary immunodeficiency disorders in the neonatal period and early infancy.

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Targeted screening for primary immunodeficiency disorders in the neonatal period and early infancy.

Afr Health Sci. 2019 Mar;19(1):1449-1459

Authors: Galal N, Ohida M, Meshaal S, Elaziz DA, Elhawary I

Abstract
Background: Primary immunodeficiency diseases (PID) comprise a group of more than 300 diseases that affect development and /or function of the immune system.
Objectives: The aim of this study was diagnosis of PID among a suspected group of neonates and infants within the first six months of life as well as identifying the warning signs of PID characteristic to this period.
Method: Fifty neonates presenting with warning signs of PID were enrolled in the study.
Results: The study revealed that twenty six patients (52%) were diagnosed with Primary Immunodeficiency, T cell/combined immunodeficiency were noted as the most common PID class (88.5%) with fourteen T-B-SCID patients (70%) and six T-B+ SCID patients (30%), phagocytic disorders were estimated to be 7.7% while 3.8% were unclassified immunodeficiency. The mean age of presentation for PID group was 1.42±1.38 months with a diagnostic lag of 3.08±1.78 months. Consanguinity was positive in 76.9% of the PID group. Lower respiratory tract infections, persistent fungal infections and lymphopenia were the most significant warning signs for diagnosing PID with a p value of (0.01). Combined, lower respiratory tract infections, fungal infections and lymphopenia were 12.3 times more likely to be associated with PID.
Conclusion: Focused screening in high risk neonates proved to be a valuable tool for diagnosis of PID disorders.

PMID: 31148972 [PubMed – in process]

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Patient-derived Orthotopic Xenograft Models for Human Urothelial Cell Carcinoma and Colorectal Cancer Tumor Growth and Spontaneous Metastasis.

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Patient-derived Orthotopic Xenograft Models for Human Urothelial Cell Carcinoma and Colorectal Cancer Tumor Growth and Spontaneous Metastasis.

J Vis Exp. 2019 May 12;(147):

Authors: Moret R, Hellmers L, Zhang X, Gills J, Hite N, Klinger A, Maresh GA, Canter D, Bardot S, Margolin DA, Li L

Abstract
Cancer patients have poor prognoses when lymph node (LN) involvement is present in both high-grade urothelial cell carcinoma (HG-UCC) of the bladder and colorectal cancer (CRC). More than 50% of patients with muscle-invasive UCC, despite curative therapy for clinically-localized disease, will develop metastases and die within 5 years, and metastatic CRC is a leading cause of cancer-related deaths in the US. Xenograft models that consistently mimic UCC and CRC metastasis seen in patients are needed. This study aims to generate patient-derived orthotopic xenograft (PDOX) models of UCC and CRC for primary tumor growth and spontaneous metastases under the influence of LN stromal cells mimicking the progression of human metastatic diseases for drug screening. Fresh UCC and CRC tumors were obtained from consented patients undergoing resection for HG-UCC and colorectal adenocarcinoma, respectively. Co-inoculated with LN stromal cell (LNSC) analog HK cells, luciferase-tagged UCC cells were intra-vesically (IB) instilled into female non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, and CRC cells were intra-rectally (IR) injected into male NOD/SCID mice. Tumor growth and metastasis were monitored weekly using bioluminescence imaging (BLI). Upon sacrifice, primary tumors and mouse organs were harvested, weighed, and formalin-fixed for Hematoxylin and Eosin and immunohistochemistry staining. In our unique PDOX models, xenograft tumors resemble patient pre-implantation tumors. In the presence of HK cells, both models have high tumor implantation rates measured by BLI and tumor weights, 83.3% for UCC and 96.9% for CRC, and high distant organ metastasis rates (33.3% detected liver or lung metastasis for UCC and 53.1% for CRC). In addition, both models have zero mortality from the procedure. We have established unique, reproducible PDOX models for human HG-UCC and CRC, which allow for tumor formation, growth, and metastasis studies. With these models, testing of novel therapeutic drugs can be performed efficiently and in a clinically-mimetic manner.

PMID: 31132059 [PubMed – in process]

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