Manish Butte

Int J Neonatal Screen. 2021 Jul 12;7(3):42. doi: 10.3390/ijns7030042.

ABSTRACT

After it was demonstrated in 2005 that T cell receptor excision circle (TREC) quantification for dried blood spot (DBS) samples on Guthrie cards is an effective means of SCID screening and following several pilot studies, the practice was formally recommended in the US in 2010. More and more countries have adopted it since then. In France, before the health authorities could recommend adding SCID to the list of five diseases that were routinely screened for, feasibility and cost-effectiveness studies had to be conducted with a sufficiently large cohort of neonates. We carried out three such studies: The first sought to verify the effectiveness of the assay. The second, DEPISTREC, evaluated the feasibility of universal SCID screening in France and assessed the clinical benefit and economic advantage it would provide. Through the third study, NeoSKID, still under way and to continue until recommendations are issued, we have been offering SCID screening in the Pays de la Loire region of France. This review briefly describes routine newborn screening (NBS) and management of primary immunodeficiency diseases (PIDs) in France, and then considers the lessons from our studies and the status of SCID screening implementation within the country.

PMID:34287257 | DOI:10.3390/ijns7030042

Health Psychol Behav Med. 2021 Jul 6;9(1):619-635. doi: 10.1080/21642850.2021.1948416. eCollection 2021.

ABSTRACT

PURPOSE: The Health state descriptive system includes standardized self-administered instruments for measuring Health-Related Quality of Life (HRQoL) respectively among adolescents, and children. The objectives of the current study were: (1) to translate and adapt the pediatric-adolescent version 16D and 17D from English into French (Canada), (2) to demonstrate their feasibility in pediatric conditions.

METHODS: The translation methodology combined forward and back translations, and cognitive debriefing with eight adolescents and eight children. Four bilingual translators were involved in the process. We administered the translated versions to two clinical samples, being treated for Primary immunodeficiency (PID, n = 48, aged 14.1 years, 20 girls), and having recovered from pediatric Acute Lymphoblastic Leukemia (ALL, n = 153, aged 14.7 years, 77 girls).

RESULTS: Cognitive debriefing indicated that that the instructions, items, and response options were clear, easy to understand, and easy to answer. Adjustments were made for clarity. Translated versions were highly usable (measurement completion >90%). HRQoL levels were high for both samples (range 0.85-0.96). Participants reported lower levels if they were adolescents, particularly if they were girls. Older boys with PID reported a lower HRQoL than their counterparts with a history of ALL. PID and ALL patients mainly reported issues with discomfort and pain, concentration/learning, physical appearance, and psychological distress and sleeping, although to a different degree.

CONCLUSION: The French-language versions of the 16D and 17D are easy to administer and may be used to identify problematic domains. Greater availability of translated versions of short evaluation tools may facilitate broader uptake of screening practices in pediatric care.

PMID:34285826 | PMC:PMC8266233 | DOI:10.1080/21642850.2021.1948416

Cell Death Dis. 2021 Jul 20;12(8):717. doi: 10.1038/s41419-021-03999-9.

ABSTRACT

Renal cell carcinoma (RCC) cells have increased lipogenesis and cholesterol synthesis. Sterol regulatory element-binding protein-1 (SREBP1) is cleaved by site 1 protease (S1P) to release the transcriptionally active amino-terminal domain. PF-429242 is a potent and competitive S1P inhibitor. We here tested its activity in RCC cells. In established and primary human RCC cells, PF-429242 potently inhibited cell proliferation, migration, and invasion. The S1P inhibitor provoked apoptosis activation in RCC cells. Furthermore, shRNA-mediated S1P silencing or CRISPR/Cas9-induced S1P knockout led to RCC cell growth inhibition and apoptosis activation. Conversely, ectopic overexpression of SREBP1 or S1P augmented RCC cell proliferation and migration. Daily i.v. injection of a single dose of PF-429242 robustly inhibited RCC xenograft growth in severe combined immunodeficiency mice. Additionally, intratumoral injection of S1P shRNA lentivirus inhibited RCC xenograft growth in mice. SREBP1, S1P, and its target gene low density lipoprotein receptor (LDLR) were significantly elevated in human RCC tissues. These results suggest that targeting S1P by PF-429242 inhibited RCC cell growth in vitro and in vivo.

PMID:34285190 | DOI:10.1038/s41419-021-03999-9

J Feline Med Surg. 2021 Jul 21:1098612X211028837. doi: 10.1177/1098612X211028837. Online ahead of print.

ABSTRACT

OBJECTIVES: The primary goal of this study was to characterize the clinical presentation of feline cutaneous lymphoma. The secondary aims included determining if treatment or initial response to treatment affected the overall survival of patients, and understanding if disease characteristics such as immunophenotype, cell size or the presence of epitheliotropism influenced response to treatment.

METHODS: Veterinary medical oncologists at four academic veterinary teaching hospitals submitted cases of feline patients with cutaneous lymphoma diagnosed by histopathology or cytology. Signalment, feline leukemia virus (FeLV)/feline immunodeficiency virus (FIV) status, physical examination findings, clinical signs, diagnostic tests, therapy, response and outcome, and necropsy findings, when available, were recorded.

RESULTS: Forty-one patients were identified and described. The majority of patients were domestic shorthair cats (n = 29). The median age at diagnosis was 12.3 years. Males were over-represented in the population (n = 30). In the majority of patients (n = 33), the FIV/FeLV status was unknown. Twenty patients were fully staged. Thirty-four patients were treated with a variety of modalities, including surgery, radiation, single-agent or combination chemotherapy, or prednisolone only. In multiple patients, surgery or radiation was combined with a systemic therapy. Of 34 patients treated with some form of therapy, 20 responded (achieving either a partial response or complete remission).

CONCLUSIONS AND RELEVANCE: Clinical signs and physical examination findings varied among patients. Response to therapy appeared to be associated with survival (P = 0.0025); however, this population was highly censored. Immunophenotype, cell size and the presence of epitheliotropism did not influence treatment response. Results were limited by small numbers of patients, heterogeneous disease manifestations and treatment protocols. Further studies are necessary to evaluate the effect of specific treatment modalities and disease subtype on prognosis.

PMID:34284671 | DOI:10.1177/1098612X211028837

mBio. 2021 Jul 20:e0153021. doi: 10.1128/mBio.01530-21. Online ahead of print.

ABSTRACT

Epstein-Barr virus (EBV) is associated with 200,000 cancers annually, including B-cell lymphomas in immunosuppressed hosts. Hypomorphic mutations of the de novo pyrimidine synthesis pathway enzyme cytidine 5′ triphosphate synthase 1 (CTPS1) suppress cell-mediated immunity, resulting in fulminant EBV infection and EBV⁺ central nervous system (CNS) lymphomas. Since CTP is a critical precursor for DNA, RNA, and phospholipid synthesis, this observation raises the question of whether the isozyme CTPS2 or cytidine salvage pathways help meet CTP demand in EBV-infected B cells. Here, we found that EBV upregulated CTPS1 and CTPS2 with distinct kinetics in newly infected B cells. While CRISPR CTPS1 knockout caused DNA damage and proliferation defects in lymphoblastoid cell lines (LCLs), which express the EBV latency III program observed in CNS lymphomas, double CTPS1/2 knockout caused stronger phenotypes. EBNA2, MYC, and noncanonical NF-κB positively regulated CTPS1 expression. CTPS1 depletion impaired EBV lytic DNA synthesis, suggesting that latent EBV may drive pathogenesis with CTPS1 deficiency. Cytidine rescued CTPS1/2 deficiency phenotypes in EBV-transformed LCLs and Burkitt B cells, highlighting CTPS1/2 as a potential therapeutic target for EBV-driven lymphoproliferative disorders. Collectively, our results suggest that CTPS1 and CTPS2 have partially redundant roles in EBV-transformed B cells and provide insights into EBV pathogenesis with CTPS1 deficiency.

PMID:34281398 | DOI:10.1128/mBio.01530-21

Perfusion. 2021 Jul 19:2676591211033946. doi: 10.1177/02676591211033946. Online ahead of print.

ABSTRACT

OBJECTIVE: Extracorporeal Membrane Oxygenation (ECMO) may serve as a life-saving rescue therapy in critically ill children with respiratory failure. While survival rates of ECMO in children with secondary immunodeficiency is considered relatively poor, survival rates in children with primary immunodeficiencies (PID) has yet to be thoroughly investigated.

DESIGN: Retrospective analysis of prospectively collected data from children (29 days-18 years old). PID patients were identified by using International Classification of Diseases (ICD) codes.

SETTING: Data were retrieved from Extracorporeal Life Support Organization Registry (1989-2018).

INTERVENTIONS: ECMO for a pulmonary support indication. The survival-to-discharge rate was calculated and factors influencing outcomes were compared between survivors and non-survivors.

MEASUREMENTS AND MAIN RESULTS: A total of 73 eligible ECMO runs were included. The survival-to-discharge rate in pediatric PID patients was 45.2%. No differences were noted in survival based on type of immunodeficiency (p = 0.42) or decade of support (p = 0.98). There was no difference in the rate of pre-ECMO infection in survivors versus non-survivors (p = 0.69). The survival-to-discharge rate in patients with a culture positive infection during the ECMO run was 45.0% versus 45.3% in those with no infection (p = 0.98). In multivariate analysis, only cardiac complications (OR 5.09, 95% CI: 1.15-22.53), pulmonary complications (OR: 13.00, 95% CI: 1.20-141.25), and neurologic complications (OR: 9.86, 95% CI: 1.64-59.21) were independently associated with increased mortality.

CONCLUSION: Children with a PID who require extracorporeal life support due to respiratory failure have a reasonable chance of survival and should be considered candidates for ECMO. The presence of a pre-ECMO infection should not be considered an ECMO contraindication.

PMID:34278883 | DOI:10.1177/02676591211033946

J Crohns Colitis. 2021 Jul 18:jjab124. doi: 10.1093/ecco-jcc/jjab124. Online ahead of print.

ABSTRACT

BACKGROUND: Hypogammaglobulinemia is a disorder characterized by low serum immunoglobulin levels and had high prevalence of gastrointestinal manifestations. In some cases, clinical and endoscopic features are indistinguishable from those of inflammatory bowel disease (IBD).

METHODS: This was a multicenter case series performed as a part of the European Crohn’s and Colitis Organisation (ECCO) Collaborative Network of Exceptionally Rare case reports (CONFER) project.

RESULTS: This report includes 27 patients with primary hypogammaglobulinemia and IBD-like features [20 males and 7 females, median age 45.6 years (Interquartile range (IQR) 35.2-59]. Crohn’s disease-like features were noted in 23 patients, four patients had ulcerative colitis-like features. The diagnosis of hypogammaglobulinemia preceded IBD-like features diagnosis in 20 patients (median of 7 years prior, IQR 2.6-20.6 years), and followed IBD-like features appearance in 7 cases (median of one year after, IQR 0.45-5.6 years).Hypogammaglobulinemia etiologies were common variable immunodeficiency (66.6%), agammaglobulinemia (7.4%), selective IgA-deficiency (11.1%), Goods syndrome (7.4%), IgG subclass deficiency with IgA deficiency (3.7%) and hyper-IgM (3.7%). In addition to antibiotics and intravenous immunoglobulin (IVIG) for hypogammaglobulinemia, 12 patients received IBD-related treatment including 5-ASA (2 patients), corticosteroids (1 patient), thiopurines (3 patients), anti-TNFs (4 patients) and vedolizumab (2 patients). By the end of the follow-up [44.5 months (IQR 18-81)], 21/27 (77%) patients were in clinical remission.

CONCLUSION: This case series describes IBD-like features in patients with hypogammaglobulinemia. The diagnosis of IBD-like features mainly occurred after that of hypogammaglobulinemia, with successful recovery in the majority of cases after appropriate treatment.

PMID:34274962 | DOI:10.1093/ecco-jcc/jjab124

J Allergy Clin Immunol Pract. 2021 Jul 14:S2213-2198(21)00778-9. doi: 10.1016/j.jaip.2021.06.045. Online ahead of print.

ABSTRACT

Since its outbreak in late December 2019 in Wuhan, COVID-19 pandemic has posed a therapeutic challenge for the world population, with a plenty of clinical pictures and a broad spectrum of severity of the manifestations. In spite of initial speculations on a direct role of primary or acquired immune deficiency in determining a worse disease outcome, recent studies have provided evidence that specific immune defects may either serve as an experimentum naturae entailing this risk or may not be relevant enough to impact the host defense against the virus. Taken together, these observations may help unveil pathogenetic mechanisms of the infection and suggest new therapeutic strategies. Thus, in this review we summarize current knowledge regarding the mechanisms of immune response against SARS-CoV-2 infection and clinical manifestations with a special focus on children and patients presenting with congenital or acquired immune deficiency.

PMID:34273582 | DOI:10.1016/j.jaip.2021.06.045

J Pediatr (Rio J). 2021 Jul 14:S0021-7557(21)00096-6. doi: 10.1016/j.jped.2021.05.011. Online ahead of print.

ABSTRACT

OBJECTIVES: To compare the frequency of hospitalization in children with Inborn Errors of Immunity with antibody deficiency previous to intravenous immunoglobulin (pre- IVIG) with a one-year period after initial IVIG (post-IVIG).

METHODS: Medical reports of 45 patients during an eight-year period were reviewed from 2018 to 2019. Wilcoxon-test was used for related samples.

RESULTS: Forty-five children were included in the study, aged 29-249 months of age, and most of them (64.4%) were males. Median ages at onset symptoms and at diagnosis were 6 and 73 months old, respectively. Specific antibody deficiency and unclassified hypogammaglobulinemia were the predominant diagnoses (31.1% and 17.8%, respectively). X-linked agammaglobulinemia, Hyper IgE syndrome, Hyper IgM, transient hypogammaglobulinemia of infancy, and Common Variable Immunodeficiency (CVID) were also reported, in a low frequency. Forty-four (97.8%) patients were hospitalized before IVIG, and 10 patients (22.2%) after. Annual mean hospital admission reduced from 2.5 to 0.5, pre and post-IVIG, respectively (p < 0.0001). Mean length of stay (LOS) reduced from 71 to 4.7 days/year (p < 0.0001) in general ward and in the PICU from 17.2 days/year to zero (p < 0.0002). Pneumonia was the main cause of hospital admission with a reduction in the number of episodes per patient from an average of 2.2-0.1 per year (p < 0.001). Concomitant use of antibiotic prophylaxis did not influence the number of hospital admission.

CONCLUSION: One-year intravenous IVIG significantly decreased the number of hospitalizations and length of stay in children with impaired antibody production. Social and economic impacts would be required.

PMID:34273274 | DOI:10.1016/j.jped.2021.05.011

Clin Immunol. 2021 Jul 13:108796. doi: 10.1016/j.clim.2021.108796. Online ahead of print.

ABSTRACT

INTRODUCTION: Inherited phagocyte defects are one of the subgroups of primary immunodeficiency diseases (PIDs) with various clinical manifestations. As oral manifestations are common at the early ages, oral practitioners can have a special role in the early diagnosis.

MATERIALS AND METHODS: A comprehensive search was conducted in this systematic review study and data of included studies were categorized into four subgroups of phagocyte defects, including congenital neutropenia, defects of motility, defects of respiratory burst, and other non-lymphoid defects.

RESULTS: Among all phagocyte defects, 12 disorders had reported data for oral manifestations in published articles. A total of 987 cases were included in this study. Periodontitis is one of the most common oral manifestations.

CONCLUSION: There is a need to organize better collaboration between medical doctors and dentists to diagnose and treat patients with phagocyte defects. Regular dental visits and professional oral health care are recommended from the time of the first primary teeth eruption in newborns.

PMID:34271191 | DOI:10.1016/j.clim.2021.108796