J Pediatr. 2020 05;220:193-199
Authors: Grineski S, Morales DX, Collins T, Wilkes J, Bonkowsky JL
Abstract
OBJECTIVE: To examine disparities in the diagnosis of leukodystrophies including geographic factors and access to specialty centers.
STUDY DESIGN: Retrospective cohort study of pediatric patients admitted to Pediatric Health Information System hospitals. Patients with leukodystrophy were identified with International Classification of Diseases, Tenth Revision, Clinical Modification diagnostic codes for any of 4 leukodystrophies (X-linked adrenoleukodystrophy, Hurler disease, Krabbe disease, and metachromatic leukodystrophy). We used 3-level hierarchical generalized logistic modeling to predict diagnosis of a leukodystrophy based on distance traveled for hospital, neighborhood composition, urban/rural context, and access to specialty center.
RESULTS: We identified 501 patients with leukodystrophy. Patients seen at a leukodystrophy center of excellence hospital were 1.73 times more likely to be diagnosed than patients at non-center of excellence hospitals. Patients who traveled farther were more likely to be diagnosed than those who traveled shorter. Patients living in a Health Professionals Shortage Area zip code were 0.86 times less likely to be diagnosed than those living in a non-Health Professionals Shortage Area zip code.
CONCLUSIONS: Geographic factors affect the diagnosis of leukodystrophies in pediatric patients, particularly in regard to access to a center with expertise in leukodystrophies. Our findings suggest a need for improving access to pediatric specialists and possibly deploying specialists or diagnostic testing more broadly.
PMID: 32143930 [PubMed - indexed for MEDLINE]
Neurol Neuroimmunol Neuroinflamm. 2019 09;6(5):e592
Authors: Piquet AL, Khan M, Warner JEA, Wicklund MP, Bennett JL, Leehey MA, Seeberger L, Schreiner TL, Paz Soldan MM, Clardy SL
Abstract
Objective: To describe novel clinical features of GlyRα1-IgG-positive patients.
Methods: Patients with a positive serum GlyRα1-IgG were identified during a 2-year period from July 2016 to December 2018 at 2 academic centers and followed prospectively. All patients in this series were evaluated in the Neuroimmunology and Autoimmune Neurology clinics at the University of Utah or the University of Colorado.
Results: Thirteen of 17 patients had phenotypes more typically associated with glutamic acid decarboxylase (GAD65) antibody syndromes, consisting of stiff-person syndrome (SPS) with parkinsonism or cerebellar signs. One patient with parkinsonism had a presentation similar to rapidly progressive multiple system atrophy with severe dysautonomia. Ten of 17 patients had various visual symptoms including visual snow, spider web-like images forming shapes and 3-dimensional images, palinopsia, photophobia, visual hallucinations, synesthesia, and intermittent diplopia. Three of 17 patients presented with primarily autoimmune epilepsy accompanied by psychiatric symptoms.
Conclusions: Clinicians should consider testing for GlyR antibodies in GAD65 antibody-negative or low-positive GAD65 antibody patients with SPS-like presentations, especially in the setting of atypical features such as visual disturbances, parkinsonism, or epilepsy.
PMID: 31355325 [PubMed - indexed for MEDLINE]
Neurol Neuroimmunol Neuroinflamm. 2019 09;6(5):e583
Authors: Cook LJ, Rose JW, Alvey JS, Jolley AM, Kuhn R, Marron B, Pederson M, Enriquez R, Yearley J, McKechnie S, Han MH, Tomczak AJ, Levy M, Mealy MA, Coleman J, Bennett JL, Johnson R, Barnes-Garcia M, Traboulsee AL, Carruthers RL, Lee LE, Schubert JJ, McMullen K, Kister I, Rimler Z, Reid A, Sicotte NL, Planchon SM, Cohen JA, Ivancic D, Sedlak JL, Sand IK, Repovic P, Amezcua L, Pruitt A, Amundson E, Chitnis T, Mullin DS, Klawiter EC, Russo AW, Riley CS, Onomichi KB, Levine L, Nelson KE, Nealon NM, Engel C, Kruse-Hoyer M, Marcille M, Tornes L, Rumpf A, Greer A, Kenneally Behne M, Rodriguez RR, Behne DW, Blackway DW, Coords B, Blaschke TF, Sheard J, Smith TJ, Behne JM, Yeaman MR, Guthy-Jackson Charitable Foundation International Clinical Consortium (GJCF–ICC)
Abstract
Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment.
Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks.
Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female.
Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD.
PMID: 31355319 [PubMed - indexed for MEDLINE]
Front Immunol. 2019;10:783
Authors: Shwetank, Frost EL, Mockus TE, Ren HM, Toprak M, Lauver MD, Netherby-Winslow CS, Jin G, Cosby JM, Evavold BD, Lukacher AE
Abstract
Programmed cell death-1 (PD-1) receptor signaling dampens the functionality of T cells faced with repetitive antigenic stimulation from chronic infections or tumors. Using intracerebral (i.c.) inoculation with mouse polyomavirus (MuPyV), we have shown that CD8 T cells establish a PD-1hi, tissue-resident memory population in the brains (bTRM) of mice with a low-level persistent infection. In MuPyV encephalitis, PD-L1 was expressed on infiltrating myeloid cells, microglia and astrocytes, but not on oligodendrocytes. Engagement of PD-1 on anti-MuPyV CD8 T cells limited their effector activity. NanoString gene expression analysis showed that neuroinflammation was higher in PD-L1-/- than wild type mice at day 8 post-infection, the peak of the MuPyV-specific CD8 response. During the persistent phase of infection, however, the absence of PD-1 signaling was found to be associated with a lower inflammatory response than in wild type mice. Genetic disruption and intracerebroventricular blockade of PD-1 signaling resulted in an increase in number of MuPyV-specific CD8 bTRM and the fraction of these cells expressing CD103, the αE integrin commonly used to define tissue-resident T cells. However, PD-L1-/- mice persistently infected with MuPyV showed impaired virus control upon i.c. re-infection with MuPyV. Collectively, these data reveal a temporal duality in PD-1-mediated regulation of MuPyV-associated neuroinflammation. PD-1 signaling limited the severity of neuroinflammation during acute infection but sustained a level of inflammation during persistent infection for maintaining control of virus re-infection.
PMID: 31105690 [PubMed - indexed for MEDLINE]
J Allergy Clin Immunol Pract. 2019 Jul - Aug;7(6):1970-1985.e4
Authors: Farmer JR, Foldvari Z, Ujhazi B, De Ravin SS, Chen K, Bleesing JJH, Schuetz C, Al-Herz W, Abraham RS, Joshi AY, Costa-Carvalho BT, Buchbinder D, Booth C, Reiff A, Ferguson PJ, Aghamohammadi A, Abolhassani H, Puck JM, Adeli M, Cancrini C, Palma P, Bertaina A, Locatelli F, Di Matteo G, Geha RS, Kanariou MG, Lycopoulou L, Tzanoudaki M, Sleasman JW, Parikh S, Pinero G, Fischer BM, Dbaibo G, Unal E, Patiroglu T, Karakukcu M, Al-Saad KK, Dilley MA, Pai SY, Dutmer CM, Gelfand EW, Geier CB, Eibl MM, Wolf HM, Henderson LA, Hazen MM, Bonfim C, Wolska-Kuśnierz B, Butte MJ, Hernandez JD, Nicholas SK, Stepensky P, Chandrakasan S, Miano M, Westermann-Clark E, Goda V, Kriván G, Holland SM, Fadugba O, Henrickson SE, Ozen A, Karakoc-Aydiner E, Baris S, Kiykim A, Bredius R, Hoeger B, Boztug K, Pashchenko O, Neven B, Moshous D, Villartay JP, Bousfiha AA, Hill HR, Notarangelo LD, Walter JE
Abstract
BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series.
OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency.
METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology.
RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients.
CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.
PMID: 30877075 [PubMed - indexed for MEDLINE]
Sci Rep. 2019 03 08;9(1):3938
Authors: Tanner WD, VanDerslice JA, Goel RK, Leecaster MK, Fisher MA, Olstadt J, Gurley CM, Morris AG, Seely KA, Chapman L, Korando M, Shabazz KA, Stadsholt A, VanDeVelde J, Braun-Howland E, Minihane C, Higgins PJ, Deras M, Jaber O, Jette D, Gundlapalli AV
Abstract
Community-associated acquisition of extended-spectrum beta-lactamase- (ESBL) and carbapenemase-producing Enterobacteriaceae has significantly increased in recent years, necessitating greater inquiry into potential exposure routes, including food and water sources. In high-income countries, drinking water is often neglected as a possible source of community exposure to antibiotic-resistant organisms. We screened coliform-positive tap water samples (n = 483) from public and private water systems in six states of the United States for blaCTX-M, blaSHV, blaTEM, blaKPC, blaNDM, and blaOXA-48-type genes by multiplex PCR. Positive samples were subcultured to isolate organisms harboring ESBL or carbapenemase genes. Thirty-one samples (6.4%) were positive for blaCTX-M, ESBL-type blaSHV or blaTEM, or blaOXA-48-type carbapenemase genes, including at least one positive sample from each state. ESBL and blaOXA-48-type Enterobacteriaceae isolates included E. coli, Kluyvera, Providencia, Klebsiella, and Citrobacter species. The blaOXA-48-type genes were also found in non-fermenting Gram-negative species, including Shewanella, Pseudomonas and Acinetobacter. Multiple isolates were phenotypically non-susceptible to third-generation cephalosporin or carbapenem antibiotics. These findings suggest that tap water in high income countries could serve as an important source of community exposure to ESBL and carbapenemase genes, and that these genes may be disseminated by non-Enterobacteriaceae that are not detected as part of standard microbiological water quality testing.
PMID: 30850706 [PubMed - indexed for MEDLINE]
