Ana Esteve-Sole1,2, Suly P Sánchez-Dávila3, Angela Deyà-Martínez1,2, Alexandra F Freeman4, Adrian M Zelazny5, John P Dekker5, Pavel P Khil5, Steven M Holland4, Antoni Noguera-Julian6,7,8,9, Jacinta Bustamante10,11,12,13, Jean-Laurent Casanova10,11,13,14,15, Manel Juan2,16, Wilmer Cordova3, Laia Alsina17,18. 1. Functional Unit of Clinical Immunology and Primary Immunodeficiencies, Hospital Sant Joan de Déu, University of Barcelona, Pediatric Research Institute Sant Joan de Déu, Barcelona, Spain. 2. Functional Unit of Clinical Immunology, Hospital Sant Joan de Déu-Hospital Clinic, Barcelona, Spain. 3. National reference center Allergy Asthma Immunology, National Institute of Child Health, Lima, Peru. 4. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 5. Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA. 6. Infectious Diseases and Systemic Inflammatory Response in Pediatrics, Infectious Diseases Unit, Pediatrics Department, Pediatric Research Institute Sant Joan de Déu, Barcelona, Spain. 7. Department of Pediatrics, University of Barcelona, Barcelona, Spain. 8. CIBER of Epidemiology and Public Health, CIBERESP, Madrid, Spain. 9. Translational Research Network in Pediatric Infectious Diseases (RITIP), Madrid, Spain. 10. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM-U1163, Paris, France. 11. Imagine Institute, Paris Descartes University, Paris, France. 12. Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, France. 13. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller branch, The Rockefeller University, New York, NY, USA. 14. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France. 15. Howard Hughes Medical Institute, New York, NY, USA. 16. Immunology Department, Biomedical Diagnostics Center, Hospital Clinic-IDIBAPS, Barcelona, Spain. 17. Functional Unit of Clinical Immunology and Primary Immunodeficiencies, Hospital Sant Joan de Déu, University of Barcelona, Pediatric Research Institute Sant Joan de Déu, Barcelona, Spain. lalsina@hsjdbcn.org. 18. Functional Unit of Clinical Immunology, Hospital Sant Joan de Déu-Hospital Clinic, Barcelona, Spain. lalsina@hsjdbcn.org.
Abstract
PURPOSE: Mendelian suceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing to severe disease caused by mycobacteria and other intracellular pathogens. Delay in diagnosis can have an impact on the patient's prognosis. METHODS: We evaluated the IFN-γ circuit by studying IFN-γ production after mycobacterial challenge as well as IL-12Rβ1 expression and STAT4 phosphorylation in response to IL-12p70 stimulation in whole blood of a 6-year-old Peruvian girl with disseminated recurrent mycobacterial infection diagnosed as multidrug-resistant tuberculosis. Genetic studies with Sanger sequencing were used to identify the causative mutation. Microbiological studies based on PCR reactions were used to diagnose the specific mycobacterial species. RESULTS: We identified a homozygous mutation in the IL12RB1 gene (p. Arg211*) causing abolished expression of IL-12Rβ1 and IL-12 response. MSMD diagnosis led to a microbiological reevaluation of the patient, revealing a BCG vaccine-related infection instead of tuberculosis. Treatment was then adjusted, with good response. CONCLUSIONS: We report the first Peruvian patient with IL-12Rβ1 deficiency. Specific mycobacterial species diagnosis within Mycobacterium tuberculosis complex is still challenging in countries with limited access to PCR-based microbiological diagnostic techniques. Awareness of MSMD warning signs and accurate microbiological diagnosis of mycobacterial infections are of the utmost importance for optimal diagnosis and management of affected patients.
PURPOSE: Mendelian suceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing to severe disease caused by mycobacteria and other intracellular pathogens. Delay in diagnosis can have an impact on the patient's prognosis. METHODS: We evaluated the IFN-γ circuit by studying IFN-γ production after mycobacterial challenge as well as IL-12Rβ1 expression and STAT4 phosphorylation in response to IL-12p70 stimulation in whole blood of a 6-year-old Peruvian girl with disseminated recurrent mycobacterial infection diagnosed as multidrug-resistant tuberculosis. Genetic studies with Sanger sequencing were used to identify the causative mutation. Microbiological studies based on PCR reactions were used to diagnose the specific mycobacterial species. RESULTS: We identified a homozygous mutation in the IL12RB1 gene (p. Arg211*) causing abolished expression of IL-12Rβ1 and IL-12 response. MSMD diagnosis led to a microbiological reevaluation of the patient, revealing a BCG vaccine-related infection instead of tuberculosis. Treatment was then adjusted, with good response. CONCLUSIONS: We report the first Peruvian patient with IL-12Rβ1 deficiency. Specific mycobacterial species diagnosis within Mycobacterium tuberculosis complex is still challenging in countries with limited access to PCR-based microbiological diagnostic techniques. Awareness of MSMD warning signs and accurate microbiological diagnosis of mycobacterial infections are of the utmost importance for optimal diagnosis and management of affected patients.
Authors: Andrés Augusto Arias; Carlos M Perez-Velez; Julio César Orrego; Marcela Moncada-Velez; Jessica Lineth Rojas; Alejandra Wilches; Andrea Restrepo; Mónica Trujillo; Carlos Garcés; Catalina Arango-Ferreira; Natalia González; Carmen Oleaga-Quintas; Diana Fernández; Johana Marcela Isaza-Correa; Diego Eduardo Gongóra; Daniel Gonzalez-Loaiza; Juan Esteban Sierra; Jean Laurent Casanova; Jacinta Bustamante; José Luis Franco Journal: J Clin Immunol Date: 2017-09-01 Impact factor: 8.317
Authors: J Lucian Davis; Laurence Huang; Joseph A Kovacs; Henry Masur; Patrick Murray; Diane V Havlir; William O Worodria; Edwin D Charlebois; Padmini Srikantiah; Adithya Cattamanchi; Charles Huber; Yvonne R Shea; Yuenwah Chow; Steven H Fischer Journal: Clin Infect Dis Date: 2009-03-15 Impact factor: 9.079