International Consensus Document (ICON): Common Variable Immunodeficiency Disorders

The International Collaboration in Asthma, Allergy and Immunology initiated an international coalition among the American Academy of Allergy, Asthma & Immunology; the European Academy of Allergy and Clinical Immunology; the World Allergy Organization; and the American College of Allergy, Asthma & Immunology on common variable immunodeficiency. An author group was formed and then divided into individual committees. Within the committee, teams of authors were subgrouped to generate content for specific sections of the document. Content was derived from literature searches, relevant published guidelines, and clinical experience. After a draft of the document was assembled, it was collectively reviewed and revised by the authors. Where evidence was lacking or conflicting, the information presented represents the consensus expert opinion of the group. The full document was then independently reviewed by 5 international experts in the field, none of whom was among the authors of the original. The comments of these reviewers were incorporated before submission for publicatio

Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis

Background: Impaired signaling in the IFN-gamma/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis. Objective: We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections. Methods: PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-gamma/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated. Results: We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-gamma-induced gene expression, but we found impaired respo Conclusion: Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-gamma-mediated inflammation

Critical appraisal of the management of severe malnutrition: 3 Complications

Abstract: The high case-fatality of severe malnutrition is due to infections, dehydration, electrolyte disturbances and heart failure. We focus on the evidence about managing these complications of severe malnutrition. Signs of circulatory collapse in severely malnourished children should be treated with intravenous or bone marrow infusion of Ringer's lactate with additional dextrose and potassium at a rate 20–40 mL/kg fast with close monitoring of vital signs. Recommendations for slow or restricted fluids in the face of shock are unsafe, and hypotonic or maintenance solutions must be avoided to prevent hyponatraemia. However, the evidence that severely malnourished children do not tolerate excessive fluid administration is good, so caution must be exercised with regards to fluids in the initial phase of treatment. There is also good evidence that wide spectrum antibiotics need to be given empirically for severe malnutrition to prevent the otherwise unavoidable early mortality. There is a need for improved protocols for tuberculosis diagnosis, HIV management and treatment of infants under 6 months with severe malnutrition. The contribution of environmental enteropathy to poor growth and nutrition during the weaning period means that there should be more priority on improving environmental health, particularly better hygiene and less overcrowding. A T-cell mediated enteropathy contributes to growth failure and malnutrition, and it is related to environmental contamination of enteric organisms in the weaning period rather than allergic responses