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We describe the use of a multipathogen platform, TaqMan array card (TAC) real-time polymerase chain reaction, for the detection of pathogens in patients hospitalized with severe respiratory illness (SRI). Prospective hospital-based syndromic surveillance for acute and chronic SRI was carried out at two sentinel sites in South Africa between January and December 2017. We tested respiratory specimens for 21 respiratory pathogens and blood samples for nine bacteria using TAC. Pathogen detection was compared by age group and HIV status using