Abstract
In well-resourced settings the systematic use of rapid diagnostics tests (e.g. pneumococcal urinary antigen test) that define the causal pathogen to direct therapy has not resulted in significantly improved outcomes in adults withpneumonia. The management of pneumonia in many low-resource settings is complicated by a substantial burden of tuberculosis and HIV-associated opportunistic infections, in addition to the usual spectrum of pathogens seenin well-resourced settings. Clinical features alone do not reliably distinguish between these different aetiologiesand physicians often have to treat empirically. Given the limitations in diagnostic laboratory capability present inmost low-resource settings, rapid and point-of-care diagnostic tests could become valuable tools to guide treatment decisions. Pneumococcal and Legionella urinary antigen tests are specific and moderately sensitive, but their utilityin low-resource settings is uncertain. The Xpert MTB/RIF (Cepheid, USA) platform and rapid assays for urinary lipoarabinomannan can substantially speed up tuberculosis diagnosis; the current challenge is to translate this intoearlier treatment and hopefully improve patient outcome. In HIV-infected patients, 1-3-β-D-glucan is a serum marker of Pneumocystis jirovecii infection with excellent sensitivity. Further studies are needed to assess the clinical utilityand cost-effectiveness of these rapid diagnostic assays when they are incorporated into treatment algorithms.
Highlights
ĎƐƚƌĂĐƚ /Ŷ ǁĞůůͲƌĞƐŽƵƌĐĞĚ ƐĞƫŶŐƐ ƚŚĞ ƐLJƐƚĞŵĂƟĐ ƵƐĞ ŽĨ ƌĂƉŝĚ ĚŝĂŐŶŽƐƟĐƐ ƚĞƐƚƐ ;ĞŐ ƉŶĞƵŵŽĐŽĐĐĂů ƵƌŝŶĂƌLJ ĂŶƟŐĞŶ ƚĞƐƚͿ ƚŚĂƚ ĚĞĮŶĞ ƚŚĞ ĐĂƵƐĂů ƉĂƚŚŽŐĞŶ ƚŽ ĚŝƌĞĐƚ ƚŚĞƌĂƉLJ ŚĂƐ ŶŽƚ ƌĞƐƵůƚĞĚ ŝŶ ƐŝŐŶŝĮĐĂŶƚůLJ ŝŵƉƌŽǀĞĚ ŽƵƚĐŽŵĞƐ ŝŶ ĂĚƵůƚƐ ǁŝƚŚ ƉŶĞƵŵŽŶŝĂdŚĞ ŵĂŶĂŐĞŵĞŶƚ ŽĨ ƉŶĞƵŵŽŶŝĂ ŝŶ ŵĂŶLJ ůŽǁͲƌĞƐŽƵƌĐĞ ƐĞƫŶŐƐ ŝƐ ĐŽŵƉůŝĐĂƚĞĚ ďLJ Ă ƐƵďƐƚĂŶƟĂů ďƵƌĚĞŶ ŽĨ ƚƵďĞƌĐƵůŽƐŝƐ ĂŶĚ,/sͲĂƐƐŽĐŝĂƚĞĚ ŽƉƉŽƌƚƵŶŝƐƟĐ ŝŶĨĞĐƟŽŶƐŝŶ ĂĚĚŝƟŽŶ ƚŽ ƚŚĞ ƵƐƵĂů ƐƉĞĐƚƌƵŵ ŽĨ ƉĂƚŚŽŐĞŶƐ ƐĞĞŶ ŝŶ ǁĞůůͲƌĞƐŽƵƌĐĞĚ ƐĞƫŶŐƐ ůŝŶŝĐĂů ĨĞĂƚƵƌĞƐ ĂůŽŶĞ ĚŽ ŶŽƚ ƌĞůŝĂďůLJ ĚŝƐƟŶŐƵŝƐŚ ďĞƚǁĞĞŶ ƚŚĞƐĞ ĚŝīĞƌĞŶƚ ĂĞƟŽůŽŐŝĞƐ ĂŶĚ ƉŚLJƐŝĐŝĂŶƐ ŽŌĞŶ ŚĂǀĞ ƚŽ ƚƌĞĂƚ ĞŵƉŝƌŝĐĂůůLJ 'ŝǀĞŶ ƚŚĞ ůŝŵŝƚĂƟŽŶƐ ŝŶ ĚŝĂŐŶŽƐƟĐ ůĂďŽƌĂƚŽƌLJ ĐĂƉĂďŝůŝƚLJ ƉƌĞƐĞŶƚ ŝŶ ŵŽƐƚ ůŽǁͲƌĞƐŽƵƌĐĞ ƐĞƫŶŐƐƌĂƉŝĚ ĂŶĚ ƉŽŝŶƚͲŽĨͲĐĂƌĞ ĚŝĂŐŶŽƐƟĐ ƚĞƐƚƐ ĐŽƵůĚ ďĞĐŽŵĞ ǀĂůƵĂďůĞ ƚŽŽůƐ ƚŽ ŐƵŝĚĞ ƚƌĞĂƚŵĞŶƚ decisions
ŽĨ ƉŶĞƵŵŽĐŽĐĐĂů ƉŶĞƵŵŽŶŝĂ ƉĂƌƟĐƵůĂƌůLJ ĨŽƌ ƉĂƟĞŶƚƐ ĂůƌĞĂĚLJ ƚƌĞĂƚĞĚ ǁŝƚŚ ĂŶƟďŝŽƟĐƐ ς͘ dŚĞ ŵĞĂŶ ĚƵƌĂƟŽŶ ŽĨ ŝŶĂdžEKtͲ^W ƉŽƐŝƟǀŝƚLJ ŝƐ ƵƉ ƚŽ Θ ǁĞĞŬƐ ŚĞŶĐĞ ŝƚ ĐĂŶŶŽƚ be used as a test of cure and should not be used in cases of ƌĞĐƵƌƌĞŶƚ ƉŶĞƵŵŽŶŝĂ ůĞƐƐ ƚŚĂŶ κ ŵŽŶƚŚƐ ĂŌĞƌ ƉŶĞƵŵŽŶŝĂ caused by S. pneumoniae ς͘
Cost, training needs and other ůŽŐŝƐƟĐĂů ĐŽŶƐƚƌĂŝŶƚƐ ŚĂǀĞ ƚŽ ĚĂƚĞ ůĂƌŐĞůLJ ƌĞƐƚƌŝĐƚĞĚ ƚŚĞ ƌŽůůŽƵƚ ŽĨ ƚŚĞ yƉĞƌƚ DdͬZ/& ƉůĂƞŽƌŵ ƚŽ ĐĞŶƚƌĂů ůĂďŽƌĂƚŽƌŝĞƐ /Ŷ ƐĞƫŶŐƐ ŽĨ ƉŽŽƌ ŝŶĨƌĂƐƚƌƵĐƚƵƌĞƚŚŝƐ ƐĞƉĂƌĂƟŽŶ ŽĨ ƚŚĞ ƉĂƟĞŶƚ ĂŶĚ ƚĞƐƚ ƌĞƐƵůƚ ŵĂLJ ŝŵƉĞĚĞ ƚŚĞ ƟŵĞůLJ ŝŶŝƟĂƟŽŶ ŽĨ ƚƌĞĂƚŵĞŶƚ ϮϮ͘ ƌĞĐĞŶƚ ƐƚƵĚLJ ĚĞŵŽŶƐƚƌĂƚĞĚ ŚŽǁĞǀĞƌƚŚĂƚ ƚŚĞ yƉĞƌƚ DdͬZ/& ƐLJƐƚĞŵ can be accurately administered by a trained nurse in ƉƌŝŵĂƌLJ ŚĞĂůƚŚͲĐĂƌĞ ĐĞŶƚƌĞƐ ƚŽ ĨĂĐŝůŝƚĂƚĞ ŝŵƉƌŽǀĞĚ ƌĂƚĞƐ ŽĨ ƐĂŵĞͲĚĂLJ ĚŝĂŐŶŽƐŝƐ ĂŶĚ ƚƌĞĂƚŵĞŶƚ ŝŶŝƟĂƟŽŶ ϯε͘ &ƵƚƵƌĞ ĞīŽƌƚƐ ǁŝůů ďĞ ĨŽĐƵƐĞĚ ŽŶ ĨƵƌƚŚĞƌ ƌŽůůŽƵƚ ĂŶĚ ĚĞĐĞŶƚƌĂůŝƐĂƟŽŶ ŽĨ ƚŚĞ yƉĞƌƚ DdͬZ/& ƐLJƐƚĞŵ
Summary
Streptococcus pneumoniae ŝƐ ƚŚĞ ŵŽƐƚ ĐŽŵŵŽŶůLJ ŝĚĞŶƟĮĞĚ ĐĂƵƐĂƟǀĞ ŽƌŐĂŶŝƐŵ ŽĨ W ŝŶ ŵŽƐƚ ƐĞƫŶŐƐ Ϯϯ͘ ůĂƐƐŝĐĂů ŵŝĐƌŽďŝŽůŽŐŝĐĂů ƚĞĐŚŶŝƋƵĞƐ ŽĨ ĞƐƚĂďůŝƐŚŝŶŐ ƚŚĞ ĚŝĂŐŶŽƐŝƐ ŽĨ ƉŶĞƵŵŽĐŽĐĐĂů ƉŶĞƵŵŽŶŝĂ ;ĞŐ ƐƉƵƚƵŵ 'ƌĂŵͲƐƚĂŝŶ ƐƉƵƚƵŵ Žƌ ďůŽŽĚ ĐƵůƚƵƌĞͿ ĂƌĞ ŚŝŐŚůLJ ƐƉĞĐŝĮĐďƵƚ ŝŶƐĞŶƐŝƟǀĞ ĂŶĚ ŽŌĞŶ ƐůŽǁ ρ͘ dŚĞ ůĞƌĞ ŝŶĂdžEKt Streptococcus pneumoniae ŶƟŐĞŶ ĂƌĚ ;ŝŶĂdžEKtͲ^WůĞƌĞh^ Ϳ ŝƐ an immunochromatographic test for the presence of the ƉŶĞƵŵŽĐŽĐĐĂů ͲƉŽůLJƐĂĐĐŚĂƌŝĚĞ ĐŽĂƚ ƉƌŽƚĞŝŶ ŝŶ ƵƌŝŶĞthe test can produce a result within 15 minutes of the ƐƉĞĐŝŵĞŶ ďĞŝŶŐ ŽďƚĂŝŶĞĚ ĂŶĚ ƌĞƋƵŝƌĞƐ ŵŝŶŝŵĂů ůĂďŽƌĂƚŽƌLJ ŝŶĨƌĂƐƚƌƵĐƚƵƌĞ Žƌ ƐƚĂī ĞdžƉĞƌƟƐĞ ƚŽ ƉĞƌĨŽƌŵ ς͘ ĐĐƵƌĂƚĞ ĂƐƐĞƐƐŵĞŶƚ ŽĨ ƚŚĞ ĚŝĂŐŶŽƐƟĐ ƉĞƌĨŽƌŵĂŶĐĞ ĐŚĂƌĂĐƚĞƌŝƐƟĐƐ ŽĨ ŝŶĂdžEKtͲ^W ŚĂƐ ďĞĞŶ ŚĂŵƉĞƌĞĚ ďLJ ƚŚĞ ůĂĐŬ ŽĨ Ă ƐĞŶƐŝƟǀĞ ĂŶĚ ƐƉĞĐŝĮĐ ƌĞĨĞƌĞŶĐĞ ƐƚĂŶĚĂƌĚ ƚĞƐƚƌĞĐĞŶƚ ŵĞƚĂͲĂŶĂůLJƐŝƐ ƚŚĂƚ ƵƐĞĚ Ă ůĂƚĞŶƚ ĐůĂƐƐ ŵŽĚĞů ĂƉƉƌŽĂĐŚ ƚŽ ĂĚũƵƐƚ ĨŽƌ ƚŚĞ variable and imperfect nature of the reference standard, ĞƐƟŵĂƚĞĚ ƚŚĞ ƐĞŶƐŝƟǀŝƚLJ ĂŶĚ ƐƉĞĐŝĮĐŝƚLJ ŽĨ ŝŶĂdžEKtͲ^W ĨŽƌ the diagnosis of S. pneumoniae ŝŶĨĞĐƟŽŶ ŝŶ ĂĚƵůƚƐ ǁŝƚŚ W ǁĂƐ ϳκй ĂŶĚ εϳйƌĞƐƉĞĐƟǀĞůLJ ρ͘ /Ŷ ƉƌĂĐƟĐĞ ǁŚĞŶ ƵƐĞĚ ŝŶ ĐŽŶũƵŶĐƟŽŶ ǁŝƚŚ ĐůĂƐƐŝĐĂů ŵŝĐƌŽďŝŽůŽŐŝĐĂů ŵĞƚŚŽĚƐƚŚĞ ĂƐƐĂLJ ŐŝǀĞƐ ĂŶ ŝŶĐƌĞŵĞŶƚĂů ŝŵƉƌŽǀĞŵĞŶƚ ŝŶ ĚĞƚĞĐƟŽŶ. ŜŶĂdžEKtͲ^W ŚĂƐ ƉŽŽƌ ƐƉĞĐŝĮĐŝƚLJ ĂŶĚ ŚĞŶĐĞ ůŝŵŝƚĞĚ ƵƟůŝƚLJŝŶ ĐŚŝůĚƌĞŶ ŽǁŝŶŐ ƚŽ ŚŝŐŚ ƌĂƚĞƐ ŽĨ ĂƐLJŵƉƚŽŵĂƟĐ nasal carriage of S. pneumoniae ϳ͘ /Ŷ ŵĂŶLJ ůŽǁͲƌĞƐŽƵƌĐĞ ƐĞƫŶŐƐ ƚŚĞƌĞ ĂƌĞ ĂůƐŽ ŚŝŐŚ ƌĂƚĞƐ ŽĨ ŶĂƐŽƉŚĂƌLJŶŐĞĂů ĐŽůŽŶŝƐĂƟŽŶ ŝŶ ĂĚƵůƚƐ Θε͘ /Ŷ Ă ƌĞĐĞŶƚ ƐƚƵĚLJ ŽĨ εΘ ŚĞĂůƚŚLJ Thai women, S. pneumoniae ŶĂƐŽƉŚĂƌLJŶŐĞĂů ĐŽůŽŶŝƐĂƟŽŶ ;ƉƌĞƐĞŶƚ ŝŶ Ϯρй ŽĨ ǁŽŵĞŶͿ ǁĂƐ ŶŽƚ ĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚ ƉŽƐŝƟǀĞ ŝŶĂdžEKtͲ^W ϭϬ͘ /Ŷ ǁĞůůͲƌĞƐŽƵƌĐĞĚ ƐĞƫŶŐƐƚŚĞ ƐĞŶƐŝƟǀŝƚLJ ĂŶĚ ƐƉĞĐŝĮĐŝƚLJ ŽĨ ŝŶĂdžEKtͲ^W ĂƌĞ ƌĞƉŽƌƚĞĚůLJ ƵŶĂīĞĐƚĞĚ ďLJ ,/sͲƐƚĂƚƵƐ ϭϭ͘ dŚĞ ĐŽŵďŝŶĞĚ ĞĨĨĞĐƚ ŽĨ ,/sͲŝŶĨĞĐƚŝŽŶ ĂŶĚ ƉŶĞƵŵŽĐŽĐĐĂů ŶĂƐŽƉŚĂƌLJŶŐĞĂů ĐŽůŽŶŝƐĂƚŝŽŶ ǁŚŝĐŚ ŝƐ ĐŽŵŵŽŶ ŝŶ ůŽǁͲƌĞƐŽƵƌĐĞ ƐĞƫŶŐƐ ŽŶ ƚŚĞ ƐƉĞĐŝĮĐŝƚLJ ŽĨ ƚŚĞ ƚĞƐƚ ŚĂƐ ŶŽƚ LJĞƚ ďĞĞŶ ƐƚƵĚŝĞĚ ŝŶ detail. ZĞŐĂƌĚůĞƐƐ ŽĨ ŝƚƐ ƉĞƌĨŽƌŵĂŶĐĞ ĐŚĂƌĂĐƚĞƌŝƐƟĐƐƚŚĞ ƉƌĂĐƟĐĂů ǀĂůƵĞ ŽĨ Ă ĚŝĂŐŶŽƐƟĐ ƚĞƐƚ ĨŽƌ ƉŶĞƵŵŽĐŽĐĐĂů ƉŶĞƵŵŽŶŝĂ ŵĞƌŝƚƐ ĐĂƌĞĨƵů ĐŽŶƐŝĚĞƌĂƟŽŶ ;dĂďůĞ ϭͿ ZĞĐŽŵŵĞŶĚĞĚ ĞŵƉŝƌŝĐĂů ƚŚĞƌĂƉLJ ĂůǁĂLJƐ ŝŶĐůƵĚĞƐ ĂŶƟͲƉŶĞƵŵŽĐŽĐĐĂů ĐŽǀĞƌĂŐĞ ĐŽŶĮƌŵĞĚ ĚŝĂŐŶŽƐŝƐ ŵĂLJ ďĞ ĚĞƐŝƌĂďůĞ ŝŶ ŽƌĚĞƌ ƚŽ ũƵƐƟĨLJ ŶĂƌƌŽǁŝŶŐ ƚŚĞ ƐƉĞĐƚƌƵŵ ŽĨ ƚŚĞƌĂƉLJ ǁŝƚŚ ƚŚĞ Ăŝŵ ŽĨ ƌĞĚƵĐŝŶŐ ƚŚĞ ƌŝƐŬ ŽĨ ĐŽŵƉůŝĐĂƟŽŶƐ ŽĨ ďƌŽĂĚ ƐƉĞĐƚƌƵŵ ĂŶƟďŝŽƟĐƐ ;ĞŐ ůŽƐƚƌŝĚŝƵŵ ĚŝĸĐŝůĞͿ ĂŶĚ ĚĞĐƌĞĂƐŝŶŐ ƚŚĞ ƉƌĞǀĂůĞŶĐĞ ŽĨ ĐŽŵŵƵŶŝƚLJ ĂŶƟďŝŽƟĐ ƌĞƐŝƐƚĂŶĐĞ ρ͘ ŽŶǀĞƌƐĞůLJƚŚĞ ƉŽƐƐŝďŝůŝƚLJ ŽĨ ƉŽůLJŵŝĐƌŽďŝĂů ŝŶĨĞĐƟŽŶ ĂŶĚ ƚŚĞ ƉŽƚĞŶƟĂů ďĞŶĞĮƚ ŽĨ ĐŽŵďŝŶĂƟŽŶ ƚŚĞƌĂƉŝĞƐ ŝŶ ĐĂƐĞƐ ŽĨ ƐĞǀĞƌĞ ƉŶĞƵŵŽĐŽĐĐĂů ƉŶĞƵŵŽŶŝĂ ƐƵƉƉŽƌƚ ĐŽŶƟŶƵĞĚ broad empirical treatment even when pneumococcal ŝŶĨĞĐƟŽŶ ŝƐ ĐŽŶĮƌŵĞĚ ϭϭϮ͘ /Ŷ Ă ƌĞĐĞŶƚ ƌĂŶĚŽŵŝƐĞĚ ƚƌŝĂů ŶĂƌƌŽǁŝŶŐ ƚŚĞ ƐƉĞĐƚƌƵŵ ŽĨ ĂŶƟďŝŽƟĐ ƚƌĞĂƚŵĞŶƚ ŽŶ the basis of pneumococcal and Legionella ƵƌŝŶĂƌLJ ĂŶƟŐĞŶ tests in adults hospitalised with CAP, failed to demonstrate ĂŶLJ ƐŝŐŶŝĮĐĂŶƚ ĐůŝŶŝĐĂů Žƌ ĞĐŽŶŽŵŝĐ ďĞŶĞĮƚ ĂŶĚ ŵŽƌĞŽǀĞƌ ǁĂƐ ĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚ Ă ŚŝŐŚĞƌ ƌŝƐŬ ŽĨ ĐůŝŶŝĐĂů ƌĞůĂƉƐĞ ϭ͘ /Ŷ ƐĞƫŶŐƐ ǁŚĞƌĞ ƚŚĞ ŵĂũŽƌŝƚLJ ŽĨ ƉĂƟĞŶƚƐ ŚŽƐƉŝƚĂůŝƐĞĚ with pneumonia have HIV, and typically advanced ŝŵŵƵŶŽƐƵƉƉƌĞƐƐŝŽŶ ƉŽůLJŵŝĐƌŽďŝĂů ŝŶĨĞĐƟŽŶ ǁŝƚŚ ŶŽƚ only other typical CAP pathogens but M. tuberculosis ĂŶĚ ŽƚŚĞƌ ŽƉƉŽƌƚƵŶŝƐƟĐ ƉĂƚŚŽŐĞŶƐ ŝƐ ĐŽŵŵŽŶ ϭϯϭκ͘ In this context, clinicians should have a low threshold ĨŽƌ ĂĚĚŝƟŽŶĂů ŝŶǀĞƐƟŐĂƟŽŶ ĞǀĞŶ ĂŌĞƌ ƉŶĞƵŵŽĐŽĐĐĂů ƉŶĞƵŵŽŶŝĂ ŝƐ ĐŽŶĮƌŵĞĚŝĨ ƉĂƟĞŶƚƐ ĨĂŝů ƚŽ ŝŵƉƌŽǀĞ Žƌ ƐŚŽǁ ĐůŝŶŝĐĂů ĨĞĂƚƵƌĞƐ ŚŝŐŚůLJ ƐƵŐŐĞƐƟǀĞ ŽĨ ĂůƚĞƌŶĂƟǀĞ ĂĞƟŽůŽŐŝĞƐ
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