Late detection of emerging viral transmission allows outbreaks to spread uncontrolled, the devastating consequences of which are exemplified by recent epidemics of Ebola virus disease. Especially challenging in places with sparse healthcare, limited diagnostic capacity, and public health infrastructure, syndromes with overlapping febrile presentations easily evade early detection. There is a clear need for evidence-based and context-dependent tools to make syndromic surveillance more efficient. Using published data on symptom presentation and incidence of 21 febrile syndromes, we develop a novel algorithm for aetiological identification of case clusters and demonstrate its ability to identify outbreaks of dengue, malaria, typhoid fever, and meningococcal disease based on clinical data from past outbreaks. We then apply the same algorithm to simulated outbreaks to systematically estimate the syndromic detectability of outbreaks of all 21 syndromes. We show that while most rare haemorrhagic fevers are clinically distinct from most endemic fevers in sub-Saharan Africa, VHF detectability is limited even under conditions of perfect syndromic surveillance. Furthermore, even large clusters (20+ cases) of filoviral diseases cannot be routinely distinguished by the clinical criteria present in their case definitions alone; we show that simple syndromic case definitions are insensitive to rare fevers across most of the region. We map the estimated detectability of Ebola virus disease across sub-Saharan Africa, based on geospatially mapped estimates of malaria, dengue, and other fevers with overlapping syndromes. We demonstrate "hidden hotspots" where Ebola virus is likely to spill over from wildlife and also transmit undetected for many cases. Such places may represent both the locations of past unobserved outbreaks and potential future origins for larger epidemics. Finally, we consider the implications of these results for improved locally relevant syndromic surveillance and the consequences of syndemics and under-resourced health infrastructure for infectious disease emergence.

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Background The COVID-19 pandemic has highlighted the importance of evidence-based clinical decision-making. Clinical management guidelines (CMGs) may help reduce morbidity and mortality by improving the quality of clinical decisions. This systematic review aims to evaluate the availability, inclusivity, and quality of pandemic influenza CMGs, to identify gaps that can be addressed to strengthen pandemic preparedness in this area. Methods Ovid Medline, Ovid Embase, TRIP (Turning Research Into Practice), and Guideline Central were searched systematically from January 2008 to 23rd June 2022, complemented by a grey literature search till 16th June 2022. Pandemic influenza CMGs including supportive care or empirical treatment recommendations were included. Two reviewers independently extracted data from the included studies and assessed their quality using AGREE II (Appraisal of Guidelines for Research & Evaluation). The findings are presented narratively. Results Forty-eight CMGs were included. They were produced in high- (42%, 20/48), upper-middle- (40%, 19/48), and lower-middle (8%, 4/48) income countries, or by international organisations (10%, 5/48). Most CMGs (81%, 39/48) were over 5 years old. Guidelines included treatment recommendations for children (75%, 36/48), pregnant women (54%, 26/48), people with immunosuppression (33%, 16/48), and older adults (29%, 14/48). Many CMGs were of low quality (median overall score: 3 out of 7 (range 1–7). All recommended oseltamivir; recommendations for other neuraminidase inhibitors and supportive care were limited and at times contradictory. Only 56% (27/48) and 27% (13/48) addressed oxygen and fluid therapy, respectively. Conclusions Our data highlights the limited availability of up-to-date pandemic influenza CMGs globally. Of those identified, many were limited in scope and quality and several lacked recommendations for specific at-risk populations. Recommendations on supportive care, the mainstay of treatment, were limited and heterogeneous. The most recent guideline highlighted that the evidence-base to support antiviral treatment recommendations is still limited. There is an urgent need for trials into treatment and supportive care strategies including for different risk populations. New evidence should be incorporated into globally accessible guidelines, to benefit patient outcomes. A ‘living guideline’ framework is recommended and further research into guideline implementation in different resourced settings, particularly low- and middle-income countries.