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Diagnostic Tests for Crimean-Congo Haemorrhagic Fever: a Widespread Tickborne Disease

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Diagnostic Tests for Crimean-Congo Haemorrhagic Fever: a Widespread Tickborne Disease Analysis BMJ Glob Health: first published as 10.1136/bmjgh-2018-001114 on 20 February 2019. Downloaded from Diagnostic tests for Crimean-Congo haemorrhagic fever: a widespread tickborne disease Laura T Mazzola, Cassandra Kelly-Cirino To cite: Mazzola LT, ABSTRACT Summary box Kelly-Cirino C. Diagnostic Crimean-Congo haemorrhagic fever (CCHF) is a tests for Crimean-Congo widespread tickborne disease that circulates in wild and ► Diagnostic tests for Crimean-Congo haemorrhagic haemorrhagic fever: a domestic animal hosts, and causes severe and often fatal widespread tickborne fever virus (CCHFV), a WHO R&D Blueprint priority haemorrhagic fever in infected humans. Due to the lack disease. BMJ Glob Health pathogen, include commercial reverse transcriptase 2019;4:e001114. doi:10.1136/ of treatment options or vaccines, and a high fatality rate, PCR and serological diagnostic assays and multiplex bmjgh-2018-001114 CCHF virus (CCHFV) is considered a high-priority pathogen panels to distinguish from other viral haemorrhagic according to the WHO R&D Blueprint. Several commercial fever agents. reverse transcriptase PCR (RT-PCR) and serological Handling editor Seye Abimbola ► Despite the extensive range of tests available, diag- diagnostic assays for CCHFV are already available, nostic gaps remain, including a need for improved ► Additional material is including febrile agent panels to distinguish CCHFV from surveillance for early detection, a lack of point-of- published online only. To view other viral haemorrhagic fever agents; however, the please visit the journal online care testing options and issues with limited avail- majority of international laboratories use inhouse assays. (http:// dx. doi. org/ 10. 1136/ ability of clinical specimens for test validation. As CCHFV has numerous amplifying animal hosts, a cross- bmjgh- 2018- 001114). ► Refinement of target product profiles for CCHFV sectoral ‘One Health’ approach to outbreak prevention diagnostics to include these needs will help to en- is recommended to enhance notifications and enable hance surveillance, prevention and management of Received 14 August 2018 early warning for genetic and epidemiological shifts in CCHFV in both human and animal hosts. Revised 17 October 2018 the human, animal and tick populations. However, a lack Accepted 23 October 2018 of guidance for surveillance in animals, harmonisation of case identification and validated serodiagnostic kits for on human diagnostics for screening, diag- animal testing hinders efforts to strengthen surveillance nosis and surveillance. systems. Additionally, as RT-PCR tests tend to be lineage- specific for regional circulating strains, there is a need for History and epidemiology of CCHF http://gh.bmj.com/ pan-lineage sensitive diagnostics. Adaptation of existing CCHF virus (CCHFV) is an orthonairovirus tests to point-of-care molecular diagnostic platforms that of the family Nairoviridae causing severe and can be implemented in clinic or field-based settings would be of value given the potential for CCHFV outbreaks in often fatal haemorrhagic fever in humans. remote or low-resource areas. Finally, improved access to The disease was first described in the Crimea clinical specimens for validation of diagnostics would help in 1944 and became known as ‘Crimean haem- orrhagic fever’, but the virus was first isolated to accelerate development of new tests. These gaps should on September 24, 2021 by guest. Protected copyright. be addressed by updated target product profiles for CCHFV in Congo in 1956 and was named ‘Congo diagnostics. virus’; the two names converged as CCHF in 1969.2 4 5 CCHF is considered an ‘emerging’ disease across the globe, with many coun- tries reporting new infections in recent INTRODUCTION decades.6–8 CCHF is now found in Europe, Crimean-Congo haemorrhagic fever (CCHF) the Mediterranean, China and Central Asia, is one of the high-priority pathogens identi- Africa, the Middle East and India (figure 1), © Author(s) (or their fied on the WHO R&D Blueprint because of employer(s)) 2019. Re-use and has been reported after long periods of 9 10 permitted under CC BY. its high case fatality rate, potential for noso- absence. Cases are typically sporadic and Published by BMJ. comial outbreaks and difficulties in treatment seasonal, and occur in remote or agricultural 1–3 Emerging Threats Programme, and prevention. CCHF is widespread, now regions. Foundation for Innovative New found in Europe, Asia, Africa, the Middle East Diagnostics (FIND), Geneva, and the Indian subcontinent, with currently CCHF reservoir and mode of transmission Switzerland no vaccine available for widespread human Ixodid (hard) ticks are a reservoir and a vector Correspondence to or animal use. This landscape analysis is for CCHFV, now commonly found in dry or Dr Cassandra Kelly-Cirino; intended to provide a view to the current state semiarid environments across Africa, Europe, cassandra. kelly@ finddx. org of CCHF diagnostics, with particular emphasis the Middle East and Asia.7 11 12 Numerous Mazzola LT, Kelly-Cirino C. BMJ Glob Health 2019;4:e001114. doi:10.1136/bmjgh-2018-001114 1 BMJ Global Health BMJ Glob Health: first published as 10.1136/bmjgh-2018-001114 on 20 February 2019. Downloaded from Figure 1 Geographical distribution of Crimean-Congo haemorrhagic fever (CCHF) (http://www.who.int/emergencies/diseases/ crimean-congo-haemorrhagic-fever/en/). wild and domestic animals, including cattle, goats, sheep, seroprevalence have been detected in specific regions of 18 19 camels and hares, serve as amplifying hosts after being Turkey and Greece. http://gh.bmj.com/ bitten by infected ticks, but animal infections are difficult The haemorrhagic phase is generally 2 weeks in dura- to detect as the tick–animal–tick cycle is asymptomatic.13 tion with rapid progressive haemorrhage. Severely ill CCHFV persists throughout the tick life-cycle, enabling patients may experience rapid deterioration, shock and reservoirs of infection over long periods without verte- multiorgan failure.20 In documented outbreaks, fatality brate hosts. rates in hospitalised patients have ranged as high as Transmission to humans occurs most frequently among 50%, with an average mortality of 30% occurring in the on September 24, 2021 by guest. Protected copyright. 1 2 agricultural workers following the bite of an infected tick, second week of illness. For survivors, recovery generally and among slaughterhouse or veterinary workers exposed begins 10–20 days after the onset of illness; however, full 11 16 to the blood and tissue of infected livestock. Human-to- recovery may take up to a year. The long-term effects human transmission is infrequent, but has arisen from of CCHFV infection have not been studied well enough contact with infected patients or contaminated medical in survivors to determine whether or not specific compli- equipment.14–17 cations exist. Molecular epidemiology Clinical presentation CCHFV displays a high degree of sequence diversity, CCHFV infection typically has four distinct phases— with divergence of 20%, 31% and 22% for the S, M incubation, prehaemorrhagic, haemorrhagic and conva- and L segments among isolates in GenBank. Based on lescence. The incubation period is in the range of 1–5 an analysis of the viral S segment, six or seven viral line- days following a tick bite, and 5–7 days following contact ages/clades have been identified,6 11 16 21 22 suggesting a 4 11 16 with infected blood or tissues. The prehaemorrhagic lengthy history of geographical dispersion of the virus phase is characterised by the sudden onset of a wide range from Africa to Europe, the Middle East and then Asia. of non-specific symptoms that mimic other diseases and Genome diversity can be greater in the tick than in the lasts for 4–5 days. CCHFV infections may be subclinical or mammalian host.23–25 The extensive sequence diversity of asymptomatic in some people; for example, high levels of CCHFV is likely due to genetic reassortment, enhanced by 2 Mazzola LT, Kelly-Cirino C. BMJ Glob Health 2019;4:e001114. doi:10.1136/bmjgh-2018-001114 BMJ Global Health BMJ Glob Health: first published as 10.1136/bmjgh-2018-001114 on 20 February 2019. Downloaded from circulation and adaptation of strains into new geograph- tick feeding.8 46 Infection control of CCHFV in wildlife ical regions.22 26–29 populations will remain a challenge, however. Currently there are no vaccines available for use in animals,1 2 Therapeutic efforts although the MVA GP vaccine is currently being evalu- Treatment for confirmed cases of CCHF is general ated in sheep.52 supportive care with management of symptoms.2 There is no approved antiviral treatment. Although the anti- viral drug ribavirin is widely used based on its in vitro activity, clinical evidence is inconclusive.30–36 Postex- CCHF DIAGNOSTICS posure prophylaxis using ribavirin is controversial but Laboratory tests used to diagnose CCHF include reverse recommended as a safe option for healthcare providers transcriptase (RT)-PCR, immunofluorescence assay with high-risk/direct exposure to CCHF-infected patient (IFA), antibody (IgG, IgM) and antigen-capture ELISA, fluids or tissue.15 17 37 38 and virus isolation. Patients suspected of CCHF are Development of new therapies has been slow in part primarily diagnosed by RT-PCR as these assays provide due to the requirement for a high-containment labora- the highest detection sensitivity to active infection at tory and the lack of a suitable animal model.6 39 40 Favip- the earliest time point. Lineage detection may
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