Multi-antigen serology and a diagnostic algorithm for the detection of arbovirus infections as novel tools for arbovirus preparedness in southeast Europe (MERMAIDS-ARBO): a prospective observational study - 21/02/25

Doi : 10.1016/S1473-3099(24)00654-6

Louella M R Kasbergen, MSc ^a,⁎ , Erwin de Bruin, BSc ^a, Felicity Chandler, BSc ^a, Louise Sigfrid, PhD ^b,^c, Xin Hui S Chan, BMBCh DPhil ^d, Lauren Hookham, MBBS ^d, Jia Wei, DPhil ^d, Siyu Chen, DPhil ^d,^e, Corine H GeurtsvanKessel, PhD ^a, Sandra Scherbeijn, BSc ^a, Remi N Charrel, ProfMD PhD ^f, Nazli Ayhan, PhD ^f,^g, James L Lee, MSc ^b, Victor M Corman, MD ^h,ⁱ, Chantal Reusken, PhD ^a,^j, Katherine Loens, PhD ^k, Corneliu Petru Popescu, PhD ^l,^m, Mihaela Lupse, ProfMD PhD ^n,^o, Violeta Briciu, PhD ^n,^o, Anca Meda Văsieşiu, PhD ^p, Pellumb Pipero, ProfPhD ^q, Arjan Harxhi, ProfMD PhD ^r, Edmond Puca, PhD ^q, Albina Ponosheci Biçaku, PhD ^s, Maja Travar, ProfMD PhD ^t, Maja Ostojić, PhD ^u, Rusmir Baljic, ProfMD PhD ^v, Jurica Arapović, ProfMD PhD ^u,^w, Dragan Ledina, PhD ^x, Đurđica Cekinović Grbeša, PhD ^y, Ivica Čabraja, MD ^z, Ivan-Christian Kurolt, PhD ^aa, Stela Halichidis, PhD ^ab,^ac, Victoria Birlutiu, ProfMD PhD ^ad,^ae, Irina M Dumitru, ProfMD PhD ^af, Ruxandra Moroti, PhD ^l,^ag, Aleksandra Barac, PhD ^ah,^ai, Goran Stevanovic, ProfMD PhD ^ah,^ai, Athina Pyrpasopoulou, PhD ^aj, Vasilios Koulouras, ProfMD PhD ^ak, Ljiljana Betica Radić, PhD ^al, Metaxia N Papanikolaou, MD ^am, Emmanuel Roilides, ProfMD PhD ^aj, Alemka Markotić, ProfMD PhD ^aa, Ushma Galal, MSc ^an, Emmanuelle Denis, MSc ^b, Lynsey Goodwin, MD ^ao, Lance Turtle, ProfFRCP ^ao, Simin Aysel Florescu, ProfMD PhD ^l,^m, Hamdi Ramadani, ProfMD PhD ^s,^ap, Herman Goossens, ProfPhD ^aq, Margareta Ieven, ProfPhD ^k,^aq, Christian Drosten, ProfMD ^h, Peter W Horby, ProfPhD ^b, Reina S Sikkema, PhD ^a, Marion P G Koopmans, ProfDVM ^a
on behalf of the
PREPARE MERMAIDS ARBO investigator group^{^†}
Members listed at the end of the Article
Louella M R Kasbergen, Erwin De Bruin, Felicity Chandler, Louise Sigfrid, Xin-Hui S Chan, Lauren Hookham, Jia Wei, Siyu Chen, Corine H GeurtsvanKessel, Sandra Scherbeijn, Remi N Charrel, Nazlı Ayhan, James L Lee, Victor M Corman, Chantal Reusken, Katherine Loens, Corneliu Petru Popescu, Mihaela Lupse, Violeta Briciu, Anca Meda Vasiesiu, Pellumb Pipero, Arjan Harxhi, Edmond Puca, Albina Ponosheci Biçaku, Maja Travar, Maja Ostojić, Rusmir Baljic, Jurica Arapović, Dragan Ledina, Đurđica Cekinović Grbeša, Ivica Čabraja, Ivan-Christian Kurolt, Stela Halichidis, Victoria Birlutiu, Irina M Dumitru, Ruxandra Moroti, Aleksandra Barac, Goran Stevanovic, Athina Pyrpasopoulou, Vasilios Koulouras, Ljiljana Betica Radić, Metaxia N Papanikolaou, Ioannis Andrianopoulos, Catalin Apostolescu, Silvia Bino, Maria Chondrogiorgi, Natalie Cleton, Daniel Codreanu, Tomasović Domagoj, Edita Dražić Maras, Mario Duvnjak, Adriana Hristea, Raluca M Hrisca, Kevin Jacobs, Ilias Iosifidis, Puškarić Ivana, Alma Gabriela Kosa, Iris Koshovari, Mandy Kuijstermans, Arsim Kurti, Santini Marija, Iosif Marincu, Julia Melchert, Pieter Moons, Visnja Mrdjen, Cristian M Niculae, Nenad Pandak, Lul Raka, Iordanis Romiopoulos, Željana Sulaver, Gratiela Tardei, Nijaz Tihic, Skuhala Tomislava, Antonija Verhaz, Mihaela Zaharia, Mačak Šafranko Željka, Ivana Vrkic, Ankica Vujovic, Emmanuel Roilides, Alemka Markotić, Ushma Galal, Emmanuelle Denis, Lynsey Goodwin, Lance Turtle, Simin Aysel Florescu, Hamdi Ramadani, Herman Goossens, Margareta Ieven, Christian Drosten, Peter W Horby, Reina S Sikkema, Marion P G Koopmans

^a Department of Viroscience, Erasmus University Medical Center, Rotterdam, Netherlands
^b ERGO, Pandemic Sciences Institute, University of Oxford, Oxford, UK
^c Policy and Practice Research Group, Pandemic Sciences Institute, University of Oxford, Oxford, UK
^d Nuffield Department of Medicine, University of Oxford, Oxford, UK
^e High Meadows Environmental Institute, Princeton University, Princeton, NJ, US
^f Unite des Virus Emergents, Aix-Marseille Université, Universita di Corsica, IRD 190, Inserm 1207, IRBA, Marseille, France
^g Centre National de Référence des Arbovirus, Inserm-IRBA, Marseille, France
^h Institute of Virology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
ⁱ German Center for Infection Research (DZIF), Berlin, Germany
^j Centre for Infectious Disease Control, National Institute for Public Health and the Environment, RIVML, Bilthoven, Netherlands
^k Department of Medical Microbiology, University of Antwerp UIA, Antwerp, Belgium
^l Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
^m Dr Victor Babes Clinical Hospital of Infectious and Tropical Diseases, Bucharest, Romania
ⁿ Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
^o The Teaching Hospital for Infectious Diseases, Cluj-Napoca, Romania
^p Department of Infectious Diseases, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, Târgu Mureş, Romania
^q Department of Infectious Diseases, Mother Teresa University Hospital Center, Tirana, Albania
^r Faculty of Medicine, Medical University of Tirana, Tirana, Albania
^s Clinic of Infectious Diseases, University Clinical Center of Kosovo, Prishtina, Kosovo
^t Department of Microbiology, Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina
^u School of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina
^v Unit for Infectious Disease, Clinical Center of the University of Sarajevo, Sarajevo, Bosnia and Herzegovina
^w Department of Infectious Diseases, University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina
^x Department of Infectious Diseases, University Hospital Split, Split, Croatia
^y Clinic for Infectious Diseases, Clinical Hospital Center Rijeka, Rijeka, Croatia
^z Department of Infectious Diseases, Dr Josip Benčević General Hospital, Slavonski Brod, Croatia
^aa Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia
^ab Clinical Infectious Diseases Hospital, Constanța, Romania
^ac Faculty of Medicine, Ovidius University, Constanța, Romania
^ad Faculty of Medicine, Lucian Blaga University of Sibiu, Sibiu, Romania
^ae County Clinical Emergency Hospital, Sibiu, Romania
^af Ovidius University of Constanța, Clinical Hospital of Infectious Diseases, Academy of Romanian Scientists, Bucharest, Romania
^ag National Institute for Infectious Diseases Matei Bals, Bucharest, Romania
^ah Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Belgrade, Serbia
^ai Faculty of Medicine, University of Belgrade, Belgrade, Serbia
^aj Infectious Diseases Unit, Hippokration General Hospital, Thessaloniki, Greece
^ak Intensive Care Unit, University Hospital of Ioannina, University of Ioannina, Ioannina, Greece
^al Department of Infectious Diseases, General Hospital Dubrovnik, Dubrovnik, Croatia
^am Intensive Care Unit, Ippokrateion Athens General Hospital, Athens, Greece
^an Nuffield Department of Primary Care Health Sciences, Clinical Trials Unit, University of Oxford, Oxford, UK
^ao NIHR Health Protection Research Unit for Emerging Zoonotic Infections, University of Liverpool, Liverpool, UK
^ap Department of Infectious Diseases, University Clinical Centre, Pristina, Kosovo
^aq Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium

^*Correspondence to: Ms Louella M R Kasbergen, Department of Viroscience, Erasmus University Medical Center, Rotterdam 3015 GD, NetherlandsDepartment of ViroscienceErasmus University Medical CenterRotterdamGD3015Netherlands

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Summary

Background

Arboviruses are increasingly affecting Europe, partly due to the effects of climate change. This increase in range and impact emphasises the need to improve preparedness for emerging arboviral infections that often co-circulate and might have overlapping clinical syndromes. We aimed to strengthen surveillance networks for four clinically relevant arboviruses in southeast Europe.

Methods

This study reports an in-depth analysis of the MERMAIDS-ARBO prospective observational study in adults (ie, aged ≥18 years) hospitalised with an arbovirus-compatible disease syndrome in 21 hospitals in seven countries in southeast Europe over four arbovirus seasons (May 1–Oct 31, 2016–19) to obtain arbovirus prevalence outcomes. The main objectives of the MERMAIDS-ARBO study, describing the clinical management and outcomes of four arboviruses endemic to southeast Europe, including Crimean–Congo haemorrhagic fever virus (CCHFV), tick-borne encephalitis virus (TBEV), Toscana virus, and West Nile virus (WNV), are reported elsewhere. In this analysis, given the challenges associated with arbovirus diagnostics, we developed a diagnostic algorithm accounting for serology outcomes and sample timing to study arbovirus prevalence in southeast Europe. Serum samples were collected on days 0, 7, 28, and 60 after hospital admission and tested for anti-CCHFV IgG and IgM antibodies with ELISAs (confirmed with an indirect immunofluorescence test) and for IgG and IgM antibodies specific to TBEV, Toscana virus, and WNV with custom-printed protein microarrays (confirmed with virus neutralisation tests). All acute-phase samples were tested by PCR for all four viruses. Descriptive analyses were performed for virus-reactive cases by geography and year, and possible factors (eg, age, sex, and insect bites) associated with virus reactivity were assessed.

Findings

Of 2896 individuals screened, 913 were eligible for inclusion, of whom 863 (514 men, 332 women, and 17 unknown) had samples sent to the study reference laboratories and were included in molecular and serological analyses. Some individuals had insufficient clinical data to be included in the clinical analysis, but met the eligibility criteria for and were included here. Serum sampling was incomplete (eg, samples missing from one or more timepoints or no data on time since symptom onset) for 602 (70%) patients, and the timing of collection was often heterogeneous after symptom onset up to 40 days (average median delay of 5–6 days across all timepoints), affecting the ability to diagnose arbovirus infection by serology. By use of an interpretation table incorporating timing and completeness of sampling, one (<1%) participant had a confirmed recent infection with CCHFV, ten (1%) with TBEV, 40 (5%) with Toscana virus, and 52 (6%) with WNV. Most acute confirmed infections of Toscana virus were found in Albania (25 [63%] of 40), whereas WNV was primarily identified in Romania (36 [69%] of 52). Albania also had the highest overall Toscana virus seropositivity (168 [60%] of 282), mainly explained by patients confirmed to be exposed or previously exposed (104 [62%] of 168). Patients without antibodies to WNV or Toscana virus were significantly younger than patients with antibodies (mean difference –8·48 years [95% CI –12·31 to –4·64] for WNV, and –6·97 years [–9·59 to –4·35] for Toscana virus). We found higher odds of Toscana virus reactivity in men (odds ratio 1·56 [95% CI 1·15 to 2·11]; p=0·0055), WNV reactivity with mosquito bites versus no mosquito bites (2·47 [1·54 to 3·97]; p=0·0002), and TBEV reactivity with tick bites versus no tick bites (2·21 [1·19 to 4·11]; p=0·018).

Interpretation

This study shows that despite incomplete and heterogeneous data, differential diagnosis of suspected arbovirus infections is possible, and the diagnostic interpretation algorithm we propose could potentially be used to strengthen routine diagnostics in clinical settings in areas at risk for arboviral diseases. Our data highlight potential hotspots for arbovirus surveillance and risk factors associated with these particular arbovirus infections.