Syndromic Approach to Arboviral Diagnostics for Global Travelers as a Basis for Infectious Disease Surveillance

Abstract

Background: Arboviruses have overlapping geographical distributions and can cause symptoms that coincide with more common infections. Therefore, arbovirus infections are often neglected by travel diagnostics. Here, we assessed the potential of syndrome-based approaches for diagnosis and surveillance of neglected arboviral diseases in returning travelers.

Method: To map the patients high at risk of missed clinical arboviral infections we compared the quantity of all arboviral diagnostic requests by physicians in the Netherlands, from 2009 through 2013, with a literature-based assessment of the travelers' likely exposure to an arbovirus.

Results: 2153 patients, with travel and clinical history were evaluated. The diagnostic assay for dengue virus (DENV) was the most commonly requested (86%). Of travelers returning from Southeast Asia with symptoms compatible with chikungunya virus (CHIKV), only 55% were tested. For travelers in Europe, arbovirus diagnostics were rarely requested. Over all, diagnostics for most arboviruses were requested only on severe clinical presentation.

Conclusion: Travel destination and syndrome were used inconsistently for triage of diagnostics, likely resulting in vast under-diagnosis of arboviral infections of public health significance. This study shows the need for more awareness among physicians and standardization of syndromic diagnostic algorithms.

Fig 1. Geographical distribution of medically important arboviruses that cause febrile disease in humans.

All arboviruses cause febrile symptoms, but symptoms more specific to certain viruses are represented in three columns: 1) Arthralgia-Rash (AR); 2) Neurological symptoms (NS), and 3) Hemorrhagic symptoms (HS). Arboviruses not known to cause more than febrile symptoms are preceded with a §-sign. Arboviruses more likely to be diagnosed in travelers are followed by *. DENV^ is a serocomplex encompassing multiple dengue viruses that can cause similar clinical disease in humans. For viruses in gray type, diagnostics are unavailable in the Netherlands but in most cases can tested through the European Network for Imported Viral Diseases (ENVID). Geographical regions based on UN definitions of world regions. EU, Sub-Saharan Africa and South & Southeast Asia regions are grouped in these representations for visual clarity but are subdivided according to UN definitions for analysis as can been seen in Figs 3–6. AR = arthralgia-rash; NS = neurological symptoms; HS = hemorrhagic symptoms; AKHV = Alkhurma hemorrhagic fever virus; BANV = Banna virus; BFV = Barmah Forest virus; BWAV = Bwamba virus; BUNV = Bunyamwera virus; CEV = California encephalitis virus; CHIKV = Chikungunya virus; CTFV = Colorado tick fever virus; CCHFV = Crimean-Congo hemorrhagic fever; DENV = Dengue virus; EEEV = Eastern equine encephalitis virus; GROV = Guaroa virus; ILEV = Ilesha virus; ILHV = Ilheus virus; JEV = Japanese encephalitis virus; KFDV = Kyasanur Forest disease virus; LCV = La cross virus; LIV = Louping Ill virus; MAYV = Mayaro virus; MURV = Murray Valley virus; NRIV = Ngari virus; OHFV = Omsk hemorrhagic fever virus; ONNV = O’Nyong Nyong virus; OROV = Oropouche virus; RVFV = Rift Valley fever virus; ROCV = Rocio virus; RRV = Ross river virus; SFV = Sandfly fever (Naples / Sicilian / other); SFTS V = Severe Fever with Thrombocytopenia Syndrome Virus; SINV = Sindbis virus; SLEV = St. Louis encephalitis virus; TAHV = Tahyna virus; TATV = Tataguine virus; TBEV = Tick-borne encephalitis virus; TOSV = Toscana virus; VEEV = Venezuelan equine encephalitis virus; WEEV = Western equine encephalitis virus; WNV = West Nile virus; YFV = Yellow fever virus; ZIKV = Zika virus.

Fig 2. Geographical depiction of the number of diagnostic tests requested after travel to each region (see gray shading and tables) from 2009 to 2013.

Boxes show number and percentage of all vacations booked from the Netherlands to each region in 2011.

Fig 3. Percentage of patients (left axis) with arbovirus diagnostic requests presenting with symptoms by travel destination (horizontal axis).

The number of patients per group is shown in parentheses on the horizontal axis (based on 2153 patients with both travel and clinical history).

Fig 4. Heatmapsshowing percentage of patients with a travel history to Africa, divided by region (right axis) and recorded symptoms (left axis), who were tested for each arbovirus (horizontal axes) posing a risk on that continent (see Fig 1).

The number of patients in each region-symptom combination follows each region in parentheses, far right. Groups in which a 100% of patients with a specific region-symptom combination were tested are depicted as black, with a sliding scale to white for groups in which 0% of patients were tested. Region-symptom combinations that are atypical for a certain arbovirus are depicted as diagonal lines.

Fig 5. Heatmap showing percentage of patients with a travel history to Asia, divided by region (right axis) and recorded symptoms (left axis), who were tested for each arbovirus (horizontal axes) posing a risk on that continent (see Fig 1).

The number of patients in each region-symptom combination follows each region in parentheses, far right. Groups in which a 100% of patients with a specific region-symptom combination were tested are depicted as black, with a sliding scale to white for groups in which 0% of patients were tested. Region-symptom combinations that are atypical for a certain arbovirus are depicted as diagonal lines.

Fig 6. Heatmap showing percentage of patients with a travel history to Americas, divided by region (right axis) and recorded symptoms (left axis), who were tested for each arbovirus (horizontal axes) posing a risk on that continent (see Fig 1).

The number of patients in each region-symptom combination follows each region in parentheses, far right. Groups in which a 100% of patients with a specific region-symptom combination were tested are depicted as black, with a sliding scale to white for groups in which 0% of patients were tested. Region-symptom combinations that are atypical for a certain arbovirus are depicted as diagonal lines.