Frequency and persistence of post-acute symptoms after chikungunya, dengue, Zika and malaria in travellers: a prospective multi-centre study

Background
Long-term follow-up data on the travel-associated burden of vector-borne diseases (VBDs) are scarce. A prospective multi-site observational study was conducted to delineate the longitudinal course, symptom patterns, physical and mental burden and factors associated with prolonged illness in travellers after four VBDs.

Methods
Patients with confirmed travel-associated acute chikungunya, dengue, Zika or falciparum malaria were recruited at 15 GeoSentinel sites from 2016 to 2021. Persistent signs and symptoms were evaluated at 1, 3, 6, 12 and 18 months (M) post-diagnosis, using a multi-modular study questionnaire with quality of life (QOL) evaluated by 12-item short-form health survey (SF-12). Demographic, premorbid and acute disease characteristics were tested in multivariate analyses to determine factors associated with persistence of symptoms at M3. Missing data were imputed by rules and statistical methods.

Results
Among 273 patients enrolled, 35 (13%) had chikungunya, 110 (40%) dengue, 19 (7%) Zika and 109 (40%) falciparum malaria. Median age was 38 years (interquartile range 30-49), 148/273 (54%) were men. At M3, 24/35 (69%) of chikungunya, 27/110 (25%) of dengue, 8/19 (42%) of Zika and 12/109 (11%) of malaria patients had persistent symptoms. The proportion of symptomatic chikungunya patients was 18/35 (51%) at M6, mainly due to musculoskeletal symptoms including arthritis and stiffness. In dengue patients, fatigue and musculoskeletal symptoms without arthritis persisted until 1 year. Zika patients reported persisting headaches, musculoskeletal symptoms including arthritis and fatigue. One month after malaria, fatigue was the main persisting symptom, which resolved almost completely at M3. At M12, 6/35 (17%) of chikungunya, 5/110 (5%) dengue, 3/19 (16%) Zika and only 1/109 (1%) of malaria patients were still symptomatic. Impaired QOL was noted at M3 by 23/35 (66%) of patients with chikungunya, 20/110 (18%) with dengue and 6/19 (32%) with Zika but only 4/109 (4%) with malaria. Female sex, Zika, chikungunya and musculoskeletal symptoms during acute infection were associated with persistent M3 symptoms.

Results
Among 273 patients enrolled, 35 (13%) had chikungunya, 110 (40%) dengue, 19 (7%) Zika and 109 (40%) falciparum malaria. Median age was 38 years (interquartile range 30-49), 148/273 (54%) were men. At M3, 24/35 (69%) of chikungunya, 27/110 (25%) of dengue, 8/19 (42%) of Zika and 12/109 (11%) of malaria patients had persistent symptoms. The proportion of symptomatic chikungunya patients was 18/35 (51%) at M6, mainly due to musculoskeletal symptoms including arthritis and stiffness. In dengue patients, fatigue and musculoskeletal symptoms without arthritis persisted until 1 year. Zika patients reported persisting headaches, musculoskeletal symptoms including arthritis and fatigue. One month after malaria, fatigue was the main persisting symptom, which resolved almost completely at M3. At M12, 6/35 (17%) of chikungunya, 5/110 (5%) dengue, 3/19 (16%) Zika and only 1/109 (1%) of malaria patients were still symptomatic. Impaired QOL was noted at M3 by 23/35 (66%) of patients with chikungunya, 20/110 (18%) with dengue and 6/19 (32%) with Zika but only 4/109 (4%) with malaria. Female sex, Zika, chikungunya and musculoskeletal symptoms during acute infection were associated with persistent M3 symptoms.

Conclusions
Post-arboviral symptoms and impaired QOL persisted beyond 6 months after chikungunya, dengue and Zika. In contrast, post-malaria fatigue syndrome resolved within 3 months.