Severe imported Plasmodium falciparum malaria with hyperparasitaemia: evaluation of determinants of critical disease in adult returning travellers

Background: Severe Plasmodium falciparum (P.f.) malaria remains a major health threat for travellers. World Health Organization (WHO) defines criteria for severe malaria, including hyperparasitaemia ≥10% infected red blood cells (iRBCs), as major risk factors for adverse outcome. Additionally, WHO recognizes ‘uncomplicated hyperparasitaemia’ with 4–10% iRBC, a parasite density usually defining severe malaria outside endemic areas. Overall, the role of hyperparasitaemia as an independent risk factor in imported severe malaria is unclear, with most data predating the artemisinin era. Methods: We retrospectively analysed adult in-patients with hyperparasitaemia (≥4% iRBC) and/or severe P.f. malaria according to WHO criteria who received artemisinin-based treatment at two German university hospitals 2013–2023, to assess the risk for critical disease with need for organ replacement therapy or vasopressors. Based on multivariable nominal logistic regression, we developed a scoring system to identify patients with critical disease and validated it on an independent cohort. Results: Of 168 patients, 33 (20%) developed critical disease, all of whom presented with at least one WHO criterion other than hyperparasitaemia. Of 72 patients with isolated hyperparasitaemia, none developed critical disease. Hyperparasitaemia was no independent risk factor for critical disease in logistic regression (adjusted odds ratio (aOR) 0.85 95%CI 0.23–3.12), in contrast to creatinine >3 mg/dl (aOR 6.74 95%CI 1.06–42.75), oligo-/anuria (aOR 5.94 95%CI 1.27–27.82), lactate ≥5 mmol/l (aOR 8.16 95%CI 8.16–35.03), confusion (aOR 4.07 95%CI 1.39–11.94) and circulatory shock and respiratory failure, which are inherently critical conditions. The risk score identified all 33 patients with and 131/135 (97.0%) without critical disease (AUC=0.99; sensitivity: 100%; specificity: 97.0%). In the validation cohort, all eight patients with critical disease and 39/44 (89%) without were correctly identified. Conclusion: Isolated hyperparasitaemia was no independent risk factor for critical disease in this patient cohort treated with artemisinins, suggesting that such patients can be managed outside intensive care units.