Reply to Zayet et al

To the Editor—We thank Zayet et al for their comment on our work [1]. In this study, we quantified neurofilament light chain (NfL) in plasma from 167 children with uncomplicated malaria (UM) and severe malaria (SM) from Mozambique. We reported that NfL levels were similar in all malaria cases at hospital admission, but levels increased over time and the increment was more pronounced in SM with neurological manifestations. We appreciate the opportunity to extend the discussion of these findings. We defined neurological manifestations as presenting to the hospital with coma, impaired consciousness, or a history of ≥2 seizures in the previous 24 hours. However, we agree that results from our study cannot be generalized to all forms of malaria with some kind of neurological involvement. The association of NfL longitudinal levels with other neurological manifestations during the acute phase of the disease, postmalarial neurological complications, or long-term neurocognitive impairment could bring new insights. As Zayet et al point out, NfL levels in blood and cerebrospinal fluid of healthy individuals vary by age. The literature available suggests NfL levels are higher in younger children, decrease progressively until children reach 10–15 years old, and increase afterwards during adulthood [2–4]. As we included children from 1 to 12 years old, we adjusted linear mixed-effects models for child age. In all models, NfL levels were negatively associated with age. Future studies on NfL need to consider age carefully in the design and analysis stages. Moreover, it will be important to determine how NfL levels and longitudinal dynamics vary between pediatric and adult populations with malaria disease. As noted, there were 2 deaths in the SM group with neurological manifestations. These deaths occurred rapidly and we only had information on their NfL levels at one timepoint. One of the deaths corresponds to a 4-year-old boy, who at admission displayed impaired consciousness and had a plasma NfL concentration of 14.7 pg/mL. The other death occurred in a 2-year-old boy, who was admitted with coma and a history of repeated seizures, and had a plasma NfL level of 67.3 pg/mL at 12 hours postadmission. Although some studies have previously associated NfL levels with mortality in patients with infectious diseases [5, 6], we cannot draw meaningful conclusions about the NfL prognostic accuracy for death in children with malaria. A final point raised is that a past history of malaria in children could contribute to cumulative neuronal damage. We indicated this in the limitations, but we lacked detailed information on previous episodes of malaria to consider this in our analysis. However, while previous infections could affect basal NfL levels, in our study we also evaluated NfL longitudinal dynamics during a specific malaria episode. Further research is necessary to confirm and extend our results. Larger cohorts; additional timepoints for NfL measurement; consideration of other potential confounders; and evaluation of neuroimaging, electroencephalographic results, and long-term neurocognitive outcomes are warranted. Only then would we be able to determine the clinical utility of NfL and how its measurement, including cutoff values for intervention, could improve outcome for malaria patients. Nevertheless, our results advance our knowledge of brain injury pathobiology in pediatric malaria and suggest that NfL may prove useful in identifying and quantifying brain injury in malaria. We hope that these results will motivate additional research with a goal of reducing neurocognitive impairment and other adverse outcomes in malaria. Financial support. The discussed work was supported by the Canadian Institutes of Health Research Foundation grant FDN-148439 (to K. C. K.); a Canada Research Chair in Molecular Parasitology (to K. C. K.); and the Thomas Mather Fund (to K. C. K.). ISGlobal receives support from the grant CEX2018-000806-S funded by MCIN/AEI/10.13039/501100011033, and support from the Generalitat de Catalunya through the CERCA program. This research is part of ISGlobal's Program on the Molecular Mechanisms of Malaria, which is partially supported by the Fundación Ramón Areces. Centro de Investigação em Saúde de Manhiça is supported by the Government of Mozambique and the Spanish Agency for International Development. N. B. is supported by an FPU predoctoral fellowship from the Spanish Ministry of Universities (FPU18/04260). B. B. is a Beatriu de Pinos postdoctoral fellow granted by the Government of Catalonia's Secretariat for Universities and Research and by the Marie Sklodowska-Curie Actions COFUND Program (BP3, 801370). R. V. had a fellowship from the program Río Hortega of the Instituto de Salud Carlos III (CM16/00024) during the conduct of the study.

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