Revisiting the Loa loa microfilaremia thresholds above which serious adverse events may occur with ivermectin treatment.

Background: Loiasis was long deemed to be a benign condition, but individuals with high Loa loa microfilarial densities (MFD) are at risk of serious adverse events (SAEs) including encephalopathy following ivermectin (IVM) administration. The risk of marked AE or SAE is usually considered when MFD exceeds 8000 microfilariae (mf)/mL or 30,000 mf/mL, respectively. There are no international guidelines on the treatment of loiasis, resulting in a variety of practices worldwide for the treatment of infected individuals outside endemic areas. Our objective was to determine the probabilities of SAEs after IVM administration at the usual thresholds, and to refine those thresholds using individual characteristics such as age and sex.

Methods: We used data from two clinical trials conducted in Cameroon where L. loa MFD were determined before IVM administration. The risk of SAE was modeled as a logistic function of age, sex, and MFD transformed as a first-order fractional polynomial.

Principal findings: SAEs probabilities were found to be <104 for MFD<2000 mf/mL, > 1‰ for MFD >8000 mf/mL, >1% for MFD>20,000 mf/mL, and >2.5% for MFD>30,000 mf/mL. We showed that specific categories may be at a higher risk of SAE than expected. Specifically, in order not to exceed 1% risk, the corresponding thresholds would be 18,000 mf/mL for females in the 31-40 age group; 16,000 mf/mL for males in the 21-30 age group; 12,000 mf/mL for males in the 31-40 age group; and 19,000 mf/mL for males in the 41-50 age group.

Conclusions: Our study suggests that IVM should be used with caution for males or individuals in specific age categories with a high L. loa MFD. For these high risk groups, lowering the thresholds to 8000 mf/mL should be considered. The increased risk in males requires further investigation to understand the pathophysiological phenomena involved that are crucial to prevent and manage SAEs.