Results from the first 200 ordered clinical modified ham (mHam) functional complement tests

Abstract

Abstract The bioluminescent modified Ham (mHam) test was invented to help diagnose complement-mediated thrombotic microangiopathy (CM-TMA)/atypical hemolytic uremic syndrome (aHUS). CM-TMA/aHUS is rare, life-threatening, and typically a diagnosis of exclusion. There are effective treatment options if a TMA can be established as complement-mediated; thus, getting the diagnosis quickly and correctly is key. The mHam is a functional cell-based assay where patient serum is mixed with a genetically-modified, complement-sensitized reporter cell line. Serum from aHUS patients will kill reporter cells, measured as a loss of bioluminescence. This killing is blocked by addition of a complement inhibitor (e.g., eculizumab). The mHam became available clinically in December 2024. The clinical mHam result is reported alongside soluble C5b-9 (sC5b-9, also known as soluble MAC) levels; sC5b-9 is a biomarker associated with fluid-phase complement activation. Here, we described the mHam and sC5b-9 results from the first 200 clinical samples ordered from our clinical reference laboratory. For some patients, we were also able to include additional clinical context (e.g., diagnosis, genetics). Patients with a negative mHam and normal sC5b-9 or with a positive mHam and elevated sC5b-9 were straight-forward to interpret since both tests were in agreement regarding whether complement activation was present. Surprisingly, about half of the patients where testing was ordered had an elevated sC5b-9 with a negative mHam result. By correlating the test results with the clinical story where available, we think the mHam is specific for aHUS while sC5b-9 can also be elevated by other causes.