Pediatric Nephrology | 2021
Treatment strategy for Streptococcus pneumoniae-associated hemolytic uremic syndrome
Abstract
Dear Editors, We read with great interest the article by Holle and colleagues about complement activation in Streptococcus pneumoniaeassociated hemolytic uremic syndrome (SpHUS) [1]. The authors report a series of 7 children diagnosed with SpHUS over 24 years, two of whom had functional and genetic abnormalities in complement regulatory proteins (risk haplotype in MCP gene). Three children were treated with the complement C5 inhibitor eculizumab in the context of signs of complement activation and/or suspicion of atypical HUS. They received one dose, three doses, and 6 months of eculizumab therapy, respectively. All three treated patients survived and showed rapid hematological recovery. Kidney outcome was good among those treated by eculizumab with CKD stages 1, 2, and 3b at the time of last follow-up (2 to 5 years after disease onset). The authors conclude that some SpHUS patients may benefit from complement inhibition. During quite a similar period (2004–2019), we also managed 7 children with SpHUS (5 boys, median age 8 months, four pneumonia/three meningitis, acute dialysis required in 6) at our institution and found a different prognosis with eculizumab treatment. Overall prognosis was poor: one patient died within the acute phase, two did not recover and progressed to kidney failure, and two have impaired kidney function. The diagnostic workup included ADAMTS-13 activity (low in one case) and assessment of complement function. Two patients showed decreased serum C3 level in a context of inflammatory state. Transient decreased expression of MCP on peripheral leucocytes was observed in one case. Genetic studies using high throughput sequencing of known aHUS genes (MCP, Factor H, Factor I, Factor B, C3, and DGKE in some cases) was carried out in 6 patients and revealed no genetic susceptibility factors. Two patients with C3 consumption received eculizumab therapy (1 to 3 doses) without evidence for improvement in clinical response. SpHUSmay account for 5–10% of HUS cases, but appears to be underdiagnosed owing to the severity of invasive pneumococcal disease. Its pathogenesis remains unclear, although the role of the Thomsen-Friedenreich antigen (T antigen) has been hypothesized. Streptococcus pneumoniae produces neuraminidase, thereby exposing the T antigen on the surface of cell membranes. This specific T antigen may induce endothelial injury leading to SpHUS. More recently, new insights into the mechanisms underlying the pathology of SpHUS have been provided suggesting a role for the complement system. It has been postulated that complement Factor H binding and function on desialylated membranes may be impaired in SpHUS. Streptococcus pneumoniae Factor H binding proteins like pneumococcal surface protein C (PspC) have been identified promoting enhanced binding of plasminogen and, thus, plasmin generation that may lead to endothelial injury in SpHUS [2]. Whether complement system dysregulation leads to thrombotic microangiopathy in SpHUS, or is a consequence of invasive pneumococcal disease without a major role in kidney injury, is unknown. The current management of SpHUS is supportive. Fresh frozen plasma should be avoided in children with no bleeding manifestations. The findings from Holle et al. and from other groups further support the concept that Streptococcus pneumoniae may initiate complement activation directly, providing a rationale for complement blockade in SpHUS [1, 3]. In the absence of other specific treatment, it is therefore tempting to give eculizumab to selected SpHUS patients. There are anecdotal case reports of SpHUS treated with eculizumab showing conflicting results. Contrary to the report by Holle et al. which provides further knowledge on the use of C5 inhibitor in SpHUS, the lack of clinical improvement associated with eculizumab therapy in our experience has been disappointing. * Jerome Harambat [email protected]