A clinical manifestation of TMA is HUS which is a rare, life-threatening syndrome. This disease is caused by adhesion of platelets to the vascular endothelium and consequently, their aggregation and activation results in the formation of platelet thrombi in the microvasculature. Therefore, the presentations of the disease occur, including acute renal failure, consumptive thrombocytopenia, and microangiopathic hemolytic anemia [17]. Typical HUS, or Shiga toxin–producing Escherichia coli–associated HUS (STEC-HUS), is the most common form of the disease that is associated with infection [18]. The bacteria's toxin leads to the deposition of complement on endothelial cells by increasing P-selectin expression, and it may disrupt the function of complement regulatory proteins. Moreover, children with STEC-HUS show complement activation as evidenced by elevated levels of alternative pathway products, including C3b, C3c, C3d, increased C5 convertase levels, and higher levels of the terminal complement complex sC5b-9 in their blood plasma [19–21].
In cases of atypical HUS, complement activation is triggered by genetic dysfunction of the complement alternative pathway [6]. Indeed, a specific trigger is often needed for the disease to manifest. External factors can lead to endothelial dysfunction and complement activation, which are usually controlled by various regulatory mechanisms in healthy individuals [22]. Individuals with genetic abnormalities that impact complement regulation are especially susceptible to complement attacks. When the complement cascade goes beyond a critical point, C3b formation and deposition happen on the vascular endothelium. This leads to further activation of alternative pathway, resulting in microangiopathic injury and thrombosis. Multiple studies have indicated that atypical HUS may start or recur due to bacterial and viral infections [12, 23]. This has been seen in COVID-19 patients as well. Recent findings support the idea that COVID-19 can stimulate renal TMA through the complement alternative pathway [24, 25]. In our case, it is also implied that COVID-19 infection has triggered the activation of alternative complement pathway in a previously healthy 8-year-old patient who had a homozygous pathogenic variant in the CD46 gene.
Aiello et al. demonstrated that the C5a/C5aR axis acts as a prothrombotic effector, promoting platelet aggregation and thrombus formation in the microcirculation in both COVID-19 and aHUS [26]. Previous studies have also indicated that the recurrence of aHUS can be triggered by infectious agents, such as viral pathogens like influenza A (H1N1 virus) and influenza B [27, 28]. While the connection between COVID-19 and aHUS has been documented, it remains limited to a few cases. Ville and colleagues have presented a case of a 28-year-old female patient who experienced a recurrence of aHUS, with genetic analysis revealing the presence of a pathological heterozygous variant in the MCP [29]. Furthermore, Kaufelld et al. have reported two cases in which patients with a pathogenic factor H mutation had their first aHUS attack following COVID-19 infection [30]. Smarz-Widelska et al. also discussed two related patients with a heterozygous mutation of MCP/CD46 in the complement system in whom familial aHUS relapse was triggered following an infection with COVID-19 [31].
Eculizumab, a humanized monoclonal antibody, has transformed the way patients with aHUS are treated. Several clinical trials have demonstrated the effectiveness and safety of Eculizumab treatment [32–34]. It is implied that starting Eculizumab treatment early provides the best chance for restoring renal function, preventing disease progression, and avoiding critical complications of TMA [35–37]. In the present case, plasmapheresis was useful for controlling the disease at the first patient’s admission to the hospital. However, the use of Eculizumab became a necessity during the patient's second hospitalization because plasmapheresis alone could not control the patient's symptoms.
In conclusion, this case report illustrates the potential for COVID-19 infection to trigger episodes of atypical hemolytic uremic syndrome, particularly in patients with underlying genetic predispositions to complement dysregulation. The diagnostic workup and management of aHUS require a multidisciplinary approach involving nephrologists, hematologists, and geneticists. Prompt recognition of the clinical features and genetic evaluation are necessary steps in the management of the disease. In addition, initiation of appropriate complement-targeted therapies such as Eculizumab are considered crucial for improving outcomes once COVID-19-associated HUS is established in order to prevent its consequent damages, such as organ failure. Therefore, treating COVID-19-associated HUS patients with the C5-blocker may be vital similar to typical cases of HUS.