Eculizumab is a humanized monoclonal antibody to complement factor 5 that blocks complement activation. It was first used to prevent the breakdown of red blood cells in adults with paroxysmal nocturnal hemoglobinuria (PNH) and was approved by the United States Food and Drug Administration (FDA) in 2007. It is also used in adults and children weighing at least 5 kg to treat a blood disease called atypical hemolytic uremia (aHUS, approved in 2011), as well as generalized myasthenia gravis (gMG, approved in 2017) with positive anti-acetylcholine receptor (AchR) and neuromyelitis optica spectrum disorder with positive anti-aquaporin-4 (AQP4) (NMOSD, approved in 2019) (Patriquin and Kuo, 2019; Zhang et al., 2024). On 28 May 2024, the FDA approved eculizumab-aeeb as the first interchangeable biosimilar to eculizumab. One month later, on 22 July 2024, the FDA approved eculizumab-aagh. Both are approved as interchangeable biosimilars to eculizumab (brand name: Soliris) to treat the following indications: aHUS and PNH.

In recent years, there has been a high demand for the use of eculizumab in an increasing number of diseases characterized by complement dysregulation, whether it is on-label or off-label. The FDA has added a black box warning regarding serious and life-threatening infections caused by Neisseria meningitidis (Avasarala et al., 2021). Eculizumab specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9 (Patriquin and Kuo, 2019). For these reasons, eculizumab indeed increases the infection risk of capsule-forming bacteria such as Neisseria spp. (Niitsuma-Sugaya et al., 2021). In addition to Neisseria spp., severe Neisseria gonorrheae (Niitsuma-Sugaya et al., 2021), bacteremia (Kawakami et al., 2018), Cryptococcus (Lortholary et al., 2023) and virus-related infections (Okusa et al., 2024) have been reported.

As eculizumab is expected to lead to increased susceptibility to infection, more studies on the incidence of infection induced by eculizumab are needed. To the best of our knowledge, no studies on this incidence have been published in clinical trials. We therefore summarized all available evidence from RCTs for a comprehensive and rigorous meta-analysis of the risk of infection associated with eculizumab.

As eculizumab increases susceptibility to infection, along with its high efficacy, it has been widely used for different indications and for different diseases. However, whether eculizumab increases the risk of infection remains uncertain. This meta-analysis is the first to provide a comprehensive overview of eculizumab-associated infection risk on the basis of nine RCTs, including 691 patients. The major findings were as follows: (1) eculizumab did not increase the risk of overall infection or the incidence of both general and serious infections; (2) eculizumab use was associated with a greater risk of general urinary system infection and severe bacteraemia; and (3) eculizumab use might increase the risk of other severe infections, such as cellulitis and conjunctivitis.

Several meta-analyses and systematic reviews have focused on eculizumab. However, owing to its large-scale application and indications in different systemic diseases, these meta-analyses are based on the efficacy or safety of one disease (Beyer and Fridovich, 1987; Zhou et al., 2021; Tang et al., 2023). In these studies, the overall incidence of adverse events (AEs) was considered, but no systematic analysis of specific adverse events (such as infection) was performed. However, eculizumab-induced infections were previously limited to those reported on N. meningitidis and Neisseria gonorrheae infections. In clinical treatment, eculizumab is contraindicated in patients who are not currently vaccinated against N. meningitidis unless the risk of delaying eculizumab treatment outweighs the risk of developing a meningococcal infection. Seven of nine included RCTs required patients to have been vaccinated against Neisseria meningitides. In the other two studies, if patients’ meningococcal vaccination was not performed, all enrolled patients received antibiotic prophylaxis against N. meningitidis from the time of the first dose of the study drug to 8 weeks after the last administration. Currently, several pharmacovigilance studies have investigated the FAERS database and published literature on eculizumab-related infection adverse events (Okusa et al., 2024; Zhang et al., 2024). Pharmacovigilance studies have shown that eculizumab is associated with a significantly increased risk of N. meningitidis infection, as well as gonococcal and streptococcal infection. Considering an important limitation of that study, i.e., that only some AEs with a high incidence were retrieved, their assessment of the risk of infection was not comprehensive. The Associazione Italiana Emoglobinuria Parossistica Notturna (AIEPN) (Girmenia et al., 2023) has produced recommendations for the management of infection in PNH patients treated with eculizumab, but this recommendation is still limited to Neisseria spp. Therefore, considering the limitations of previous studies, this meta-analysis included all the infection events reported in RCTs, regardless of whether they were common or not, to systematically evaluate the risk of infection associated with eculizumab. Eculizumab increases the risk of life-threatening infections with Neisseria spp. The estimated risk is 0.5% per year or 5% after 10 years of treatment (Goh et al., 2024). The absence of Neisseria infections in our analysis may be attributed to effective vaccination protocols in most studies, comprehensive antibiotic prophylaxis strategies and potential sample size and the duration of follow-up limitations. However, the potential risk should not be underestimated. This underscores the importance of sustained vigilance and patient education. However, the risk of Neisseria infection should be closely monitored in clinical practice because vaccinated patients also have the possibility of becoming infected (McNamara et al., 2017). With respect to Neisseria gonorrheae infections, guidelines do not suggest any prevention strategy other than paying attention to lifestyle (Girmenia et al., 2023).

Moreover, in addition to the currently published study data, we also included data on infection-related adverse effects published publicly available on the ClinicalTrials.gov website to make the study more comprehensive. We ultimately confirmed that, compared with placebo or standard of care, eculizumab was associated with a relatively high risk of severe bacteremia and other infections. However, three RCTs in the article did not adopt a double-blind design, which may introduce bias. The diagnosis of bacteremia primarily relies on laboratory tests (e.g., blood cultures), which are less susceptible to subjective influence and thus may have lower bias. In contrast, the diagnosis of urinary tract infection (UTI) depends not only on urine cultures but may also involve symptom reporting (e.g., urinary frequency, dysuria), making it more prone to reporting bias in non-blinded trials, potentially leading to false-positive results. We acknowledge that the impact of underreporting mild infections cannot be entirely ruled out, which may lead to an underestimation of the overall infection risk and an overestimation of the relative risk of severe infections. Nevertheless, considering all the evidence, we believe the main conclusions remain valid.

Eculizumab has diverse clinical indications, and many of the included RCTs investigated off-label uses of this drug. Notably, we observed variations in the initial dosing regimens of eculizumab across studies (600 mg weekly vs. 900 mg weekly). 3/4 studies reporting severe bacteremia used 900mg, suggesting dose-related risk - though confirmation is limited by scarce 600 mg data (Supplementary Figure S5). However, this observation requires cautious interpretation due to the limited number of RCTs using the 600 mg regimen. Further studies are needed to validate this finding.

We also assessed the association of bacteremia with prophylactic antibiotic use during eculizumab treatment. However, of the four RCTs included, three studies did not use antibiotics prophylactically, whereas only one RCT was used; thus, more studies are needed in the future.

In view of related studies (Marks et al., 2019; Pittock et al., 2019), the high incidence of general urinary tract infections (including urinary tract infections, cystitis, pyelonephritis, etc.) in patients treated with eculizumab, especially in patients with underlying kidney diseases, requires special attention. In Garnier et al. (Garnier et al., 2023) and Marks et al. (Marks et al., 2019)studies, patients had higher baseline creatinine levels, and most patients were already on dialysis when receiving eculizumab treatment. Structural urinary tract abnormalities, voiding dysfunction, or concomitant use of immunosuppressants in patients with underlying kidney diseases may have potentially influenced the results. Underlying kidney disease may increase susceptibility to UTIs, as several studies related to complement inhibitors have reported corresponding UTI risks (Gäckler et al., 2021; Socié et al., 2019). Therefore, in clinical practice, it is recommended to strengthen UTI monitoring in patients receiving complement inhibitors, especially those with renal insufficiency. For example, clinicians should first conduct a comprehensive assessment of patients’ conditions for possible risk factors, such as age, history of infection, history of urinary surgery, and history of immunosuppressant exposure and vaccination.

Second, this study suggests a high risk of severe bacteremia associated with eculizumab (with or without antibiotic prophylaxis). Therefore, prophylaxis of meningococcal infections with antibiotics should be given until 14 days after the administration of the meningococcal vaccine. Alternatively, long-term antibiotic prophylaxis has been implemented in some countries. While waiting for more data, a cautious approach is advised. Third, in our findings, the incidence of other serious infections (including cellulitis, otitis media, conjunctivitis, or some fungal-related infections that do not indicate the site of infection) was higher in the eculizumab group than in the placebo group, but the difference was not significant. However, adequate laboratory and instrumental tests are also necessary to make an early diagnosis and promptly start treatment where appropriate. Current guidelines (Lee et al., 2020; Girmenia et al., 2023; Goh et al., 2024; Red Blood Cell Disease GroupChinese Society of HematologyChinese Medical Association, 2024) primarily emphasize meningococcal infection prophylaxis, while few mentioned routine infection monitoring. Notably, no specific recommendations address UTI/bacteremia surveillance. Based on our risk stratification analysis, we propose the following evidence-based recommendations: (1) inclusion of severe bacteremia in eculizumab’s significant adverse drug reaction profile; (2) development of tailored monitoring algorithms for high-risk populations. For all eculizumab-treated patients, immediately take the blood cultures during febrile episodes. High-risk subgroups (e.g., indwelling catheters) could consider periodic inflammatory marker testing (e.g., C-reactive protein). Urine cultures for all symptomatic UTIs in eculizumab-treated patients; (3) implementation of targeted clinical trials to assess active surveillance strategies. It should be noted that the inherent limitations of meta-analytic methodology preclude definitive conclusions regarding optimal screening frequency, which would require prospective cohort studies. In summary, although the overall risk of eculizumab infection is not clearly elevated, it is important to understand and identify the risk of bacteremia or urinary tract infection with eculizumab as early as possible for clinical treatment.

The major advantage of this study was that we comprehensively assessed the risk of infection in patients treated with eculizumab on the basis of evidence from RCTs. There are several limitations in this meta-analysis. First, three of the included RCTs were non-double-blind studies, with moderate evidence of quality, although the sensitivity analysis revealed that their effect on the results was not significant. Second, the clinical trials included in our study were performed at various international institutions, which might have varying expertise and ability to detect infection, making it possible that the reported incidence was biased. In addition, this meta-analysis included all indications for eculizumab, and some inherent differences in the underlying conditions of patients may have affected the results. Fourth, the timing of infection occurrence might be related to the duration of treatment and follow-up. We initially excluded patients with less than 4 weeks of treatment, but the longer the follow-up period was, the greater the number of reported infections was; therefore, the results must be interpreted with caution. Fifth, owing to the limited number of cases, certain infections (otitis media acute, tinea pedis, cellulitis, etc.) were not included in the subgroup of different types of infection in the meta-analysis. Finally, this study only evaluated the infection risk of eculizumab on the basis of data from RCTs; to extend RCT findings to large patient populations in real-world clinical practice, further research with larger samples of real-world studies evaluating eculizumab safety is necessary.

In conclusion, by systematically evaluating evidence from RCTs, we confirmed that although eculizumab did not significantly increase the overall risk of infection, regardless of general or severe infection, it did significantly increase the risk of general urinary system infection and severe bacteremia. These findings can help clinicians assess the risk of infection in patients treated with eculizumab.