Recombinant human granulocyte-colony stimulating factors (G-CSF) is a member of the hematopoietic growth factor family that mobilizes and increases peripheral blood hematopoietic stem cells in both blood donors and cancer patients. G-CSF is primarily used to promote an increase in neutrophil count during bone marrow transplantation and prevent chemotherapy-induced febrile neutropenia (Link, 2022). The common adverse reactions of G-CSF include fever, back pain, headache, bone pain, and myalgia. Severe adverse events include acute lung injury, acute coronary syndrome, and acute aortitis (D'Souza et al., 2008). According to Japanese Adverse Drug Event Report database, aortitis occurring after G-CSF administration is considered an adverse reaction of G-CSF (Oshima et al., 2019). Aortitis induced-by G-CSF is extremely rare, with an incidence rate of 0.3%–0.74% in patients with malignant neoplasms (Sasaki et al., 2021; Takamatsu et al., 2022; Lee et al., 2020).

Aortitis associated with G-CSF administration primarily presents as a systemic symptoms, manifesting as fever and increased levels of c-reactive protein (CRP) (Lee et al., 2020). Due to the similarity of symptoms, it is highly likely to be misdiagnosed as an infection, thereby delaying the timely treatment of aortitis. CT is one of the crucial diagnostic tools for definitive diagnosis.

Based on the cases reported to date, there are four types of G-CSF associated with aortitis, including filgrastim, lenograstim, pegfilgrastim and lipegfilgrastim. Filgrastim and lenograstim, are short-acting G-CSF, which have a similar structure and biological activity to endogenous human G-CSF (Lee et al., 2020). Pegfilgrastim and lipegfilgrastim are long-acting agent of G-CSF (Lee et al., 2020). Most notably, pegfilgrastim and filgrastim account for the majority of reported cases of aortitis. Although adverse events of arteritis caused by G-CSF have been reported in previous studies (Ito et al., 2023; Ito et al., 2024; Hoshina and Takei, 2019), adverse events of arteritis have not been described in large-scale cohort studies.

In the present study, we attempted to explore distribution, occurrence and combination therapy characteristics of G-CSF-induced aortitis. To achieve this aim, we analyzed data from case reports of aortitis induced by G-CSF published in databases.

Among all the published case reports, G-CSF-induced aortitis tended to affect elderly women over the age of 60. In addition, the cases of male G-CSF-induced aortitis observed in this review may reflect a higher likelihood of occurrence of prostatic cancer in men. The reason why G-CSF-induced aortitis is more likely to occur in females compared to males is not yet clear, so more samples would be needed to verify the gender differences in G-CSF-induced aortitis. Moreover, G-CSF-induced aortitis was frequently observed in patients with breast cancer as the primary tumor and in patients who received the anticancer drugs docetaxel and cyclophosphamide. The two drugs were used as combination therapy for patients with esophageal cancer (docetaxel and cyclophosphamide). Although, several reports have discussed the relationship between G-CSF-induced aortitis and anticancer drugs, especially docetaxel (Hoshina and Takei, 2021; Taimen et al., 2020). Our finding was that more patients with G-CSF induced aortitis have been using docetaxel, which is consistent with previous reports. However, the causal relationship between docetaxel and G-CSF-induced aortitis remains unclear. In addition, the drug instructions indicate that cyclophosphamide may lead to adverse reactions such as vasculitis. Therefore, when G-CSF is necessary, close attention should be paid to the clinical symptoms of patients when using cyclophosphamide in combination.

We discovered that over three-fourths of all cases occured in Asian populations, particularly in Japan and Korea. Human leucocyte antigen (HLA) as the genetic system with the richest polymorphism in humans, plays a crucial role in intercellular recognition, antigen recognition, and antigen presentation, resulting in different susceptibility of HLA genes to diseases. Evidence shows that HLA-DRB1*09:01 is one of the most common HLA-DRB1 alleles in Asians but is rare in European and American populations (Tsuchiya, 2013). Meanwhile, HLA-DRB1*09:01 has been shown to be associated with antineutrophil cytoplasmic antibody-associated vasculitis in Japan (Tsuchiya, 2013). In addition, previous literature has shown that the HLA-DRB1*04 and DRB1*07 alleles were strongly associated with aortitis in a Chinese Han population (Dang et al., 2002). The reason why G-CSF-induced aortitis was more common in Asian regions such as Japan and South Korea may be related to susceptibility genes in the Asian population that predispose to the development of aortitis. However, there is no evidence to support the correlation between HLA genes and G-CSF-induced aortitis. Therefore, it is necessary that further research will be conducted on the correlation between aortitis and HLA genes in populations prone to G-CSF- induced aortitis.

Our research findings also provided a deeper understanding of asymptomatic G-CSF-induced aortitis, which occurred in 4 out of 72 cases. These 4 asymptomatic patients with aortitis were found to have occurred between 1 and 2 weeks after using G-CSF through CT examination. Due to early detection, only G-CSF was discontinued for these asymptomatic patients and they did not receive treatment with glucocorticoids or NSAIDs. If G-CSF failed to discontinue medication timely in this type of patient, it was not clear whether it would lead to severe symptoms in the later stage. Therefore, considering the rarity of asymptomatic vasculitis and the issue of health economics, whether it is necessary to use ultrasound or CT for screening is not yet conclusive.

Currently, two types of G-CSF are clinically available, one being short-acting G-CSF including filgrastim and lenograstim, and another type being long-acting G-CSF including pegfilgrastim and lipegfilgrastim. We found that the proportion of pegfilgrastim was highest in G-CSF-induced aortitis cases, followed by filgrastim. In terms of pharmacokinetics, the half-life of filgrastim is 3.5 h, and that of pegfilgrastim is 33.2 h (Zamboni, 2003). Compared with filgrastim, pegfilgrastim was more likely to induce aortic inflammation, potentially due to its longer pharmacological effect. G-CSF-induced aortitis lesions were reported to be common in the aortic arch and proximal bifurcation. The distribution patterns of the aortitis are consistent with the findings of a single-center analysis by Takamatsu et al. (Lee et al., 2020). Owing to the unique anatomical structure of the aortic arch, hemodynamic instability heightens the risk of aortic dissection occurring at this location (Williams et al., 2022). Therefore, for patients with arteritis in the aortic arch and its branches, the treating physicians should be vigilant and actively treat to prevent the occurrence of aortic aneurysm and aortic dissection.

According to etiology, arteritis can be broadly classified as infectious and non-infectious (Benhuri et al., 2020). However, the underlying mechanism of aortitis-induced by G-CSF is still unclear. Functionally, G-CSF is a growth factor that regulates many aspects of neutrophil biology, including proliferation, differentiation, release, trafficking, and survival of granulocytes (Martin et al., 2021). However, in autoimmune and inflammatory diseases, the neutrophil response must be strictly regulated, as excessive recruitment and activation, or prolonged neutrophil survival time, can lead to chronic inflammation and sometimes irreversible organ damage (Martin et al., 2021). In this study, pegfilgrastim had the highest proportion of arterial inflammation, which may be related to its longer biological half-life.

G-CSF-induced aortitis exhibited good responsiveness to corticosteroids or NSAIDs and had a favorable prognosis. However, among all the collected cases, 2 cases had aortic dissection (Shiraki et al., 2022; Sato et al., 2017) and 1 case had aortic aneurysm (Miller et al., 2016). One case was a 58-year-old healthy male who was injected with filgrastim to donate bone marrow stem cells. Six months later, an iliac artery aneurysm was discovered (Miller et al., 2016). In the other two cases, after corticosteroids treatment, the symptoms of G-CSF-induced aortitis improved, but CT scans revealed aortic dissection (Shiraki et al., 2022; Sato et al., 2017). These cases suggested that even after the symptoms improve during corticosteroids therapy, there was still a risk of developing aortic dissection. Therefore, before corticosteroids reduction, it should be recommended to recheck CT to clarify the recovery status of arteritis.

There is controversy concerning the acceptability of re-administration or change dosage form of G-CSF in patients with a history of G-CSF-induced aortitis. Among all collected cases, three underwent pegfilgrastim re-administration later; three of the patients exhibited recurrence of pegfilgrastim-induced aortitis. One case who had clinically diagnosed pegfilgrastim-induced aortitis, after switching to filgrastim, still developed G-CSF-induced aortitis. One case who had clinically diagnosed filgrastim-induced aortitis, after switching to lenograstim, also reappeared with G-CSF-induced aortitis. This indicated that patients with a history of G-CSF-induced aortitis, whether through repeated use or changes in dosage form, cannot rule out the possibility of recurrent G-CSF-induced aortitis. However, considering the reporting bias, further validation of clinical data is needed for this possibility.

In conclusion, regardless of the dosage form of G-CSF, there is a risk of leading to arteritis. Due to the increased use of prophylactic treatment for chemotherapy-related neutropenia, the frequency of G-CSF-induced aortitis had also increased. In addition, G-CSF-induced aortitis also occured in healthy stem cell donors. Especially, asymptomatic patients with G-CSF-induced aortitis faced a greater risk of being missed by the attending physician. Given the regional characteristics of G-CSF-induced aortitis, it is recommended that physicians should pay close attention to the Asian population, especially elderly women after using G-CSF, to prevent the occurrence of complications of vasculitis.