Background

Pegfilgrastim (PEG-G) is a long-acting granulocyte colony-stimulating factor (G-CSF) widely used to prevent chemotherapy-associated febrile neutropenia in cancer patients. G-CSF preparations bind to G-CSF receptors on neutrophil progenitor cells in the bone marrow, promoting their differentiation into neutrophils. The most common adverse effects of G-CSF are bone pain and injection-site reactions, although generally less serious adverse events have been reported [1]. According to the Japanese Adverse Drug Event Report (JADER) by the Pharmaceuticals and Medical Devices Agency (PMDA), aortitis is an adverse effect of G-CSF, although this has rarely been reported [2]. Here, we report a rare case of PEG-G-induced aortic inflammation in a patient receiving post-operative chemotherapy for early breast cancer.

Case presentation

The case involved a 62-year-old postmenopausal woman without any personal or family medical history. The patient underwent a left mastectomy and sentinel lymph node biopsy for left breast cancer. A pathological examination revealed the following: invasive ductal carcinoma, pT2 (22 mm), nuclear grade 3, pN0, estrogen receptor (ER) and progesterone receptor (PgR) positive, human epidermal growth factor receptor 2 (HER2) negative, and pT2N0M0 stage IIa.

On day 1, the patient was administered a chemotherapy regimen consisting of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2), together with dexamethasone (6.8 mg). The patient was administered oral dexamethasone (8 mg) on days 2–4 and subcutaneous PEG-G on day 3. On day 10 (day 8 after PEG-G administration), the patient complained of intermittent high fever (up to 39.4 °C); the fever persisted even after the administration of levofloxacin (LVFX), which was prescribed for febrile neutropenia. In addition to fever, the patient developed other symptoms, including loss of appetite and shortness of breath, and visited our hospital on day 13 (11 days after PEG-G administration). At admission, the patient’s body temperature was 39.2 °C. Laboratory examination revealed a high neutrophil count (14,000/μL) and elevated CRP (42.78 mg/dL) without any other abnormalities. The erythrocyte sedimentation rate was 76 mm/h. The levels of anti-nuclear antibody (ANA), myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA), serine proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA), and rheumatoid factor were within normal limits. To rule out viral infections, we performed an antibody test for human T-cell lymphotropic virus type 1, cytomegalovirus, and human parvovirus B 19, which were all negative. No bacterial growth was observed in blood and urine cultures (Table 1).

Table 1 Results from laboratory examination on admission
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Contrast-enhanced computed tomography (CT) scan on pre-operation showed no abnormalities around the aorta (Fig. 1a–c). At the time of admission, CT scanning revealed soft tissue thickening with weak enhancement around the wall of the thoraco-abdominal aorta, aortic arch and left subclavian artery (Fig. 1d–f). From the patient’s clinical course and imaging data, we suspected G-CSF-associated aortitis. At that point, we could not rule out infection because we had no results of autoantibodies, viral antibody tests, or blood or urine cultures, so we continued antibiotics. On day 8 after admission, the patient’s fever resolved spontaneously and the neutrophil count and CRP level decreased to 3185/μL and 17.88 mg/dL, respectively. Based on the results of the autoantibody test, viral antibody test, and blood and urine culture tests at admission, the patient was considered not to have an infection, and antibiotics were discontinued. Corticosteroids were not administered because of the patient’s general improvement. 10 days after admission (20 days after PEG-G administration). The thickening around the aorta was reduced on CT scanning (Fig. 1g, h, Table 2).

Fig. 1
figure 1

Pre-operation computed tomography (CT) revealed no abnormalities around the aorta (a–c). CT scanning at the time of admission (d–f) revealed thickening of the arterial wall of the thoracic and abdominal aorta and increased fat concentration in the surrounding area. A CT scan after 10 days of hospitalization revealed reduced arterial thickening and fat concentration relative to the CT at the time of admission (g–i)

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Table 2 Timeline of patient treatment
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Chemotherapy was then discontinued and hormone therapy started. No recurrence of aortitis was observed for 15 months.

Discussion

Aortitis is classified as either non-infectious or infectious. Although the mechanisms of aortitis are not fully understood, non-infectious aortitis might be triggered by increased neutrophil-mediated damage and pro-inflammatory reactions (3). G-CSF stimulates proliferation and differentiation of neutrophil precursors [4] and the resulting immunological reactions can cause aortitis [5].

In the case reported here, we excluded autoimmune disease because all ANA, MPO-ANCA, and PR3-ANCA values were within normal ranges. Since viral antibody tests were also negative and no bacterial growth was observed in blood and urine cultures, we concluded that G-CSF was the most suspicious cause of this aortitis.

Corticosteroids are commonly used to treat patients with suspected autoimmune diseases, such as Takayasu arteritis (TAK). However, there is no established treatment for G-CSF-associated aortitis. In general, G-CSF-associated aortitis has good prognosis and often resolves spontaneously without the administration of corticosteroids [6]. Moreover, previous reports show that there is no difference in the therapeutic effect and the time to remission of G-CSF-associated aortitis with or without corticosteroids [7]. The cases of G-CSF-associated aortitis reported in recent years are listed in Table 3 [6,7,8,9,10,11,12,13].

Table 3 Reported cases of G-CSF-associated aortitis in recent years
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Aortitis caused by PEG-G tended to develop within 2 weeks of G-CSF administration and to resolve spontaneously within 3 weeks, as in the present case. We hypothesized that this common period of time was due to the duration of action of PEG-G, and that once the effects of PEG-G wore off, the aortitis would spontaneously abate. What is also interesting about this case is that despite the extensive lesions, the disease resolved quickly and spontaneously without corticosteroid treatment. This suggests that the extent of the lesions is not related to the need for corticosteroid treatment. On the other hand, it has been reported that G-CSF-associated aortitis lasting more than 3 weeks was relieved by corticosteroid administration, and we believe that corticosteroids should be considered in cases of long-term lack of improvement.

Although there are reports of G-CSF re-administration after symptom improvement in patients with G-CSF-associated aortitis, caution is required because some patients had recurrent aortitis [6, 14]. In this case, at the patient’s request, we shifted to endocrine therapy without re-administering PEG-G, and aortitis recurrence was not observed for 15 months after the onset of symptoms.

In breast cancer patients, dose-dense chemotherapy involving more frequent administration of chemotherapy agents than in standard chemotherapy significantly improved clinical outcomes [15, 16]. The addition of G-CSF to chemotherapy regimens to prevent chemotherapy-induced febrile neutropenia yields favorable clinical outcomes in breast cancer patients [17, 18]. Therefore, physicians should be aware that because most breast cancer patients undergo chemotherapy with PEG-G, aortitis may easily develop.

Conclusion

Clinicians should be aware of aortitis as a possible complication in patients undergoing chemotherapy with G-CSF. In cases with persistently high fever after G-CSF administration, aortitis should be suspected and a thoraco-abdominal CT scan or scintigraphy should be performed at an early stage.