Granulocyte colony stimulating factor (G-CSF)-induced aortitis in a patient undergoing adjuvant chemotherapy for breast cancer

Abstract

Granulocyte colony stimulating factor (G-CSF) is used to prevent febrile neutropenia post chemotherapy. Usually well tolerated with minimal side effects but aortitis is an extremely rare side effect previously reported. A 64-year-old woman treated with adjuvant chemotherapy including G-CSF for left breast cancer was admitted with fevers, neutropenia and markedly raised inflammatory markers after 7 days of her first cycle. Initially diagnosed with neutropenic sepsis, she did not respond to broad spectrum antibiotics with subsequent CT imaging revealing marked periaortic inflammatory changes consistent with aortitis and periaortitis. Extensive investigations for other causes of large vessel vasculitis were negative and G-CSF was the only causative factor. She rapidly responded to steroids with almost complete resolution of inflammatory changes on repeat imaging within 4 weeks and no recurrence on tapering of steroids. This diagnosis must be considered in patients presenting with fever and raised inflammatory markers post G-CSF treatment.

Background

Febrile neutropenia is a well-recognised and serious complication of chemotherapeutic agents, a major cause of infection related mortality in cancer patients and also a dose limiting toxicity resulting in frequent dose reductions and delays in treatment. Recombinant human granulocyte colony stimulating factor (G-CSF) is frequently prescribed not only to reduce the incidence of severe chemotherapy-induced febrile neutropenia but also to maintain the intended dose intensity and schedule of treatment particularly in patients treated with a radical or curative intent.

G-CSF is considered a safe and well-tolerated agent with its most common side effects often being quite mild.^{1 2} However, aortitis and large vessel vasculitis have been reported as a rare complication with G-CSF therapy.³ A recent systematic review by Muzanna et al analysed 57 patients with G-CSF-associated aortitis.⁴ It is a rare but potentially life-threatening complication with the risk of aneurysmal dilatation and aortic dissection. Aortitis can present with non-specific symptoms and can closely mimic neutropenic infections which make the diagnosis challenging.

Case presentation

A 64-year-old woman presented to the medical admissions unit 7 days after her first cycle of adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide with pegylated G-CSF support. She had 4-day history of malaise, left flank pain and developed a fever of 38°C on the day of admission. Her medical history included a previous right breast cancer in 2002 treated with mastectomy and axillary node clearance (ANC) followed by adjuvant radiotherapy and endocrine therapy. In October 2020, she was diagnosed with a T3N2M0 oestrogen receptor positive (ER+), human epidermal growth factor receptor 2 positive (HER2+) left-sided breast cancer for which she underwent a mastectomy and ANC. Beyond her breast malignancies, she had no other significant comorbidities.

On examination, her temperature was 38°C, BP 107/70 mm Hg and HR 78 /min. Clinical assessment did not identify a source of infection. Investigations revealed a raised CRP of 196 mg/L, neutrophils of 0.2×10⁹ /L and normal renal and liver function tests. Chest X-ray was normal and urine dipstick was clear. Crucially, as her admission occurred during UK lockdown conditions due to the global pandemic, her COVID-19 PCR was negative. Serum procalcitonin was not elevated, measuring only 0.05 ug/L. Of note, the patient had a tunnelled central venous catheter (CVC), which on inspection was flushing well and revealed no signs of local superficial infection.

Initial diagnosis and management

Neutropenic sepsis was suspected prompting prescription of broad-spectrum antibiotics with piperacillin-tazobactam and amikacin.

Case progression and outcome

During admission, the patient continued to be febrile and had a continued, gradual rise of CRP. On day 9 her CRP was 546 mg/L prompting a change of antibiotic therapy to meropenem. Five sets of blood cultures taken during admission both peripherally and from the CVC showed no growth. Further infection screen including a throat swab, Epstein-Barr virus (EBV), Cytomegalovirus (CMV), hepatitis B, C and HIV were also negative.

A CT abdomen, pelvis requested to investigate her flank pain did not demonstrate any infective foci, however, did comment on inflammatory changes around the descending aorta extending up to the abdominal aorta, which were suggestive of aortitis. These changes were not present at staging CT scan done at the time of her cancer diagnosis. Subsequent CT angiogram confirmed extensive periaortic inflammatory changes consistent with initial findings (figure 1).

Figure 1.

Axial CT slices demonstrating marked periaortic inflammatory changes of the lower thoracic aorta and aortic arch.

Rheumatology team requested further tests to investigate the possibility of a primary vasculitis. Rheumatoid factor, ANA, ANCA, ENA antibodies, IgG subclass 4 and syphilis screen were all negative. At this point, a diagnosis of G-CSF-induced aortitis was suspected, therefore the patient was initiated on prednisolone 20 mg daily and antibiotic therapy was stopped. Her symptoms began to improve within 48 hours with resolution of fever. She was therefore discharged with close follow-up.

Outcome and follow-up

Two weeks following discharge her symptoms had completely resolved with a decline in CRP to 11 mg/L. Subsequent CT angiogram 3 weeks after discharge showed almost complete resolution of the inflammatory changes (figure 2). Prednisolone dose was slowly tapered down to 10 mg over a period of 2 months and then to 0 mg over next 6 months. She had no symptoms or signs of disease relapse on tapering steroids.

Figure 2.

Complete resolution of periaortic inflammatory changes of the lower thoracic aorta and aortic arch post-treatment.

Discussion

Primary vasculitis syndromes causing aortitis include Takayasu, giant cell arteritis and IgG4 disease, whereas tuberculosis, salmonella and syphilis are some of the rare infectious causes. Infectious and primary inflammatory aetiologies must also be excluded before a diagnosis of G-CSF-associated aortitis is considered. Primary inflammatory vasculitis syndromes typically have an indolent and chronic course contrary to acute presentation seen in G-CSF-associated aortitis as was the case in our patient.

Apart from the infectious and inflammatory causes, some of the other chemotherapeutic agents and targeted therapies have also been implicated in drug-induced aortitis and vasculitis. These include platinum based anti-cancer drugs, gemcitabine and bevacizumab. Patients receiving these therapies must also be monitored for this rare complication. Our patient did not receive any of these chemotherapeutic agents.

G-CSF has been reported as a rare cause of drug-induced aortitis.^{5 6} Data from a Japanese database reported the incidence of G-CSF-induced aortitis as 0.47%, while another study of patients with breast cancer, reported the incidence of pegylated G-CSF-induced aortitis as 0.3%.

The underlying pathophysiology remains unclear but is thought to be mediated by pro-inflammatory cytokines including IL-6.^{2 6 7} G-CSF stimulates neutrophil precursors and promotes neutrophil-mediated inflammatory response eliciting vessel wall damage seen in aortitis.

Establishing the diagnosis can be challenging as patients often manifest with non-specific symptoms including fever, back pain and raised inflammatory markers, which can overlap with common presenting symptoms of chemotherapeutic side effects or indeed neutropenic fever.

A review of 10 published case reports identified from PubMed are summarised in table 1.^7–16 The existing case reports describe similar presenting features with patients developing an acute onset of symptoms mimicking an infective picture and most cases describing a rapid resolution of symptoms.7 8 11 12 14–16 Six of 10 cases received some form of steroid therapy as did our patient. The rest resolved spontaneously with no intervention.

Table 1.

Summary of 10 previously published case reports of G-CSF associated aortitis

Miller, Grosu, Landau7	Hoshina, Takei 2019 8	Mukai, Kubo et al 20209	Shirai, Komatsu et al 202010	Nakamura, Nishi et al11	Darie, Boutalba et al 200412	Kamentai, Otani et al13	Kinjo, Kurita et al14	Corral de la fuente et al15	Harada, Motoki et al16
52	72	66	65	66	55	56	77	59	52
Male	Female	Female	Female	Female	Female	Male	Female	Female	Female
Healthy bone marrow donor	Breast cancer	Breast cancer	Pancreatic cancer	Breast cancer	Breast cancer	Chondrosarcoma	Ovarian cancer	Breast cancer	Ovarian cancer
Pegfilgrastim	Pegfilgrastim	Pegfilgrastim	Pegfilgrastim	Pegfilgrastim	Pegfilgrastim	Pegfilgrastim	Not stated	Pegfilgrastim	Unknown
Infrarenal aorta	Descending aorta	Aortic arch & abdominal aorta	Aortic arch	Not stated	Unknown	aorta	Bilateral common carotid and left subclavian	Myocarditis and carotidynia	Aortic arch /abdominal aorta
Nil	Docetaxel, trastuzumab, pertuzumab	Docetaxel and cyclophosphamide	Folfirinox	Doxorubicin, cyclophosphamide	Unknown	Adriamycib, ifosfamide	Paclitaxel, carboplatin	Unknown	Paclitaxel, carboplatin
1 year	5 days	10 days	12 days	11 days	Unknown	4 days	2 days	11 days	14 days
CT	PET/CT	CT	CT	CT	Unknown	CT	CT	Unknown	CT and PET
Rapid improvement	Spontaneous after 19 days	Rapid	Spontaneous, rapid within 10 days	Spontaneous 3 weeks	6 months	Rapid resolution	Rapid spontaneous	Initially rapid	Rapid on commencement of steroids
Prednisolone	Nil	Methylprednisolone	Nil	Nil	Yes	Prednisolone 1 mg/kg	nil	Prednisolone	Prednisolone

It is imperative to reduce the risk of hospitalisation from neutropenic sepsis particularly in this period of a global pandemic. The patient discussed here went on to receive further adjuvant chemotherapy with paclitaxel, which confers a much lower risk of neutropenic complications and therefore does not necessitate the supportive coadministration of G-CSF. Naranjo algorithm, which is a questionnaire designed to determine the likelihood of adverse drug reaction (ADR) was also applied in our case and the score was 7 (probable ADR). A score of 9 (definite ADR) requires re-challenging with the particular drug which was not done in our case because of high risk of relapse of aortitis. In two of the identified case reports, patients were re-challenged with G-CSF and subsequently developed further episodes of large vessel vasculitis.

There are no clear predictors or risk factors of G-CSF-associated aortitis. We recommend a high index of suspicion of this rare complication from G-CSF treatment. Early imaging is essential in identifying this complication, planning treatment and prevent any further complications.

Learning points.

• Aortitis is an extremely rare but important complication of granulocyte colony stimulating factor (G-CSF) therapy

• This diagnosis must be considered in patients presenting with fever and unclear source of raised inflammatory markers post chemotherapy including G-CSF

• Early imaging can help in prompt diagnosis and discontinuation of G-CSF, preventing subsequent aortitis-related complications.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).