PEG‐GCSF‐induced aortitis in a patient with breast cancer: distinguishing between infective and immune‐mediated aortitis

Clinical record

A 64‐year‐old woman presented with non‐neutropenic fever and back pain one day after the first cycle of neoadjuvant chemotherapy (doxorubicin–cyclophosphamide) for locally advanced breast cancer. She had also received pegylated granulocyte colony stimulating factor (PEG‐GCSF) one day after chemotherapy to enable dose‐dense chemotherapy scheduling. She was originally treated with intravenous antibiotics and discharged home on oral amoxicillin–clavulanate, with improvement in symptoms.

Her symptoms recurred on day 8 prompting admission. Initial investigations demonstrated raised white cell count with neutrophilia, extremely elevated C‐reactive protein (682mg/L; reference interval, <5mg/L), and negative blood and urine cultures (Box 1). Chest x‐ray was unremarkable. The patient received five days of intravenous broad‐spectrum antibiotics (piperacillin–tazobactam) with no resolution of fevers but no clinical deterioration.

A computed tomography (CT) scan of the abdomen and pelvis demonstrated smooth circumferential aortic mural thickening, stranding surrounding the origin of coeliac axis, superior mesenteric artery and bilateral renal arteries, suggestive of aortitis. There was no stenosis or aneurysmal dilatation, and intra‐abdominal organ appearance was normal.

Infectious disease consultation postulated a non‐infective cause, with no organism found and imaging features not supportive of infection. Rheumatology review identified no symptoms or signs of autoimmune disease associated with aortitis, including giant cell arteritis. A diagnosis of PEG‐GCSF‐induced aortitis was considered.

The patient commenced high dose oral prednisolone 50mg per day (1mg/kg), with rapid improvement in fever and inflammatory markers, enabling discharge from hospital on the following day. Positron emission tomography (PET)/CT completed within one week demonstrated moderate metabolic activity from the aortic arch, descending thoracic and abdominal aorta (Box 2, A).

On outpatient follow‐up, the patient remained asymptomatic of aortitis and proceeded with further cycles of non‐dose‐dense doxorubicin–cyclophosphamide chemotherapy without PEG‐GCSF, with no subsequent flare of symptoms. A re‐staging PET/CT completed after cessation of steroids (but ongoing chemotherapy) showed tumour response and resolution of aortitis (Box 2, B).

Discussion

This case highlights aortitis as a differential diagnosis for pyrexia of unknown origin, and the importance of distinguishing infective and non‐infective causes of aortitis to determine appropriate treatment. Aortitis may present with fevers, constitutional symptoms, neck, chest and/or abdominal pain, upper or lower limb claudication. It may be secondary to infective or immune‐mediated causes (Box 3).1 Although clinical features may be non‐specific, distinction is made through laboratory, imaging and, rarely, histological results. Imaging findings specific to infection include mycotic aneurysms, gas formation and focal crescenteric involvement, while immune‐mediated causes often appear with diffuse mural thickening and contiguous involvement of longer sections of the aorta.2

The patient's undifferentiated clinical presentation prompted empiric treatment and investigation for infection. However, once aortitis was recognised, negative microbial cultures and serology, imaging features, and non‐improvement with antibiotics suggested a non‐infective cause.

The case was also unusual for typical causes of immune‐mediated aortitis given the abrupt onset and preceding chemotherapy. A paraneoplastic cause was considered unlikely because symptoms began after initiation of chemotherapy and resolved rapidly after initiation of steroids within the first chemotherapy cycle. The cause of aortitis was attributed to GCSF due to abrupt onset, unusually high inflammatory markers, exclusion of other causes, and improvement with corticosteroids, with no recurrence of symptoms after taper and cessation.

GCSF‐induced aortitis is a rare complication of GCSF in patients receiving treatment for solid organ malignancies (breast, ovarian, uterine) and lymphoma. GCSF is being used more frequently with curative breast cancer chemotherapy to enable dose‐dense scheduling, which is associated with better cancer outcomes.3 Most reported cases have occurred in women aged 60years or older. Taxane agents are the most associated chemotherapeutic class. Most cases occur within ten days of GCSF administration and present with fever unresponsive to antibiotics, accompanied by neck, chest or abdominal pain. The thoracic aorta is the most commonly involved aortic segment. GCSF may lead to fever and high inflammatory markers through stimulation of interleukin (IL)‐1, IL‐6 and prostaglandins. Treatment includes discontinuation of GCSF and high dose oral corticosteroids (1mg/kg), tapered over several weeks, but some patients may improve solely with clearance of GCSF. Prognosis with treatment is usually benign,4 although complications of aortitis may include aneurysmal dilatation and death.1

Treatment for infective aortitis consists of targeted antimicrobial treatment. Immune‐mediated aortitis is treated with high dose intravenous or oral corticosteroids (1mg/kg) followed by tapering, with introduction of steroid‐sparing agents in persistent or treatment‐refractory cases.5 The choice of immunosuppressants is dependent on the underlying diagnosis and other end‐organ manifestations. Disease is monitored using clinical parameters, relevant laboratory markers (erythrocyte sedimentation rate, C‐reactive protein, angiotensin‐converting enzyme levels, antineutrophil cytoplasmic antibody titres) and imaging (PET/CT, CT and/or magnetic resonance imaging with contrast angiography).1 Exclusion of an infective cause is critically important before immunosuppression.

Box 2 – Positron emission tomography/computed tomography (PET/CT) demonstrating aortic inflammation at the start of steroid treatment (A) and subsequent resolution after cessation of treatment (B)

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