Fatal Clostridium septicum febrile neutropenia during adjuvant chemotherapy for early breast cancer

Abstract

We report the case of a 76-year-old female patient with early breast cancer (hormone receptor-positive erbb2 amplified) that had started adjuvant chemotherapy with docetaxel, carboplatin and trastuzumab (TCH). Eight days after the first cycle of TCH chemotherapy, the patient was diagnosed with grade 1 oral mucositis, treated conservatively. The next day she started with nausea, vomiting, chills and fever, followed by a generalised tonicoclonic seizure. She presented to the emergency department with fever, hypotension and mild abdominal tenderness. Grade 4 neutropenia (370 μL/mL) and severe metabolic acidosis were documented. An abdominal CT scan documented extensive ischaemic bowel changes, with gas in portal and mesenteric veins, and pneumoretroperitoneum. Despite broad spectrum antibiotics and fluid resuscitation, she died 4 hours after admitted to hospital. Blood cultures collected on hospital admission eventually grew Clostridium septicum bacteria, an extremely rare infection in patient with breast cancer.

Background

Febrile neutropenia (FN) is a potentially fatal side effect of systemic chemotherapy. Early diagnosis is crucial in the management of these patients, since delay in starting antimicrobial treatment is associated with worse outcome.

Although historically FN is mainly associated with Gram-negative infections, in recent years an increasing number of Gram-positive infections have been reported.

Clostridium infections (mainly Clostridium difficile toxin induced colitis) are rarely associated with FN and usually isolated in patients with gastro-intestinal malignancies and attributed to bacterial translocation from the gut. There are few cases that report FN with Clostridium septicum bacteremia in the literature, being especially rare in patients with breast cancer.

Case presentation

A 76-year-old female patient with history of hypertension and dyslipidemia, presented with a palpable tumour in the upper-outer quadrant of left breast detected on self-examination, despite an unremarkable screening mammography and ultrasonography preformed 2 months before. On physical examination, a superficial 10 mm nodule was detected in the upper-outer quadrant of the left breast. The MRI confirmed the presence of a single nodule of 22 mm, without regional lymph-node involvement. The biopsy documented an invasive carcinoma. The patient was submitted to lumpectomy with sentinel lymph-node biopsy—pathology showed a 22 mm invasive ductal carcinoma (pT2), grade 3, hormone receptor-positive (oestrogen receptor 95% of tumour cells, progesterone receptor 90% of tumour cells) human epidermal growth factor receptor-type 2 (HER2) amplified (immunohistochemistry 2+, silver in situ hybridization positive). The sentinel lymph-node biopsy was negative for carcinoma. On multidisciplinary conference, adjuvant treatment with six cycles of docetaxel, carboplatin and trastuzumab (TCH), completion of 1 year of trastuzumab, external beam mammary irradiation and adjuvant hormonotherapy were recommended.

Eight days after the first cycle of adjuvant TCH chemotherapy, the patient referred mild odynophagia and dysphagia, without fever or other associated symptoms. Diagnosis of grade 1 oral mucositis was made and topical lidocaine and morphine mouthwash were prescribed. The following day, the patient started with nausea, vomiting, fever and chills followed by a tonicoclonic seizure at home. On admission to the emergency department she had already recovered her consciousness; arterial pressure was 76/61 mm Hg, tympanic temperature was 38.0°C. There was mild abdominal tenderness on deep palpation but without guarding. Peripheral blood evaluation was remarkable for grade 4 neutropenia (370 neutrophils/μL), haemoglobin of 1.3 g/L, platelets of 117 ×10⁹/L and acute kidney injury (creatinine 2.08 mg/dL, urea 42 mg/dL). Blood cultures were drawn and fluid resuscitation and antimicrobial treatment with piperacillin–tazobactam were promptly started. Arterial blood gas documented severe metabolic acidosis (pH <7.0, pCO₂ 43 mm Hg, pO₂ 41 mm Hg, HCO₃⁻ 9.9 mmol/L and lactate 129 mg/dL). An abdominal CT scan was performed that showed extensive ischaemic bowel changes, with gas inside the portal and mesenteric veins, pneumoretroperitoneum and bilateral pleural effusion (figures 1 and 2).

Figure 1.

Coronal CT scan showing extensive ischemic bowel changes, with portal and mesenteric veins gas, and pneumoretroperitoneum.

Figure 2.

Axial CT scan showing extensive ischemic bowel changes, with portal and mesenteric veins gas, and pneumoretroperitoneum.

Head CT scan was normal. Within 1 hour, the patient had another seizure and worsening hypotension that reverted with intravenous fluid therapy and corticosteroids administration. The patient had progressive clinical deterioration in the following 2 hours, with cardiorespiratory arrest that was reverted with defibrillation, intubation and fluid resuscitation. Unfortunately, the patient condition did not improve, and the patient died 4 hours after arrival to the emergency department. Blood cultures eventually grew C. septicum.

Outcome and follow-up

Although all efforts were made to improve the patient’s condition, the patient died 4 hours after admitted to the emergency department.

Discussion

TCH adjuvant chemotherapy is associated with a reported incidence of FN of 9.6%, below the European Society of Medical Oncology (ESMO) recommended threshold for primary granulocyte colony-stimulating factor (G-CSF) prophylaxis of at least 10%.^{1 2}

There are few reported cases of patients with breast cancer with FN due to Clostridium infections, which are occasionally associated with colorectal malignancies, mostly C. difficile bacteremia.^3–5 C. septicum systemic infections are particularly rare in patients with cancer, and the few reported cases are in patients with colorectal malignancies.^6–10 To our knowledge, Pagani et al reported the only case of a patient with an FN episode due to C. septicum bacteremia in a patient with locally advanced breast carcinoma treated with a docetaxel containing regimen. The patient had a large bowel perforation with ischaemic colitis, and blood cultures were positive for C. septicum. Even though surgical resection with total colectomy was performed, the patient had repeated jejunal perforations and eventually died.¹⁰

Clostridium infections in breast cancer patients are probably due to enterocolitis caused by docetaxel adjuvant chemotherapy-induced mucositis, with intestinal mucosa damage facilitating the bloodstream translocation of gut bacteria. In a patient with neutropenia, this may lead to a rapidly progressing potential fatal widespread infection, as reported in this patient. C. septicum is a Gram-positive, sporulating, spindle-shaped rod. It can be found in the gastrointestinal tract, produce several toxins, including α, β, γ and δ. The α-toxin can cause mionecrosis and haemolysis.⁵

The reported patient was initially diagnosed with grade 1 mucositis and treated conservatively. However, the following day, the patient was admitted to the hospital with sepsis, presenting as a seizure and associated nausea, vomiting and abdominal pain. Despite prompt fluid resuscitation and treatment with broad spectrum antibimicrobials, her clinical condition quickly deteriorated, with death occurring within 4 hours from ER admission. CT scan showed extensive ischaemic bowel changes, with portal and mesenteric veins gas, typical of C. septicum infections. Blood cultures confirmed C. septicum bacteremia, sensitive in vitro to the prescribed antibiotics.

While the initial complaint of dysphagia and odynophagia might have alerted her physician, there were no associated symptoms or signs, such as diarrhoea, abdominal pain or fever. The speed of clinical deterioration, with extensive bowel ischaemic changes, documented on CT scan prevented life-saving surgery. Despite all efforts to resuscitate and treat the patient, the widespread infection led to her death. This case illustrates that although extremely rare in patients with breast cancer on adjuvant chemotherapy, enterocolitis with bacteremia due to C. septicum can occur and be fatal, even in the absence of typical symptoms, such as diarrhoea. Due to its potential to cause mionecrosis and haemolysis, clinical suspicion with early diagnosis is extremely important. Prompt and adequate management with broad spectrum antibiotics and early surgery for ischaemic bowel changes are crucial to survival.

Learning points.

• Febrile neutropenia (FN) is a potentially life-threatening complication of systemic chemotherapy;

• Early diagnosis of FN is crucial and prompt antibiotic treatment is mandatory;

• Clostridium species are a rare cause of docetaxel-induced FN-associated bacteremia in patients with early breast cancer.