Good functional outcome following severe neutropenic enterocolitis and perforation in a 48-year-old woman undergoing chemotherapy for breast cancer

Abstract

Neutropenic enterocolitis (NEC) is a life-threatening bowel condition, usually resulting from chemotherapy, with a mortality rate thought to be as high as 50%. Markers of poor prognosis include gastrointestinal perforation and bowel wall thickness radiologically detected to be greater than 10 mm. NEC is associated with severe neutropenia and predominantly affects the large bowel; however, we present a case of severe NEC with oesophageal perforation requiring transfer to a specialist upper gastrointestinal unit for corrective stenting. Despite initial bowel wall thickness of 20 mm in the ascending colon, two discrete episodes of bowel perforation and an inpatient stay totalling 89 days, the patient was discharged with full independence, a good quality of life and a plan for curative mastectomy plus axillary clearance.

Background

The true incidence of neutropenic enterocolitis (NEC) is unknown; however, a pooled incidence of 5.6% in hospitalised adults with aplastic anaemia, haematological malignancy and solid tumour chemotherapy has been suggested in the first systemic review of NEC.¹ NEC should be differentiated from the term ‘necrotising enterocolitis’ which describes a distinct inflammatory illness in neonates.² Gorschlüter suggests fever, abdominal pain and bowel wall thickening >4 mm on imaging should be used as clinical diagnostic criteria for NEC, as colonoscopy carries the risk of perforation.¹ Prompt diagnosis and management are imperative to minimise complications, such as sepsis and perforation,³ and to lower mortality.⁴

NEC is also known as ‘typhlitis’ from the Greek word for caecum—typhlos—meaning blind or closed. However, there are documented cases of patients presenting with extracaecal manifestations of the disease, for example, after having undergone surgical resection of the caecum; Principe et al infer from their case of transverse colon NEC after right hemicolectomy that ‘atypical’ NEC can arise elsewhere in the gastrointestinal tract.⁵ In addition, a 2003 study demonstrated radiological abnormalities in the small bowel in up to 66% of cases;⁶ this raises the question of whether the entire gastrointestinal mucosa is, in fact, susceptible to NEC. While perforation is more common in the thin-walled large bowel, we present this case as the first instance of oesophageal perforation in NEC. This case also demonstrates that NEC can present after a single dose of chemotherapy rather than the expected onset during the third week.⁷ Based on this case, we suggest that NEC should be considered in all neutropenic patients with abdominal pain, and that there is potential for good outcomes despite poor prognostic indicators for NEC, especially in younger patients with fewer comorbidities.

Case presentation

A 48-year-old woman presented to the emergency department with a 1-day history of lower abdominal/back pain. She had received her first cycle of neoadjuvant chemotherapy (docetaxel, carboplatin, trastuzumab and pertuzumab protocol) for human epidermal growth factor receptor 2 positive left breast cancer 11-days prior. She was previously fit and well, married with two children and was still working as a secretary when seen by oncology 1-month prior to her admission. Her prior medical history includes hypertension and a problem with her throat when she was a baby—the possibility of a tracheo-oesophageal fistula was raised, although we were unable to clarify this through family or medical records.

She was found to be neutropenic and was started on appropriate treatment for neutropenic sepsis in the emergency department. A CT scan of the abdomen and pelvis was in keeping with NEC. She was promptly admitted to the intensive care unit (ICU) for fluid resuscitation and vasopressor support. Two days later, another CT was performed to exclude bowel perforation based on worsening pain, which had migrated to her chest alongside a worsening clinical picture necessitating additional respiratory and cardiovascular support. Prior to the second CT, her respiratory function had deteriorated such that she required intubation. During intubation, she regurgitated and arrested (pulseless electrical activity). Cardiopulmonary resuscitation was briefly performed and return of spontaneous circulation achieved without the need for adrenaline or cardioversion. The CT chest–abdomen–pelvis (CTCAP) performed later that day reported no perforation, but did show a small left-sided pneumothorax, pneumomediastinum and large bilateral pleural effusions. Both pleural effusions were subsequently drained, with the culture growing Candida albicans, Candida dubliniensis and Candida glabrata which microbiology advised strongly indicated oesophageal perforation. Blood cultures grew Clostridium septicum for which she received courses of caspofungin and meropenem.

After discussion with radiology about the challenges of a swallow contrast scan in an intubated patient, water-soluble contrast was administered using a partially inserted nasogastric tube and the scan showed free spill into the left hemithorax from the lower oesophagus, confirming the suspected oesophageal perforation. The patient was discussed with a regional centre and transferred; she received an oesophageal stent with planned removal after 3 months. She also suffered a pulmonary embolism and deep vein thrombosis, underwent bilateral thoracotomies and decortication, and underwent right hemicolectomy for caecal perforation. She was supported by psychiatric liaison for stress and low mood related to her long hospital admission, including a total of 71 days in intensive care. After a tracheostomy and weaning programme, she was repatriated to continue her rehabilitation. She spent 4 days in the local ICU then was moved to the surgical ward and discharged home 2 weeks later.

Investigations

Initial CT abdomen and pelvis

Markedly oedematous hypodense circumferential wall thickening of the terminal ileum, ileocaecal junction, caecum and ascending colon up to the hepatic flexure—ascending colon thickness of 20 mm—with moderate to gross ascites, in keeping with NEC.

CTCAP

Small left-sided pneumothorax, pneumomediastinum and large bilateral pleural effusions. Bowel changes in keeping with NEC as previously, with no convincing perforation.

CT thorax with water-soluble contrast

Free spill into the left hemithorax from the lower oesophagus, blebs of gas in the mediastinum—in keeping with oesophageal perforation.

(CT chest/abdomen/pelvis demonstrating oesophageal perforation)

Pleural fluid culture

C. albicans, C. dubliniensis and C. glabrata.

Blood culture

C. septicum

Differential diagnosis

Fever and abdominal pain in a neutropenic patient have multiple differential diagnoses. Those with NEC often have diarrhoea, which may be bloody, and they may also suffer malaise and weakness.⁸ Differentials include Clostridiodes difficile infection, alternative forms of colitis, including graft-versus-host disease associated colitis, and other abdominal infections such as cholangitis, appendicitis, bowel ischaemia and chemotherapy side effects.^{4 9} The clinical manifestations of many of these are similar, and in addition, may be dulled in neutropenic patients. Therefore, a combination of history, examination and investigations are required to make a definitive diagnosis.⁹

History is important—NEC should be carefully considered in the context of recent high-dose chemotherapy.⁴ Stool and blood cultures will help identify infectious agents. Imaging will exclude most mimics; bowel wall thickening is rare in non-infectious mucositis and, therefore, highly suggestive of NEC.¹ Definitive differentiation of NEC from alternative diagnoses comes from histopathology, with Sachak et al advising that diagnostic accuracy should be improved by requiring histopathology for a definitive diagnosis, with all other suspicious cases being labelled ‘suspicious for NEC’ until other diagnoses have been reasonably excluded.¹⁰ However, histopathological confirmation is rarely practical in the clinical setting due to the risk of perforation during colonoscopy.^{1 4} Wrongful or delayed identification of NEC could lead to suboptimal initial treatment, underestimation of the severity of the illness, lack of awareness of potential complications and delay in seeking critical care support, which could, in turn, contribute to poor outcomes.

Treatment

• Pharmacological: antibiotics, antifungals, analgesia, sedation and blood pressure support.

• Surgical: chest drains, oesophageal stenting, thoracotomies and decortication, and right hemicolectomy.

• Nutritional: total parenteral nutrition, jejunal feeding and dietary supplements.

• Physiotherapy: daily physiotherapy on ICU and on the ward—respiratory and mobilisation.

• Mental health: support from liaison psychiatry in both hospitals.

Outcome and follow-up

The patient attended the emergency department approximately 2 weeks after her discharge with shortness of breath following a chesty cough and was admitted under the medical team for 3 days. She was seen by the breast surgeon shortly after discharge and listed for curative breast surgery (left mastectomy with axillary node clearance and delayed reconstruction) in 4–6 weeks. However, the decision was later taken to defer the surgery because the patient was still recovering from her prolonged illness and because of the risks associated with continuing to surgery during the COVID-19 outbreak. Tamoxifen was started in the meantime. The stent removal has also been delayed due to COVID-19, and this will be reviewed regularly by telephone discussion with the surgical team. There are no operations planned at time of writing, 3 months after ICU discharge.

Discussion

NEC is characterised by intestinal mucosal injury alongside neutropenia and immunocompromise. It is thought to result from an increase in vulnerability to bacterial intramural invasion; however, the precise pathogenesis is uncertain and is likely to be multifactorial.^{2 4} It is hypothesised that NEC develops due to a combination of direct mucosal injury by cytotoxic chemotherapy, a blunted enteric immune system and a shift in the intestinal microflora from normal commensals to more opportunistic organisms.¹¹ In particular, the taxanes cause severe gastrointestinal mucositis and the frequency of NEC has increased with the rise of chemotherapy.⁹ The expected onset is during the third week of chemotherapy⁷ although our patient presented earlier, 11 days after her first dose.

While NEC has historically been accepted as a primarily caecal pathology, a study correlating CT imaging with histopathology and clinical details concluded that NEC was limited to the caecum in 28% of cases. Colonic involvement was seen in 75% of cases and 66% showed small bowel involvement.⁶ Even early published cases describe colonic involvement¹¹ and more recent case series suggest that it can affect both large and small bowel.^{5 6} It is, therefore, suggested that the entire gastrointestinal mucosa could be affected⁵ although it is not yet reported in the appendix or rectum.⁴ Our case is notable for including oesophageal perforation, which has not previously been described in NEC; we suggest that if the entire gastrointestinal tract can be affected by NEC then it may be a contributing factor or even the direct cause of the oesophageal perforation. Clinicians should be suspicious of NEC in any neutropenic patient with abdominal symptoms, including those outside the expected third week onset period, and should be vigilant for manifestations beyond the large bowel.

As with other abdominal infections, NEC is frequently polymicrobial; in our case, C. septicum was isolated in blood alongside various species of candida in pleural aspirate. One report emphasised the importance of C. septicum in this setting and suggested that fulminant sepsis and death were more common when this organism was isolated from patients with NEC.¹² In our case, C. septicum was isolated from blood cultures and the patient suffered from severe sepsis, suggesting poor prognosis; however, with critical care support and prolonged antimicrobial therapy based on advice by microbiology, she made a good recovery. It is essential to bear in mind that bacteraemic complications are common in NEC and require a close working relationship with microbiologists.

Bowel thickness on imaging has been linked to prognosis in NEC based on a study of ultrasound imaging in patients undergoing chemotherapy for haematological malignancy.¹³ Bowel wall thickening on ultrasound has a poorer prognosis in symptomatic NEC patients compared with those without thickening (29.5% mortality versus 0%, p<0.001). In addition, the degree of thickening was related to outcome with bowel wall thickness >10 mm having a significantly higher mortality rate (60% vs 4.2%, p<0.001). Although our case concerns chemotherapy for solid organ tumour and bowel wall thickness seen on CT, we extrapolate that with bowel wall thickness of 20 mm identified within the ascending colon, our patient had a particularly significant risk of mortality.

There are no formal guidelines on management of NEC and limited evidence exists regarding treatment^{5 8} although practice guidelines on gastrointestinal complications of cancer treatment published in 2012 briefly described conservative management in the first instance, alongside monitoring for complications requiring surgical intervention. Nesher and Rolston propose a more detailed algorithm⁹ with management decisions based on specific parameters for bowel wall thickness and neutrophil count. Historically, NEC was seen as a terminal complication in leukaemia patients; however, the survival of a patient following prompt surgical intervention¹⁴ led to a phase of early aggressive surgery aimed at arresting the likely progression to full-thickness involvement and related poor outcomes.⁹ Improvements in supportive care have meant that conservative medical management is now the mainstay of treatment. This includes antimicrobial therapy alongside bowel rest, nasogastric drainage, intravenous fluids and parenteral nutrition when indicated.¹⁵ Antimicrobial therapy should initially be broad spectrum with Gram negative and anaerobic cover and subject to microbiology review.⁸ In addition, antifungal treatment should be considered if there is not a good response to the initial therapy after 72 hours;² a 2019 study found invasive fungal disease in 20% of adult neutropenic ICU patients with colitis and/or enteritis.¹⁶

Surgical management is now reserved for a subset of patients meeting criteria initially laid out by Shamberger et al in the paediatric setting—these include persistence of gastrointestinal bleeding despite corrective measures, intraperitoneal free air suggestive of perforation, clinical deterioration and need for surgery for other reasons.^{2 9 17} In our case, we followed the consensus of best supportive medical management with regular surgical review in the ICU. Her transfer to a tertiary centre was triggered by her need for specialist surgery due to suspected oesophageal perforation, meeting the fourth Shamberger’s criteria. It could be claimed that the third criteria needs updating to any suspicion of perforation, since she suffered perforation, but without intraperitoneal free air.

Learning points.

• Neutropenic enterocolitis (NEC) can affect the whole length of the bowel from mouth to anus.

• NEC can present after a single dose of chemotherapy and should be considered in all neutropenic patients with abdominal pain, with need for a prompt imaging and multidisciplinary involvement.

• Bacteraemic complications are often polymicrobial and require a close working relationship with microbiology.

• There is potential for good outcomes despite poor prognostic indicators for NEC, especially in the young with few comorbidities.