Invasive Gastrointestinal Mucormycosis Presenting as Neutropenic Enterocolitis: A Case Report

Introduction

Infections are among the most common complications that can derail the treatment course of immunocompromised patients. While many microorganisms can infect this particularly vulnerable patient population, few are as devastating as the members of the Mucorales order. Mucormycosis is an aggressive fungal infection with an extremely high mortality rate [1,2].

The agents of mucormycosis are ubiquitous in the environment [3]. While most people are frequently exposed to the spores of Mucorales, the incidence of clinical disease remains disproportionately low, occurring almost exclusively in immunocompromised individuals. The most common forms of mucormycosis are rhino-orbital-cerebral and pulmonary [4]. Other, less frequent forms have been described, including gastrointestinal, cutaneous, renal, and disseminated disease.

Gastrointestinal mucormycosis typically develops through ingestion of fungal spores and is a particularly rare form of the disease. It is characterized by tissue angioinvasion and ulceration, most commonly in the stomach. Patients can present with gastrointestinal bleeding or a perforated viscus.

The global incidence of mucormycosis has been gradually rising over the past few decades [5]. Frequent reports have emerged from various regions, including the Americas, Europe, the Middle East, and Asia, with India experiencing the sharpest rise in cases, particularly following the coronavirus disease 2019 (COVID-19) pandemic [6]. In fact, mucormycosis attained notifiable disease status at the directive of the Indian government since May 2021 [7].

Poorly controlled diabetes mellitus remains one of the most common risk factors for the pathogenesis of mucormycosis in developing countries [8]. In contrast, the rising incidence in developed countries could be attributed to the growing use of corticosteroids, chemotherapy and biologic agents [5].

We report the case of a patient with B-cell acute lymphoblastic leukemia complicated by neutropenic colitis and ileocecal mucormycosis, which was managed with initial resection followed by surgical debridement for source control. This case highlights the diagnostic challenges posed by this infection, as its non-specific presentation can easily be mistaken for more common conditions, such as neutropenic colitis. Furthermore, it underscores the importance of aggressive and timely medical and surgical intervention to prevent mortality.

Case Report

A 19-year-old Saudi man who was a smoker was diagnosed with B-cell acute lymphoblastic leukemia 8 months prior to his current presentation. Cytogenetic and molecular studies revealed hyperdiploidy and detection of immunoglobulin heavy chain (IGH) gene rearrangement. He underwent a pediatric-inspired chemotherapy regimen based on Berlin Frankfurt Munich Protocol (BFM) in addition to Rituximab (R-BFM). Treatment included induction (5 weeks), consolidation (8 weeks, 2 cycles), interim maintenance (8 weeks, 4 cycles), and delayed intensification (8 weeks, 2 cycles). Each phase consisted of a combination of corticosteroids, chemotherapeutic agents, intrathecal methotrexate, and Rituximab. Fifteen days after the second delayed intensification cycle of chemotherapy, he was admitted to the intensive care unit with febrile neutropenia and methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia secondary to central line-associated bloodstream infection. He was managed by removing the catheter and a 4-week course of Cefazolin, with rapid resolution of his bacteremia.

Two weeks into his admission, he developed worsening lower abdominal pain, tenderness, and constipation, none of which had been present on admission. He developed persistent high-grade fever (temperature >38.3°C), and his absolute neutrophil count (ANC) remained very low (<100 cells/μL), consistent with profound neutropenia.

Contrast-enhanced computed tomography (CT) showed evidence of ileocecal and rectal wall thickening with enhancement, suggestive of neutropenic colitis. Other findings included small bowel dilatation with no transitional zone, suggestive of ileus, as well as reactive peritonitis and moderate ascites (Figure 1).

Although neutropenic colitis was the leading differential diagnosis, we also considered alternative diagnoses. Clostridioides difficile colitis was a possibility given the patient’s exposure to broad-spectrum antibiotics, but a negative stool PCR ruled this out. Tissue-invasive cytomegalovirus (CMV) was also considered due to the patient’s immunocompromised state and CMV IgG seropositivity. While serum CMV PCR was negative, we acknowledged that absence of viremia does not reliably exclude tissue-invasive disease. However, given the higher likelihood of neutropenic colitis and the risks associated with colon biopsy – particularly the potential for perforation – further invasive evaluation was deferred.

Upon surgical consultation, he was started on a bowel rest protocol, and his antimicrobials were escalated to meropenem, vancomycin, and caspofungin for polymicrobial coverage of neutropenic colitis and to cover the possibility of ampicillin-resistant enterococci in view of prolonged admission and recurrent antibiotics exposure. Despite these measures, the patient showed no improvement for 7–10 days, thereby triggering repeat assessment by the surgical team and repeat contrast-enhanced imaging, which showed interval development of significant ischemic changes involving the ileocecal region with diminished bowel wall enhancement, associated with a peripherally-enhancing inflammatory mass surrounding the affected bowel segment, with an adjacent peripherally-enhancing pelvic fluid collection measuring approximately 450 ml. Additionally, there was interval worsening of small bowel dilatation with a transitional zone at the right lower abdominal quadrant (Figure 2).

The patient was taken for an emergency exploratory laparotomy. Intraoperative findings included fecal peritonitis, and a large, necrotic, inflammatory mass adherent to the right lower-quadrant abdominal wall. Further inspection revealed that the anterior cecal wall had been destroyed and was detached from the terminal ileum and the ascending colon (Figure 3). Ileocecal resection was performed with end-ileostomy and mucus fistula creation at the right upper quadrant, further away from the septic focus. The resected specimen was sent for histopathologic examination.

Histopathologic examination revealed a segment of bowel and appendix with perforation and areas of transmural infarction associated with angioinvasive fungal forms. These forms were broad, ribbon-like, aseptate/pauci-septate hyphae, exhibiting random branching patterns, including some at right angles, morphologically consistent with Mucor spp. (Figure 4). Based on these findings, he was started on liposomal amphotericin 5 mg/kg intravenously, which he received for 2 weeks during his hospital stay, with interval clinical and biochemical improvement, after which he was discharged in stable condition to continue his treatment as an outpatient with a planned 6-week course of IV amphotericin followed by oral posaconazole maintenance to be continued until the end of his planned chemotherapy regimen.

Almost 1 month later, he presented to the Emergency Department with worsening lower-abdominal pain associated with vomiting. The week prior to his presentation he had been non-compliant with his treatment and had missed 5 days of his scheduled amphotericin doses. Contrast-enhanced CT of his abdomen showed a localized collection with peripheral enhancement suggestive of superimposed infection at the right iliac fossa extending into the ipsilateral lower rectus muscle and containing mesenteric fat with an estimated volume of 115 ml (Figure 5). He was re-started on liposomal amphotericin therapy 7.5 mg/kg/day with the addition of Isavuconazole. Initially, he underwent ultrasound-guided drainage of the collection. Samples were sent for cytology, fungal culture, and bacterial culture. Fungal hyphae with morphology similar to prior specimens were detected in the GMS-stained slide, suggestive of mucormycosis. Based on this, a family meeting was held to discuss the aggressive treatment plan. After obtaining consent, he underwent exploratory laparotomy with planned debridement of the lower right quadrant at the site of the previous abscess. Intraoperatively, the abscess wall was thickened, with areas that were blackish, necrotic, and nodular. The cavity wall was also inseparable from the ileal bowel loop exiting as an ileostomy. To achieve complete eradication of the source of infection, the abdominal wall debridement required excision of part of the rectus muscle and fascia, resection of the previous ileostomy site where the cavity wall was adherent, and dissection along the external iliac vessels almost down to the adventitial plane. A new end-ileostomy was fashioned at the end of the procedure. Postoperatively, he was continued on amphotericin therapy with the addition of Isavuconazole, which was well tolerated aside from manageable hypokalemia. Given the severity of infection, the decision was made to re-start the induction phase of amphotericin from the beginning, with a planned 6-week course in conjunction with Isavuconazole. He was subsequently discharged in stable condition on isavuconazole maintenance with a plan to continue secondary prophylaxis until his planned chemotherapeutic regimen was complete. He has remained on secondary prophylaxis for 6 months without relapse.

Discussion

We report a case of neutropenic colitis complicated by ileocecal perforation secondary to mucormycosis. The patient developed recurrent, histopathologically proven, relapses in the form of an intra-abdominal abscess, and, despite clinical improvement with percutaneous drainage, we employed aggressive medical and surgical treatments to maximize his chances for survival. This aligns with the widely accepted standard of care, as we determined that drainage alone, while providing temporary relief, does not constitute adequate source control due to the invasive nature of mucormycosis. With this strategy, we were able to resume leukemia treatment with no complications.

Over the past couple of decades, there has been a notable increase in reported cases of mucormycosis [5,6,9,10]. This is likely attributed to improved survival in patients with immunocompromising conditions as well as rising awareness among physicians, leading to more frequent diagnoses of this serious infection. However, reports of gastrointestinal mucormycosis remain scarce, likely reflecting under-recognition and under-reporting of these cases.

Extensive tissue necrosis is a hallmark of mucormycosis and is directly related to its predilection for angioinvasion. The fungi exhibit a high affinity for endothelial cells, attaching to them via specific fungal ligands. Once attached, they trigger host-cell-mediated endocytosis enabling direct invasion of blood vessels. This process leads to vascular occlusion, thrombosis, and, ultimately, necrosis [11].

While all forms of mucormycosis are considered life-threatening, the mortality rate associated with the gastrointestinal form of the disease is reported to be as high as 85% [10]. The literature clearly shows that the clinical outcome of all forms of Mucor infection relates to several elements, including the underlying risk factors, degree of immunosuppression, and site of infection, as well as time of making the diagnosis and initiating appropriate management. Patients with intestinal disease often present with non-specific signs and symptoms such as fever, abdominal pain, distension, and constipation. Some patients present with complications such as upper or lower gastrointestinal bleeding, bowel obstruction, perforation, and sepsis [12]. Our patient presented with most of these symptoms, yet the diagnosis was only established postoperatively after he had developed bowel ischemia and perforation. Given the time at which the patient developed symptoms and the pattern of his presentation, the working diagnosis at the time was the more common neutropenic enterocolitis, which is usually a polymicrobial infection mediated by gut flora. Unfortunately, early diagnosis is frequently confounded by the non-specificity of these symptoms and the presence of a more apparent, alternative diagnosis [13].

As such, we believe that survival heavily depends on preemptively identifying patients at risk for mucormycosis and maintaining a high index of suspicion. Diabetes mellitus and diabetic ketoacidosis are 2 of the most frequently reported risk factors. This is thought to be related to their ability to thrive in acidic environments, as they utilize ketone bodies as an energy source [14]. Furthermore, it is well established that hyperglycemia impedes phagocytosis, even when there are adequate neutrophil counts [15]. Other immunocompromising conditions such as neutropenia, hematologic malignancies, organ transplant, HIV, and steroid therapy have all been associated with cases of mucormycosis [8]. Leukemia patients may be at risk even without frank neutropenia, as their neutrophil and macrophage functions are likely to be compromised. This functional impairment renders these cells ineffective in phagocytosing and neutralizing invasive fungi [16].

Hemochromatosis and deferoxamine therapy have also been reported as risk factors for mucormycosis. While virtually all microorganisms require iron for survival, some possess unique adaptive mechanisms that allow for more efficient scavenging, safe storage, and utilization of it. These microorganisms are aptly termed “siderophiles.” Fungi within the order of Mucorales can reduce iron from the ferric to the more soluble ferrous state, facilitating its uptake. Additionally, they produce siderophores, which are small proteins that scavenge iron from their surroundings for transport back into the fungal cell. They also store iron by binding it to specialized proteins such as mycoferritin and zygoferritin and by doing so protect their internal environment from free-iron-derived oxidative damage [17]. Interestingly, Deferoxamine, which is a chelating agent used to treat hemochromatosis, paradoxically increases the risk of mucormycosis by acting as a siderophore, especially in patients on dialysis [18].

Establishing the diagnosis can be difficult, requiring a multidisciplinary team approach. While certain “classic” radiographic features have long been described in the literature regarding pulmonary disease such as the reverse halo or bird’s nest signs, no such features have been reported for gastrointestinal mucormycosis. Contrast-enhanced abdominal CT scans can show regional wall thickening with areas of increased and decreased enhancement, corresponding to congestive and ischemic changes, respectively [12]. The lack of visualization, or a discontinuity, of the affected gastrointestinal organ is common in patients with mucormycosis of the bowel [19].

Histopathologic examination remains the criterion standard for diagnosing mucormycosis. The presence of characteristic fungal elements, such as broad, aseptate hyphae with irregular branching and evidence of angioinvasion, is diagnostic. However, securing a tissue sample for histopathologic examination can be a significant diagnostic challenge, particularly in patients with severe pancytopenia, who are at higher risk of procedure-related complications such as bleeding or perforation [20]. Fungal culture can be used to confirm the diagnosis and determine the species. However, even with intestinal tissue samples, fungal cultures fail to yield growth in more than 50% of cases, highlighting the critical role of high suspicion and timely histopathological examination in establishing the diagnosis [21,22].

No specific fungal biomarkers exist to aid in the diagnosis of mucormycosis, further complicating timely identification of the infection [20]. The role of serum fungal markers such as (1,3)-β-d-glucan (BDG) is very limited. While most clinically significant yeast and mold contain this key cell wall component, most Mucorales do not contain enough of it to be clinically detectable, or have none at all, which makes the test neither sensitive nor specific for mucormycosis. While PCR-based diagnostic methods are highly sensitive, their utility when applied to non-sterile samples such as respiratory, wound or gastrointestinal specimens is not well defined. Given the ubiquity of these organisms in the environment, a positive result could suggest contamination rather than true infection. However, PCR testing on formalin-fixed paraffin-embedded tissue can still be useful when combined with histopathologic evidence of invasive mucormycosis to confirm the diagnosis, as fungal culture is likely to take longer. Some evidence suggests that PCR testing of serum samples could be used as an early marker of invasive mucormycosis, perhaps weeks before the onset of symptoms, and may be a promising addition to our armamentarium in the future [23].

While every attempt should be made to expedite the establishment of a diagnosis of mucormycosis, treatment should not be delayed if there is high clinical suspicion. The treatment approach is multifaceted, involving surgical intervention, antimicrobial therapy, and reversal of underlying risk factors. Aggressive surgical debridement is essential. Multiple surgical interventions might be required to achieve good source control. Our patient underwent 2 extensive surgical resections and debridement to optimize his clinical status and achieve infection control. The vascular invasion seen in mucormycosis results in ischemia and necrosis, which creates an environment conducive to fungal growth and limits the bioavailability of the drug in the affected region due to impaired perfusion. Evidence shows improved survival when surgical intervention is coupled with amphotericin B therapy (70%), compared to either surgery alone (57%) or amphotericin B alone (61%) [10].

One of the major challenges for clinicians treating this infection is the absence of susceptibility testing to guide antifungal selection, due to the lack of validated minimum inhibitory concentrations (MIC) breakpoints for agents used to treat mucormycosis [24]. At the initial presentation, we opted to treat our patient with amphotericin B monotherapy, the long-standing first-line agent in the treatment of mucormycosis, with a plan to transition to oral maintenance therapy with posaconazole following clinical improvement. This approach aligns with the global guidelines for the diagnosis and management of mucormycosis [25]. Posaconazole and isavuconazole are novel and generally well-tolerated Mucor-active azoles. They are increasingly used as step-down therapy or as salvage therapy in those who are unable to tolerate amphotericin. That said, the lack of clinical trials comparing their efficacy to amphotericin, as well as the longer clinical experience with amphotericin use in the setting of mucormycosis, limits their utility as first-line agents. There is limited and conflicting data regarding the role of combination therapy. A recent systematic review of the therapeutic outcome of mucormycosis suggested that combining amphotericin B and azole can reduce mortality [26]. Although the recurrence of infection may have been attributed to non-compliance, we opted to initiate combination therapy with amphotericin B and isavuconazole during the patient’s second admission to maximize the likelihood of cure and facilitate the resumption of chemotherapy for acute lymphoblastic leukemia.

Finally, the mitigation of the underlying risk factors is no less important. In fact, while the optimal treatment duration has not been identified, reversing the underlying risk factors can serve as a helpful guideline to the timing of treatment discontinuation, along with clinical and radiographic response. Most patients require a minimum of 6 weeks of intravenous amphotericin before stepping down to oral azoles maintenance therapy. Notably, maintenance therapy not only consolidates treatment response, but also serves as secondary prophylaxis to help prevent relapses in patients with prolonged or persistent underlying risk factors [27]. Treatment duration is highly individualized and can last months, years, or even lifelong in cases where the underlying risk factor cannot be eliminated.

Conclusions

Gastrointestinal mucormycosis is a rare and life-threatening fungal infection with an extremely high mortality rate. This case highlights the diagnostic challenge posed by the elusive nature of this infection, even when the patient is already symptomatic. Early recognition and intervention are pivotal, especially in high-risk populations. Clinicians must maintain a high index of suspicion and act swiftly by initiating treatment with surgical intervention, antimicrobial therapy, and reversal of underlying risk factors where feasible. This case also demonstrates the consequences of nonadherence to treatment and the importance of patient compliance in achieving favorable outcomes.