Small Bowel Perforation Caused By Disseminated Mucormycosis

AUTHORS:
Bayarmaa Mandzhieva, MD¹ • Alexandra Lackey, MD¹ • Jason Sniffen, DO² • Darian Kameh, MD³ • Edward Maharam, MD¹

AFFILIATIONS:
¹Department of Internal Medicine, AdventHealth, Orlando, Florida
²Department of Infectious Disease, AdventHealth, Orlando, Florida
³Department of Pathology, AdventHealth, Orlando, Florida

CITATION:
Mandzhieva B, Lackey A, Sniffen J, Kameh D, Maharam E. Small bowel perforation caused by disseminated mucormycosis. Consultant. 2022;62(4):e31-e35. doi:10.25270/con.2021.08.00013

Received April 10, 2021. Accepted April 21, 2021. Published online August 30, 2021.

DISCLOSURES:
The authors report no relevant financial relationships.

CORRESPONDENCE:
Alexandra Lackey, MD, 601 East Rollins Street, Suite 400, Orlando, FL 32803 (Alexandra.Lackey.MD@AdventHealth.com)

A 33-year-old postpartum woman presented to our emergency department (ED) with dyspnea, orthopnea, and generalized abdominal pain and distention for 2 days. She had been having trouble breathing at rest and had mild relief with sitting upright. She had been having flatus but had not had a bowel movement for 5 days. She was given lactulose and docusate, which failed to improve her symptoms.

She denied fever, chills, nausea, emesis, melena, hematochezia, chest pain, and cough. She had been passing lochia with no change in amount or color.

History. One month prior to presentation, while she was pregnant, the patient had been admitted to the hospital for more than 1 month because of severe preeclampsia, which required an emergency cesarean section at 34 weeks’ gestation.

She had had presented to the ED with malaise, epigastric discomfort, peripheral edema, transaminitis, and acute kidney injury, at which time the diagnosis of preeclampsia was established. On hospital day 6 after the cesarean section, she had developed acute encephalopathy, hypertension, thrombocytopenia, leukocytosis, fulminant acute liver failure, and nonoliguric acute renal failure, which led to her being transferred to the intensive care unit (ICU) with concern for hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome.

At that time, histopathologic examination of the placenta had demonstrated findings consistent with acute chorioamnionitis. Because the patient had concurrent systemic inflammatory response syndrome (SIRS), she was empirically treated with intravenous (IV) clindamycin, 900 mg, every 8 hours and meropenem, 1 g, every 8 hours for 4 days, followed by 48 hours of IV ceftriaxone, 2 g, every 24 hours.

Blood cultures did not grow bacteria at that time, and antibiotics had been discontinued. In the setting of progressive thrombocytopenia, hemolysis, elevated lactate dehydrogenase, schistocytes on peripheral blood smear, and low haptoglobin level, the patient received a diagnosis of microangiopathic hemolytic anemia, likely caused by thrombotic thrombocytopenic purpura (TTP). She had received empiric treatment with steroids for 10 days and underwent daily plasmapheresis for 7 days with significant improvement in her clinical status.

She was, therefore, discharged after hospital day 37 in stable condition with a gradual taper of oral prednisone. She followed up with her primary care provider as an outpatient, and he was concerned about an acute rise in the patient’s white blood cell count and recommended she return to the hospital.

Prior to this hospital admission, the patient had been generally healthy and had never smoked, consumed alcohol, or used illicit drugs. Her family history was nonsignificant for immunodysfunction and was otherwise not contributory.

Physical examination. At the time of her present visit, the patient was afebrile, had an oral temperature in the normal range, had tachycardia with an elevated heart rate of 124 beats/min, and had tachypnea with an elevated respiratory rate of 22 breaths/min. Her oxygen saturation was 99% to 100% on room air, and her blood pressure was elevated at 133/91 mm Hg. She was alert and oriented to person, place, and time. She was in obvious discomfort because of the abdominal pain.

A chest examination revealed decreased breath sounds bilaterally with occasional crackles. An abdominal examination was significant for hypoactive bowel sounds, firmness with generalized tenderness to palpation, and severe distention with tympany but no rebound or guarding. She also had bilateral pedal pitting edema.

Diagnostic testing. At presentation, the patient had neutrophilic leukocytosis. Results from initial laboratory testing were significant for a high white blood cell count of 24,300 cells/μL, a low hemoglobin level of 7.7 g/dL, and a high platelet count of 371 × 10³/μL. Results of a metabolic panel were significant for an elevated total bilirubin level of 1.6 mg/dL, an elevated direct bilirubin level of 1.1 mg/dL, an elevated alkaline phosphatase level of 349 U/L, an elevated alanine aminotransferase level of 37 U/L, an elevated aspartate aminotransferase level of 51 U/L, and an elevated lactate dehydrogenase level of 521 U/L. The patient’s lactic acid level was also elevated at 25.2 mg/dL.

A chest radiograph demonstrated air under the right hemidiaphragm, which was compatible with pneumoperitoneum, as well as bilateral pleural effusions and bibasilar atelectasis. These critical results prompted a computed tomography (CT) scan of the abdomen and pelvis with contrast, results of which revealed a large amount of fluid and gas throughout the abdomen and pelvis with peritonitis and bowel perforation with multifocal large connecting abscesses (Figure 1).

Figure 1. Results of a CT scan of the abdomen and pelvis demonstrated (A) small bowel perforation, (B) air near the liver consistent with pneumoperitoneum, (C) anterior pelvis fluid collection, and (D) enhancement of the pelvic peritoneal lining consistent with peritonitis.

Treatment and management. The patient underwent emergent exploratory laparotomy on the day of admission with findings significant for ischemic and perforated bowel that required resection of the jejunum and ileum. Resected areas appeared to have liquefactive necrosis with significant succus (Figure 2). The bowel was left in discontinuity, and the abdomen was temporarily closed with a negative pressure abdominal closure device because of gross contamination and septic shock that required pressors.

Figure 2. The small bowel resection specimen after sections were taken for histologic processing and post-fixation in 10% neutral-buffered formalin solution. The thick rind of peritonitis is noted to the right of the specimen. Centrally, there is dusky and green discoloration of the mucosa, denoting the areas of ischemia and perforation.

The patient remained intubated and was transferred to the surgical ICU following the initial surgery. She required pressor support with norepinephrine, 0.05-0.25 μg/kg, titrated for mean arterial pressure of 65 and vasopressin, 0.03 U/min, for 2 days and remained sedated on mechanical ventilation for 3 days.

Results of the pathology of the mid- and distal small bowel resections returned on hospital day 3 and demonstrated florid acute ischemic enteritis (Figure 3) and invasive fungal infection with Mucor (Figures 4 and 5). Underlying areas of full-thickness necrosis were intravascular fibrin thrombi embedded with fungal organisms, some of which had invaded transmurally into the surrounding tissue with numerous fungal hyphae present within the peritoneum.

Figure 3. Results of the hematoxylin and eosin stain of the small bowel resection (20× magnification) showed full-thickness ischemic changes involving both the mucosa and bowel wall. The submucosal blood vessels are occluded by fibrin thrombi.

Figure 4. Results of the periodic acid-Schiff stain of the small bowel resection (400× magnification) showed a circular structure, which is one of the occluded vessels seen in Figure 2. The stain highlights angioinvasive fungal hyphae extending into the surrounding necrotic tissue.

Figure 5. Results of the periodic acid-Schiff stain of the small bowel resection (400× magnification) showed the fungal organisms embedded in the peritonitis, which displayed broad ribbon-like, nonseptate hyphae with 90°-angle branching and nonparallel walls, consistent with a species from the class Zygomyces, such as Mucor.

The patient was immediately started on IV isavuconazonium sulfate, 372 mg, every 8 hours for 48 hours and every 24 hours thereafter, along with IV liposomal amphotericin B, 450 mg, every 24 hours.

Three days later, the patient underwent small-bowel anastomoses and abdominal fascial closure. Intraoperatively, the bowel was extremely friable, and initial attempts at stapling were complicated by serosal injuries requiring imbrication with interrupted sutures. Ultimately, side-to-side anastomoses were completed at the prior sites of resection. Although the abdominal fascia was closed, there was gross spillage of purulent material. Therefore, the surgeons opted to leave the surgical site open with placement of an incisional negative pressure device.

Five days after the second procedure, the patient was transferred out of the ICU to the medical ward. The following day, she developed a leak around the negative pressure dressings, which appeared to be enteric content likely from an underlying anastomotic leak. Despite this, she remained afebrile and hemodynamically stable with downtrending leukocytosis.

Her abdominal examination was largely unchanged from preoperatively with mild diffuse tenderness. She underwent another CT scan of the abdomen and pelvis with oral and IV contrast, results of which showed small bowel perforation with free spillage of oral contrast into a large, complex, loculated abdominopelvic collection (Figure 6). The site of bowel perforation was identified within the mid-abdomen at a small bowel anastomosis with widespread findings of peritonitis.

Figure 6. A CT scan of the abdomen and pelvis showed a small bowel perforation at the site of small bowel anastomosis (blue arrow) with associated pneumoperitoneum (yellow arrow) and enhancement of the peritoneal lining, consistent with peritonitis (green arrow).

The patient was again urgently taken to the operating room for exploratory laparotomy, abdominal washout, small-bowel resection, end ileostomy with mucous fistula creation, and wound vacuum-assisted closure placement. During the procedure, a 1-cm disruption was encountered at the prior proximal small bowel anastomosis, which was leaking enteric content and fluid. Approximately 15 cm of small bowel incorporating the leaking anastomosis was resected and submitted for surgical pathology. Pathology results of portions of small bowel resected during the third surgical procedure demonstrated no fungal elements.

Upon initial presentation, the patient was empirically treated for intraabdominal sepsis with vancomycin, 25 mg/kg, loading dose followed by 20 μg/kg every 8 hours for 4 days; fluconazole, 800 mg, on day 1 followed by 400 mg for days 2 and 3; and zosyn, 4.5 g, every 8 hours for 2 days. Two sets of blood cultures drawn on the day of admission grew Klebsiella pneumoniae, susceptible to meropenem with minimum inhibitory concentration of less than or equal to 0.25. She subsequently transitioned to therapy with meropenem, 1g, every 8 hours.

She had been recovering well, but on hospital day 14, she had persistent SIRS. A repeat CT scan of the abdomen and pelvis with oral and IV contrast was performed, results of which revealed multiple loculated collections in the abdomen and a mild degree of residual pneumoperitoneum. The largest collection in the anterior abdomen measured roughly 19.7 cm × 2.9 cm, with a right perihepatic collection measuring 14.3 cm × 3.6 cm and left subphrenic collection measuring 9 cm × 4.3 cm. Collections in the lesser sac were decreased in size, the largest measuring 4.6 cm × 3.2 cm. A right paracolic collection measuring 8.1 cm × 4.8 cm in the lower abdomen had also decreased in size. Three drains were placed by an interventional radiologist with return of frank pus. Abscess cultures were polymicrobial and showed Enterobacter cloacae, Citrobacter braakii, Stenotrophomonas maltophilia, Escherichia coli, and β lactamase-positive Bacteroides fragilis.

An infectious disease specialist was consulted, who recommended adding linezolid, 600 mg, twice daily for 5 days. Linezolid was switched to minocycline, 100 mg, twice daily for Stenotrophomonas species. Given this information, a decision was made to continue meropenem and minocycline for 6 weeks.

A follow-up CT scan of the abdomen and pelvis with oral and IV contrast prior to the patient’s discharge showed interval size decrease of previously seen multifocal loculated fluid collections throughout the abdomen, resulting from multiple percutaneous drain placements and antimicrobial treatment.

Of note, during the hematologic workup, the patient was found to have antithrombin-3 deficiency, which was treated with enoxaparin, 100 mg, twice daily during her hospital stay.

She completed a 14-day course of liposomal amphotericin B during her 17-day hospital stay and was discharged on oral isavuconazonium sulfate, 372 mg, daily for at least 3 months.

Discussion. Mucormycosis is a potentially lethal invasive fungal infection caused by Mucorales, which primarily develops in patients who receive transplants, have diabetes, take prolonged courses of glucocorticoids, or are otherwise immunocompromised. The infection is characterized by angioinvasion by Mucor hyphae, leading to extensive necrotizing vasculitis that results in thrombosis, subsequent tissue infarction and systemic dissemination. It is a critical infection associated with significant morbidity and high mortality rate.¹

The most common forms of mucormycosis are pulmonary and rhino-orbito-cerebral. Disseminated mucormycosis, which is usually seen in the setting of immunosuppression, is the most severe form.¹ Gastrointestinal mucormycosis is the rarest form, constituting only 7% of cases, and is acquired after ingesting contaminated food or from contaminated surgical instruments.^1,2 The mortality rate of gastrointestinal mucormycosis is about 85%, and its incidence has increased in recent years.^2,3 Antemortem diagnosis is made in only 25% of cases.⁴

Historically, the gastrointestinal form has been reported in premature neonates and malnourished children.² Our case is important because our patient lacks the traditional risk factors described in current literature. In a retrospective series of 31 cases, the researchers found that the 2 main underlying conditions were solid organ transplant (52%) and hematologic malignancy (48%).⁵ The most common clinical manifestation was abdominal pain and distension (68%), followed by gastrointestinal hemorrhage (48%), fever (19%), and change in bowel habits (10%). Its nonspecific presenting symptoms make diagnosis challenging, and thus, it is often missed, which results in poor outcomes and high mortality rate.⁵

With respect to gastrointestinal site involvement, an estimated 57.7% of cases are in the stomach, 32.3% in the colon, 7% in the esophagus, 6.9% in the ileum, 2.3% in the duodenum, and 1.1% in the jejunum.⁶ Gastrointestinal mucormycosis is a histopathological emergency, and the clinician should be informed of this finding on an urgent basis to institute early and appropriate management to improve outcomes. Our case suggests that clinicians should remain aware of the possibility of invasive fungal infections, including mucor, even in immunocompetent individuals.

In 2014, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) as well as the European Confederation of Medical Mycology strongly recommended direct microscopy, histopathology, cultures, and imaging as diagnostic tools to detect mucormycosis and determine the depth of infection. Diagnosis can be suspected on endoscopy with visualization of a fungal mass or necrotic lesions overlying an area of ulceration. These lesions are of particular interest because they can lead to perforation and subsequent peritonitis. On histopathologic examination, lesions of Mucor demonstrate characteristic broad, right-angle branching and nonseptate hyphae with extensive angioinvasion and resultant vascular thrombosis and necrosis. ⁷ In our patient’s case, surgical pathology revealed evidence of mucormycosis in the resected bowel.

A multidisciplinary approach is crucial for prompt diagnosis and treatment of mucormycosis. High-quality evidence regarding optimal antifungal therapy regimens is not currently available. Appropriate management is urgent surgery combined with IV liposomal amphotericin B, 5 mg/kg/d, per available ESCMID guidelines.⁷ Posaconazole or isavuconazole is prescribed as step-down therapy for patients who have responded to amphotericin B.

Isavuconazonium sulfate, an ergosterol inhibitor and prodrug of isavuconazole, was recently approved by the US Food and Drug Administration for the treatment of invasive mucormycosis and aspergillosis. This treatment option offers extended-spectrum antifungal activity with promising early study results, particularly in the setting of amphotericin-refractory infection.^8-10 Use of antifungal treatment should continue until there is clinical resolution of the signs and symptoms of infection, as well as resolution of radiographic signs of active disease.³ Aggressive and timely surgical debridement of necrotic tissue is critical for complete eradication and reduced mortality.

Conclusion. We report a case of disseminated mucormycosis presenting with small bowel perforation in a postpartum woman with recent history of TTP, successfully managed with combined amphotericin B and isavuconazonium therapy as well as surgical debridement. Timely resection of the infected tissue was critical. Because of a prompt multidisciplinary approach and team effort, our patient had a good clinical outcome and was discharged home in stable condition.

This case demonstrates that a broad differential diagnosis must be established even in patients with no traditional underlying risk factors. In a patient with unexplained abdominal distension and pain, aggressive efforts should be made to diagnose the cause. Unusual pathologies including disseminated fungal infections should remain on the differential, especially with refractory symptoms or anastomotic breakdown. Finally, steroid exposure is known to be associated with invasive mucormycosis,¹¹ and in our patient’s case, her recent treatment with steroids may have been one of the inciting factors for the ensuing fungal infection.

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