Gastrointestinal mucormycosis: an evolving disease.

Mucormycosis is a life-threatening infection caused by fungi of the subphylum Mucoromycotina, order Mucorales.1 Traditional risk factors for the development of invasive mucormycosis include diabetes, defects in host phagocytes, corticosteroid use, organ or stem cell transplantation, and increased levels of available serum iron as a result of acidosis or administration of deferoxamine.2–4 In recent years, the disease has also increasingly been described in patients without traditional risk factors.2 Mucormycosis can affect any organ system, but the most common presentations involve either the nasal sinuses, orbit, and brain (rhino-orbital-cerebral) or the lung. For many years, gastrointestinal mucormycosis was quite rare, especially in industrialized nations. However, there has been a substantial increase in the number of cases of gastric and gastrointestinal mucormycosis indexed on PubMed over the past 2 decades, particularly over the past decade. For example, a PubMed search for the title words “gastric” or “gastrointestinal” and “mucormycosis” or “zygomycosis” revealed 8 publications from 1959–1989 (31 years), 23 publications from 1990–1999 (10 years), and 50 publications from 2000–2011 (12 years). The stomach is the most common site of gastrointestinal mucormycosis, followed by the colon and ileum. In the past, gastrointestinal mucormycosis was seen primarily in premature neonates, often in association with widespread disseminated disease.5–12 For example, necrotizing enterocolitis has been described largely in premature neonates and, more rarely, in neutropenic adults.8,9,13–20 Other rare cases of gastrointestinal mucormycosis were previously described in association with other immunocompromising conditions, including AIDS, systemic lupus erythematosus, and organ transplantation.21–26 Cases of hepatic mucormycosis have also been associated with ingestion of herbal medications.27 Because this infection is acute and rapidly fatal, it is often diagnosed postmortem. The symptoms of gastrointestinal mucormycosis are varied and depend on the affected site. Nonspecific abdominal pain and distention associated with nausea and vomiting are the most common symptoms. Fever and hematochezia may also occur. The patient is often thought to have an intra-abdominal abscess. The diagnosis may be made by biopsy of the suspected area during surgery or endoscopy. Recently, an iatrogenic outbreak of gastric mucormycosis occurred due to contamination of wooden applicators that were used to mix drugs for patients with nasogastric feeding tubes.28 These patients presented with massive gastric bleeds. The diagnosis was made by culturing gastric aspirates and the wooden tongue depressors. This experience further underscores the alarming trend of increasing iatrogenic/nosocomial onset of mucormycosis. As mentioned previously, older clinical literature (prior to 1990) primarily describes cases of mucormycosis in neonates and premature infants.15–18 During the 1990s, cases were predominantly described in patients receiving immunosuppressant medications due to solid organ transplantation.23,24,29,30 While such cases continue to be described in the 21st century, a substantial proportion of the cases described since 2000 have occurred in more widely disparate patient populations; these patients may have risk factors such as diabetes mellitus or corticosteroid use, a gastric or peptic ulcer that apparently became infected with the fungi, or no predisposing risk factors.4,31–37 The case reported by Morton and colleagues is typical of the increasing experience with this illness in the 21st century.38 This patient had preexisting gastrointestinal mucosal ulcerations due to her underlying Crohn's disease, and she was immunosuppressed due to her corticosteroid therapy. When she presented with her perforation, there was no specific reason to suspect mucormycosis; indeed, the disease was much less likely than more typical causes of colonic perforations in such patients. Only the appearance of the fungi on histopathology caused the diagnosis to be made and appropriate therapy to be initiated. Thus, this case highlights the need to maintain a high index of suspicion for invasive fungal infections, including mucormycosis, in patients who are being treated with corticosteroids and who present with disease that crosses tissue planes. The need to make a rapid diagnosis is underscored by recent data from the oncology setting, in which initiation of polyene antifungal therapy within 6 days of presentation was strongly associated with improved survival.39 There have been no prospective randomized trials to define the optimal antifungal therapy for mucormycosis. Nevertheless, primary antifungal therapy for mucormycosis should be based on a polyene antifungal agent, as this drug class is by far the most active against the relevant pathogens. Most experts prefer to use lipid formulations of amphotericin B, which can be administered at higher doses and with less toxicity than amphotericin B deoxycholate.3 The role of combination therapy in mucormycosis remains unclear, although data from mouse studies and concordant retrospective data in humans suggest that combining lipid polyenes with echinocandins may improve outcomes.3 Additional research is needed to confirm this hypothesis in prospective trials. Antifungal therapy alone is typically inadequate to control mucormycosis, and surgery to debulk the fungal infection and/or resect all infected tissue is often required to effect cure. Aside from the resistance of some fungal strains to amphotericin B, several hallmark features of mucormycosis—including angioinvasion, thrombosis, and tissue necrosis—result in poor penetration of anti-infective agents to the site of infection. Therefore, even if the causative organism is susceptible to the antifungal agent in vitro, the antifungal agent may be ineffective in vivo. In a logistic regression model, surgery was found to be an independent variable for favorable outcomes in patients with mucormycosis.2 Furthermore, in multiple case series, patients who did not undergo surgical debridement of mucormycosis had a far higher mortality rate than patients who underwent surgery.40–48 While there is potential selection bias in these case series—patients who did not undergo surgery likely differed in disease severity and/or comorbidities from those who did undergo surgery—these data support the concept that surgical debridement is necessary to optimize cure rates. Finally, immunosuppressive medications, particularly corticosteroids, should be dose-reduced or stopped if at all possible. Given the increasing incidence of cancer in the aging US population, an ongoing epidemic of obesity and diabetes, and the increasing population of patients receiving corticosteroid therapy for inflammatory diseases and/or solid organ or stem cell transplantation, it is not surprising that recent studies have reported alarming increases in the incidence of mucormycosis.49–51 Clinicians will likely continue to encounter this disease more frequently in the coming years, especially in the nosocomial setting. Further research is needed regarding new diagnostic and therapeutic modalities for these devastating infections. In the meantime, improvement in patient outcomes will require a high index of suspicion and emergent diagnostic evaluation to allow early initiation of antifungal and surgical therapy.