Mucormycosis in South America: A review of 143 reported cases

Summary Mucormycosis is a rare but important invasive fungal disease that most often affects immunocompromised hosts. The incidence of mucormycosis appears to be increasing worldwide, as risk factors such as the use of immunosuppressive therapies become more common. We report the results of a literature review of 143 mucormycosis cases reported in South America between 1960 and 2018. The number of reported cases has increased by decade, from 6 in the 1960s to 51 in the 2010s. The most common underlying conditions associated with mucormycosis in South America were diabetes mellitus (42.0%) and penetrating trauma/burns (20.0%). Underlying conditions involving immunosuppression, including treatment of haematologic malignancy, solid organ transplant, and corticosteroid use, also accounted for a large proportion of cases (45.5%). Between 1960 and 2018, cases of mucormycosis associated with conditions involving immunosuppression accounted for the highest mortality rate (58.5%), followed by diabetes mellitus (45.0%), and penetrating trauma/burns (37.9%). Overall mortality decreased from 100% to 39.4% during this period, mainly driven by the increasing availability and use of antifungal therapies and surgical intervention. However, these treatments are not yet universally utilised across the region in the treatment of mucormycosis; efforts to improve availability of effective treatments would be likely to improve outcomes.

Entomophthorales is typically localised. 3,5 This review focuses only on mucormycosis.
Mucormycosis may be acquired through different routes, including the respiratory tract, injured skin, contaminated needles or catheters, or ingestion of contaminated food. 7 The most common sites of infection are the rhino-orbital-cerebral, pulmonary, gastrointestinal and cutaneous areas. 4,11,13 Following the initial infection, the disease typically progresses quickly, with rapid invasion of blood vessels leading to thrombosis and tissue necrosis. 3,7 A number of different factors are associated with an increased risk of mucormycosis. 5,10 Globally, mucormycosis is particularly common in patients with diabetes mellitus, and the risk is much higher in patients with uncontrolled diabetes, in whom the resultant ketoacidosis interferes with the normal activity of lymphocytes, increasing risk of infection. 3,4,6,7,[14][15][16] In addition, as with other IFD, patients with an impaired immune system following the use of immunosuppressive treatments are also vulnerable. This group includes patients receiving chemotherapy as treatment for cancer, especially haematological malignancies, and also hematopoietic stem cell transplantation (HSCT) and solid organ transplant (SOT) recipients. 3,4,6,7,16 Mucormycosis also affects immunocompetent individuals after penetrating trauma or burns, which exposes tissues to environmental sources of fungi, and patients with iron overload under treatment with deferoxamine. 3,4,6,7,16 Characteristically, fungi belonging to the order Mucorales exhibit high minimum inhibitory concentrations (MICs) to many antifungal agents currently available. 12 The antifungal agents with the lowest MICs for Mucorales are amphotericin B, isavuconazole and posaconazole, but the MICs vary widely depending on the genus and species. In the clinical setting, MICs of each antifungal agent for each genus and species need to be interpreted in the context of the antifungal exposures that are achievable. 17 Prompt diagnosis and rapid initiation of antifungal therapy combined with surgical removal of infected tissue are required for optimal outcomes. In addition, control of the underlying condition and/or reduction of immunosuppression are important components of treatment. 3,[12][13][14] As acknowledged by the European Confederation of Medical Mycology (ECMM), there are currently regional differences in the diagnosis and treatment of mucormycosis. As such, the ECMM has recently begun a "neglected orphan disease guidance initiative" focusing on this disease both within and beyond the European region. 18 Several previous studies have gathered data on mucormycosis in patients in Europe, Asia or other areas, [3][4][5][8][9][10][11]19,20 but to date, there has been no comprehensive review of the literature on mucormycosis in South America. Here, we collate and review mucormycosis case studies reported in South American countries, exploring patient characteristics, course of infection, treatment regimens and clinical outcomes.
No ethical approval was required as this is a review article with no original research data.  Table 1. After diabetes mellitus, the next most common conditions were SOT (22.0%) and malignancy (16.9%) in Brazil, and penetrating trauma/burns (32.1%) and malignancy (10.7%) in the other countries.

| RE SULTS
Of note, the incidence of penetrating trauma/burns as an underlying cause was much lower in Brazil than in the other countries (3.4% vs 32.1%). Thirteen of the 29 cases of penetrating trauma were from Colombia, and eight of these cases were skin and soft tissue infection after a volcanic eruption. 26 The overall mortality rate was 48.3%, 52.5% in Brazil and 45.2% in the other countries. The mortality rate in cases secondary to penetrating trauma/burns was lower than in cases occurring in immunocompromised patients (20.3% and 45.5%, respectively). Of three patients who received an allogeneic HSCT in Brazil, all three died (Table 1).
However  Table 4).  which may help to reduce infection rates. In addition, further confirmation in large data sets is required on the causes of differences between countries, such as the much higher association between penetrating trauma/burns and mucormycosis in South American countries other than Brazil, putatively related to a higher frequency of natural disasters. Such data will aid preventative efforts in the region.

| D ISCUSS I ON
Rhizopus and Mucor species were found to be the most frequently isolated organisms, but identification of the agent was not performed in half of the cases. conclusions. In addition, it is not possible to discern the causes for some of the patterns observed, such as the varying mortality rates with different sites of infection or with different underlying conditions. These issues may be addressed in future research as more cases are reported.

This case review identifies patterns of infection in South
America that are of value to physicians in the region and may aid in formulating preventative efforts against mucormycosis. It also identifies gaps in current practice that, if addressed, could improve treatment across the region. Overall, increasing use of antifungals and surgery has much improved the prognosis of mucormycosis.
However, mortality remains high, particularly in patients where surgery is not performed. 7,12,14,30 A combination of new diagnostic technologies, optimised use of available antifungal options, development of new antifungal agents and more aggressive public health policies may help to reduce mortality rates from mucormycosis in South America.

ACK N OWLED G M ENTS
The authors thank Erwin Graef of Basilea Pharmaceutica International Ltd. for his support with the medical literature search.
Medical writing support was provided by Ben Caldwell of Spirit, funded by Basilea Pharmaceutica International Ltd.

ME and KH are employees of Basilea Pharmaceutica International
Ltd. MN has received honoraria from AbbVie, Astellas, Gilead, Janssen, Merck, Pfizer, Teva and United Medical.