Mucormycosis in the Middle East and North Africa: Analysis of the FungiScope® registry and cases from the literature

Regional differences in the underlying causes, manifestations and treatment of mucormycosis have been noted in studies covering Europe, Asia and South America.


| INTRODUC TI ON
Mucormycosis is a rare opportunistic invasive fungal disease (IFD), which typically occurs in patients with a compromised immune system. 1 Diabetes mellitus is a common risk factor in middle-and low-income countries, with uncontrolled diabetes posing a particular risk as the resulting ketoacidosis can suppress immune system activity. 2,3 Other immunocompromised patients at risk for mucormycosis include recipients of haematopoietic stem cell or solid organ transplants, patients infected with human immunodeficiency virus and patients receiving chemotherapy for cancer. 3,4 In the absence of factors affecting normal immune system function, exposure to environmental sources of fungi through penetrating injuries such as trauma or burns has also been linked to mucormycosis. 3,5 In recent decades, the number of reported cases of mucormycosis has increased in both emerging and developed countries 6,7 and correlates with the rapidly increasing global prevalence of diabetes and the rising number of immunocompromised patients. 8,9 As the number of patients with these conditions continues to expand, a concomitant rise in the incidence of mucormycosis may perhaps be anticipated.
Mucormycosis can manifest at a variety of sites, with rhino-sino-orbito-cerebral, pulmonary, cutaneous and gastrointestinal involvement being the most common. 3 In the absence of treatment, survival rates have been reported to be as low as 3%, 7 and even in the modern treatment era, day 42 mortality rates of 28%-39% have been reported with antifungal therapy and surgical debridement. 10,11 Rapid initiation of treatment is critical and typically involves a combination of surgery to remove infected tissues and immediate first-line antifungal therapy. 1,12,13 The most effective antifungal agents in the treatment of mucormycosis are amphotericin B, isavuconazole and posaconazole. 1,11,12 Active treatment should also be combined with control of the underlying condition and/or reduction in the extent of immunosuppression. 1,13 Incidence of mucormycosis is possibly related to weather conditions, with case clustering observed during periods of elevated temperatures and low precipitation. 14,15 Furthermore, geographic patterns and global differences in the underlying causes, manifestations and treatment of mucormycosis have been noted in data gathered in Europe, Asia and South America. [3][4][5]7,16,17 However, a review of cases across the Middle East and North Africa (MENA) is lacking. We have therefore collated and reviewed cases of mucormycosis from this region and herein summarise the key data from the cases identified.

| ME THODS
We selected cases from the FungiScope ® database and the medical literature. FungiScope ® is a web-based registry that collects cases of rare IFDs worldwide (NCT01731353). 18 The structure and management of the FungiScope ® registry have been described previously. 19 In brief, case enrolment requires cultural, histological or molecular

TA B L E 1 (Continued)
The distribution of the identified cases across the region is shown in Figure 2.   Table S1.
Overall mortality rates have decreased over time (

| D ISCUSS I ON
Our study summarises 303 cases from the literature and seven cases from an international database. This first comprehensive review of mucormycosis across MENA countries shows that the number of cases reported across this region has risen steadily over the past few decades, and that the burden of mucormycosis and the associated mortality remain high despite recent improvements in treatment.

Mucorales NOS (n = 188)
The median age of patients identified in this analysis (41 years) was in line with those reported in a global review and a review for South America (39 years and 40 years, respectively). 7,16 However, higher median ages have been identified in studies covering Europe (50-60 years) 5,6,23 and in another global study (49 years). 17 The proportion of males (58.4%) was largely consistent with the range observed in other studies (58-70%). [5][6][7]17,23,24 The most frequent underlying condition in the MENA region was diabetes mellitus, followed by corticosteroid use, solid organ transplants, haematological malignancy and long-term neutropenia.
The dominance of diabetes and conditions associated with immunosuppression broadly aligns with reports from other regions including South America and India. 3,16,25 However, reports from Europe indicate haematological conditions as the predominant underlying pathology. 26,27 Regional differences raise the concern that other factors may influence the pathogenesis, diagnosis and treatment of mucormycosis. These may include diagnostic and therapeutic resources, climate and specific patient populations. Worldwide studies to assess true geographic differences versus confounding factors are scarce. 11  a Includes infections restricted to any of these sites; b Defined as involvement of ≥ 2 non-adjacent organs; c Infections may occur at more than one specific site in the same patient; d Includes facial bones involved in rhino-sino-orbito-cerebral mucormycosis; e Ear (n = 6), spleen (n = 5), heart (n = 3), invasive oral mucositis (n = 3), trachea (n = 2), pancreas and spleen (n = 2), peritoneum (n = 2), parotid gland (n = 1) and ureter (n = 1), fungemia (n = 1). The rhino-sino-orbito-cerebral location was the most frequent site for mucormycosis infection, followed by pulmonary and cutaneous sites. This is again broadly in agreement with the literature. 3,16 Of note, rhino-sino-orbito-cerebral mucormycosis infections have been associated with diabetes mellitus in particular and, to a lesser extent, immunosuppression, trends that have been observed across multiple regions. 3,16 Given the worldwide increase in the number of patients who have diabetes mellitus or are immunosuppressed, 8,9 such infections have growing significance in clinical practice. This may be particularly relevant for the MENA region, which had the highest comparative prevalence of diabetes in the world in 2012. 28 Moreover, almost half of diabetes cases in this region are estimated to be undiagnosed, 29 which may further increase the risk of mucormycosis. 4

TA B L E 3
The species involved remained unidentified in more than half Surgery may not always be feasible and is generally restricted to patients with limited disease. In the opinion of the authors, antifungal prophylaxis is key to improve outcome in high-risk patients.
In other immunosuppressed hosts, optimal surveillance and early treatment (whether monotherapy or combination therapy with or without surgery) is crucial to improving patient outcome. 33 It is encouraging to note the decline in the mortality rate in the MENA region over time, which may reflect improving standards of care for mucormycosis. However, the rise in the overall number of reported cases of mucormycosis and the number of deaths attributable to mucormycosis is of concern, although this may also reflect a growing awareness of such diseases and increased efforts by physi- TA B L E 4 Outcome by time period and overall in patients with mucormycosis in the Middle East and North Africa always retrievable, and the reported data were of heterogeneous quality, whereby newer reports tended to be less comprehensive.
Registries typically provide a more comprehensive dataset than case reports and can help in epidemiological and clinical investigations in rare and orphan diseases. However, to date, only a small number of mucormycosis cases from the region (n = 7) have been included in the FungiScope ® registry.
This study highlights the burden of mucormycosis in MENA countries and identifies trends in the cases from this region that may be of value to physicians treating this disease. Given the wide use of both antifungal therapy and surgery, and the decreasing mortality rate, the prognosis of patients with mucormycosis is improving, but the need for more effective treatment practices in the MENA region is clear. Progress towards this goal can be made through several avenues, including the use of technologies enabling earlier diagnosis, the development of new antifungal therapies and optimised use of existing therapies, as well as the implementation of policies to increase awareness of mucormycosis and to improve its regional documentation. Reducing the risk of mucormycosis in the region will also be key, for example through improved diabetes prevention and management strategies.

JS reports grants from Basilea Pharmaceutica International Ltd dur-
ing the conduct of the study and travel grants from Meta-Alexander