Characterizing patients with rare mucormycosis infections using real-world data

Invasive mucormycosis (IM) is a rare and life-threatening invasive fungal infection caused by fungal species of the order Mucorales [1‐3]. Mortality of patients with IM has been observed to range from 20–78%, although the small number of patients in these studies limits the reliability of these results [4, 5]. The term ‘zygomycosis’ is often used synonymously with mucormycosis, but also includes infections with species of the order Entomophthorales [3]. IM diagnoses are categorized, according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group, as ‘proven’, ‘probable’, or ‘possible’ [6]. ‘Proven’ IM is diagnosed with certainty by the established presence of fungi; ‘probable’ IM is suggested by the presence of host factor criteria, clinical features, and mycological evidence; ‘possible’ IM is suggested by the presence of only host factor criteria [7]. Diagnostic techniques include radiological procedures (for example, chest and cranial CT scans and cranial MRIs), microbiological procedures (including quantitative PCR, high-resolution melting, and multiplex targeting) and histological procedures (including biopsies, direct microscopy using fluorescent brightener, and histopathology with stains such as periodic acid–Schiff and Grocott-Gomori methenamine silver stain) [8, 9].

Diagnosis of IM through these procedures is difficult, because fungal elements may not be detected in biopsies due to unviable fungal elements in homogenized tissues and, if present, may be fragmented in patient samples [8]. Additionally, clinical, radiographic, and cytological procedures have limited sensitivity, and the time taken to produce results can delay diagnosis [10]. As a result, diagnosis by autopsy or in the 24 h before death has been reported in around 10–46% of cases when studied [8, 11]. Diagnosis at a late stage of disease progression can delay treatment, leading to an increased risk of treatment failure and increased mortality [8, 12]. Although molecular diagnostic procedures are available, radiographic and biopsy sampling diagnoses are still often used [10].

The majority of patients with IM are immunocompromised, and previous studies have shown that 44–62% of patients have hematologic malignancies (HMs) [11, 13]. Previous epidemiological studies in patients with IM identified acute myeloid leukemia (48–51% of patients) and acute lymphoblastic leukemia (22–27% of patients) as the most commonly observed malignancies [8, 11]. Treatment recommendations for IM include liposomal amphotericin B (AmB) or, in the case of pre-existing renal compromise, intravenous isavuconazonium sulfate or posaconazole [9], as well as prophylactic treatment with azoles in neutropenic patients and surgical resection in combination with the last known effective treatment in immunosuppressed patients with a prior IM diagnosis [14]. Surgery in combination with antifungal treatment, most commonly 5–10 mg/kg/day liposomal AmB, is strongly recommended as a first-line therapy in adult patients with IM [9, 14].

Due to the rarity of IM, clinical, epidemiological, and outcomes data are lacking and are largely limited to case studies [1, 2, 15]. Large administrative datasets, for example claims databases and electronic health records (EHRs), are increasingly being used to facilitate analyses across many therapy areas [16]. Analysis of large datasets can be applied to many aspects of healthcare research, including epidemiology, pharmacovigilance, clinical trial recruitment, health economics and outcomes research, drug discovery, and diagnostics [16‐18].

One example of a large dataset is the Optum® deidentified EHR dataset (2007–2019), which contains data from approximately 97 million patients from the USA. These data provide the opportunity to assess the population size and characteristics of patients with IM in a real-world setting, within the general population. This study aimed to descriptively assess data on patients with IM using the Optum® EHR dataset. It is hoped that characterizing a large pool of patient data will facilitate comparisons between real-world data and existing case studies, which will improve the diagnosis and treatment of this rare and life-threatening infection in the coming years.

In this retrospective, observational study using US patient data from the Optum® EHR dataset, we identified 1133 patients with a diagnosis of HM and IM. Of these patients, most were Caucasian, > 40 years of age, and located in the Midwest region of the USA. It should be noted, however, that the majority of patients in the overall HM cohort in this study were localized in the Midwest, so these characteristics are not necessarily associated with IM. Common comorbidities and other diagnoses included essential hypertension, malignant neoplasm of connective and other soft tissue, long-term use of other medications, encounter for immunization, and hyperlipidemia. The most commonly prescribed antifungal agents in this group were fluconazole, posaconazole, and any AmB.

The 1133 patients that we identified with HM and IM were comparatively large versus those of other studies, in which the number of patients with IM ranged from 41–851 patients [1, 8, 11, 13, 15, 23], suggesting that IM infection could be more common than existing studies show. In contrast to our study, the majority of patients in these studies were European, and the data were pooled either from prior clinical records, mycology surveys, or voluntary case registries. In one global study of 851 individual patient case reports, similar proportions of European (34%), Asian (31%), and North and South American patients (28%) were observed [23], although under-reporting may be occurring in some countries [24]. Notably, the proportion of females with IM (56.84%) was higher in the current study compared with that observed in other studies, in which the proportion of females ranged from 30–40% [11, 13, 15]; however, this could be explained by the fact that there was a higher proportion of female patients than male patients in the overall HM cohort in this study.

Several studies have identified a large number (ranging from 44.00–63.40%) of patients with IM and underlying HM [1, 11, 15]. Because IM is rare and difficult to diagnose, this study focused on patients with HM to enrich the population with true IM infections and reduce the possibility of false IM coding. Other than diabetes mellitus, which was observed in a slightly higher proportion of patients in this study (17.92%) compared with that observed in other studies (4.80–17.10%), the most common comorbidities and other diagnoses in this study were not observed elsewhere [1, 11, 15]. Diabetes mellitus is a known risk factor associated with IM, so it was not surprising that it was observed in a large proportion of patients with IM in our study [25]. The most common non-HM comorbidity in patients with HM and IM was essential primary hypertension (50.31% of patients), which seemed to be a unique finding compared with pooled data studies, although this could be because there was a large proportion of patients with hypertension in the overall HM cohort, and a large proportion of patients of ≥ 65 years of age. Interestingly, however, a history of hypertension has been observed in some individual case studies of patients with IM, suggesting a potential association between hypertension and IM that has not been reported in a larger patient population [26‐28]. Additional research into these findings could help to further our understanding of the potential predictors of IM in patients with HM.

Of the patients with HM who were prescribed any antifungal, only 0.32% had IM, which could reflect the challenges associated with the efficient diagnosis and treatment of IM. While AmB is strongly recommended as a first-line therapy for IM [14], only a relatively small percentage of patients with HM and IM in our study (15.62%) received AmB treatment compared with other studies, in which the percentage of AmB-treated patients (monotherapy or in combination with other treatments) ranged from 59.46–72.61%. However, only around one-third of patients with HM and IM received any antifungal treatment and, of these, 46.34% received AmB; this again highlights the challenges associated with the diagnosis and treatment of IM but suggests that AmB is prescribed commonly in the patients who are diagnosed and treated. Aside from AmB, the most commonly prescribed antifungal treatments in our study (patients with HM and IM; patients with HM and IM who received any antifungal, respectively) were the azoles, fluconazole (24.27%; 71.99%), and posaconazole (16.33%; 48.43%), suggesting that many patients received more than one antifungal agent. The high number of fluconazole prescriptions is surprising, given that fluconazole is not mold active [29, 30]. This could be influenced by the fact that fluconazole and posaconazole are often used as long-term prophylactic treatments in patients with neutropenia [9, 14]. Prophylactic treatment strategies may lead to overuse of antifungals, causing unnecessary exposure and the potential development of resistance, as well as an increased cost burden [31]. Antifungal stewardship (AFS) programs can be utilized to monitor and intervene in antifungal treatment strategies, although cultural and professional influences may present a barrier to the usefulness of AFS [31, 32]. The data presented here may help to illustrate large-scale prescribing behaviors, although more research is necessary to further our understanding of antifungal prescribing behaviors and reduce inappropriate antifungal use.

The frequency of azole use may have been associated with the prevention or treatment of IA. Posaconazole, for example, is recommended for salvage treatment and prophylaxis against IA [30]. However, some evidence suggests that prophylactic azoles do not prevent IM [33] and have been associated with breakthrough IM infections in some patients [11, 15]. Although coinfection with IA and IM is considered rare [34], it was observed in 14.21% of the patients with HM and IM in the current study, suggesting that it may be more common than previous patient data have indicated. Further study and increased clinical awareness of IA and IM coinfection may lead to improved diagnosis and treatment in the coming years.

This study was descriptive only, with observational data, and yielded a high-level epidemiologic view. No statistical inference testing was performed, and no outcomes data, including survival, were available; therefore, further study is required to draw meaningful conclusions from the data. There are inherent limitations with large patient datasets and how the data are collected and recorded. For example, the HM cohort mainly includes patients localized in the Midwest, which may not represent the wider population of IM patients. There were also more data available in recent years compared with earlier years, suggesting an increase over time in the number of patients with data recorded in EHR datasets. Additionally, the data were not collected for research purposes, so it may be more difficult to analyze compared with clinical data. For example, Mucorales species and the method of diagnosis could not be extracted from the data. Finally, diseases could have been miscoded, and it was not possible to retrospectively confirm diagnoses from the deidentified patient data. Despite the inherent limitations of analyzing large patient datasets, the potential benefit of this approach has been shown in this study. However, these limitations should be taken into account in future studies.

In conclusion, this study represents a promising new approach for analyzing large cohorts of patients with apparently rare diseases, which are challenging to identify prospectively. With further study, the potential applications of large dataset analysis for patients with IM include identifying risk factors, improving diagnosis, and assessing current treatment practices and outcomes. Implementation of research standards, harmonized guidance and more sophisticated methods will facilitate the continuation of informative research in future real-world studies.