Mucormycosis is an angioinvasive fungal disease, originating from saprophytic fungi within the Mucorales order (1). These ubiquitous fungi typically present as wide, ribbon-like hyphae, either aseptate or with minimal septation. Humans contract the infection chiefly through the inhalation of sporangiospores, or less frequently through ingestion of tainted food or assorted skin penetration methods (2). Over the past decades, the role of Mucorales as a pathogen has gained considerable prominence (3, 4). This escalation is particularly noticeable among patients with conditions like diabetes, cancer, and those undergoing solid organ or hematological transplants (4, 5). Notably, a substantial rise has been recorded in India and China, especially among patients with uncontrolled diabetes mellitus (3, 6, 7). Amidst the COVID-19 pandemic, the incidence of mucormycosis experienced a significant surge (seven cases per 1,000 patients), fifty times the previously highest recorded prevalence (0.14 cases per 1,000 patients) (8). Factors such as virus-induced endothelial dysfunction, high blood sugar levels, and immune disturbances due to corticosteroid use heightened the susceptibility to mucormycosis (9). Clinical manifestations of mucormycosis can varies based on the affected sites, with potential for rhino-orbital-cerebral, pulmonary, cutaneous, gastrointestinal, and disseminated forms (10). Diagnosis of mucormycosis primarily relies on histological evidence or positive cultures from lesion sites, due to the absence of recognized serologic markers, which can potentially cause delays in treatment initiation.

In 2005, Roden and his team conducted the first comprehensive review of mucormycosis, which included 929 cases documented from 1940 to 2003, and reported a pooled mortality rate of 44% (4). More recently, a meta-analysis by W. Jeong and his team, which scrutinized mucormycosis cases from 2000 to 2017, revealed that diabetes mellitus and hematological malignancies (42% of them being acute myeloid leukemia) were the most prevalent underlying conditions. Of the 851 patients, 389 succumbed to the diseases (11). Most available information on mucormycosis in hematology patients stems from case series and case reports. However, there has not been a meta-analysis specifically exploring the mortality rate of mucormycosis in hematological patients, primarily because of insufficiently diagnosed and documented cases. In this era marked by an increase in hematological stem cell transplantation, as well as the emergence of aggressive diagnostic techniques and new triazole drugs effective against both Aspergillus sp. and Mucorales (12, 13), the clinical characteristics and mortality rates of mucormycosis have seen a significant shift. As a result, we embarked on a meta-analysis to aggregate the mortality rates and the risk factors of mucormycosis in hematological patients spanning from January 2000 to December 2022. The protocol was registered in the INPLASY (registered number: 202370069).

This study was conducted and reported following the PRISMA guidelines (14).

In the identification of relevant studies, an initial search led us to a total of 1,035 potential studies (Figure 1). After eliminating 149 duplicate entries, we screened the remaining records, resulting in the exclusion of 534 studies (511 studies were unrelated about hematological patients and mucormycosis, the other 22 studies were not published in English). Out of the remaining 352 studies, we found 181 suitable for retrieval (129 studies were unrelated, and no outcome data were extracted from the other 42 studies). However, upon further assessment, we determined 22 of these studies were not directly associated with mucormycosis, while 72 reported fewer than 5 cases. Additionally, 27 studies lacked sufficient data to estimate mortality, and 4 were based on autopsy findings. 10 reviews or conference summaries, along with another 10 animal-based studies, were also eliminated. We identified 2 studies with overlapping data. Ultimately, our meta-analysis incorporated 34 articles, comprising a total of 811 patients. Out of these patients, 485 succumbed to diseases. The clinical data from these selected studies can be found in the Supplementary Table S1. The median NOS score, available in Supplementary Table S2, was 6, with a range of 5 to 9.

Our extensive systematic review offers a contemporary exploration of mucormycosis cases in hematological patients, shedding light on the impacts of this rare infection. A notably high mortality rate of 61% was found, which exceeds the 41% noted by Jeong et al.’s study (18) that incorporated a variety of underlying diseases. While the pooled mortality rate was somewhat lower in high-income countries compared to middle-income countries, the difference wasn’t significant. Our findings did not suggest any significant improvement in mortality rates over time. Remarkably, outcomes were significantly better for those treated with a combination of medical and surgical therapies, compared to those receiving medical treatment alone (mortality rates: 0.49 vs. 0.67). As one might expect, disseminated mucormycosis carried a higher death risk compared to isolated mucormycosis. Survival rates appeared to be similar across genders, those with or without breakthrough infection, those administered with mucor-active or mucor-inactive drugs prior to infection, and in both multi-drug and single-drug groups.

In both Europe and the United States, hematological malignancies emerged as the most frequent predisposing condition for mucormycosis. Our findings reveal that the susceptibility to mucormycosis is heightened in patients diagnosed with AML, ALL, myelodysplastic syndrome, aplastic anemia, and lymphoma. Particularly during the neutropenic phase, these patients’ immune function can decrease, and the infection can diffuse, result in delaying chemotherapy schedules. Yet, when the primary disease enters remission, the potential for mucormycosis recovery or elimination could emerge. Consequently, the strategy for managing mucormycosis in hematological patients largely should be early diagnosis, combined surgical treatment with systemic antifungal treatment, and opting for a less intense chemotherapy regimen or one that causes mild myelosuppression could prove to be a beneficial course of action. Anti-mucor regimen was follow the guideline of the European Confederation of Medical Mycology and the Mycoses Study Group Education and Research Consortium (19).

Challenges in promptly diagnosing and initiating treatment, coupled with intricate underlying conditions such as immunosuppression, could be contributing factors to the high mortality observed in these patient groups (20). Multiple studies have attempted to examine the death rate. A pair of prospective investigations specific to mucormycosis documented mortality rates of 41 and 47% (21, 22) respectively. However, these rates differed according to the site of the infection: a soaring 96% in disseminated cases, 85% in gastrointestinal instances, and 76% in pulmonary infections (4). However, there is no study reported the pooled mortality in hematology patients. With the advent of the new kinds of triazole drugs, the survival was improved over time in Mushu’s research (about pulmonary mucormycosis), especially in high-income countries (23), which is consistent with our research. In high-income area, physicians might have more access to diagnosis mucor as a pathogen timely and new anti-mucor drugs were accessible, which may potentially contribute to relatively better outcomes. In relative low-income area, the rate of effective drug use was quite low since patients were not affordable for the high price in mucor-active drug. In the present research, our data did not indicate that the mortality significantly improved over the years. This result may cause by the proportion of ICU patients were high in the included research (24, 25), which indicated a worse outcome certainly. And it also had the other influent factors might affect this trend.

Echoing previous observations, significantly improved survival rates were noted when surgical intervention was paired with medical treatment, in comparison to relying on medical treatment alone. The optimal recovery pathway seems to be a blend of liposomal amphotericin B and surgical intervention (21). This survival advantage associated with a surgical-medical blend has been demonstrated in other studies as well (4, 20, 21, 26).

Although the benefits of debridement appear evident, the decision to proceed with surgery is often dependent on the patient’s performance status and the primary disease’s state of remission, which could introduce bias (26, 27). Understandably, patients in a generally weak condition tend to opt for conservative medical treatment. Otherwise, the infection site could also be a factor. For instance, the advantages of pulmonary resection in patients with multifocal or disseminated mucormycosis are uncertain (26). While surgical treatment can reduce patient mortality by 55%, certain restrictions apply for thrombocytopenic patients (28). Consequently, the European Confederation of Medical Mycology and the Mycoses Study Group Education and Research Consortium endorse early comprehensive surgical treatment for mucormycosis whenever feasible, along with systemic antifungal treatment (19).

Medical practitioners may overlook early, nonspecific clinical signs, which could lead to delayed diagnosis and ultimately, fatal disseminated infections (29). Both solid organ transplant recipients and patients with hematological malignancies face a heightened risk of disseminated mucormycosis (11). Widespread disease following angioinvasion is the most dreaded manifestation of mucormycosis due to its high mortality rate. Past studies have recorded mortality rates ranging from 63.9 to 96% for disseminated mucormycosis (4, 6, 11). In contrast, localized mucormycosis, with an outcome odds ratio (OR) of 0.06 and a 95% CI between 0.01 and 0.6 (p = 0.019) (30), is linked to more favorable patient outcomes. The restrictive antifungal effect may be attributable to multiple infection sites and the differential drug permeability across various affected locations.

It’s worth noting that we discovered no significant difference in mortality rates between groups receiving either multi-drug or single-drug treatment. A recent study corroborated our findings, showing no significant variance in 6-week mortality rates when comparing initial combination therapy to monotherapy for mucormycosis treatment in adults with hematologic malignancies (43% vs. 41%, p = 0.85) (30). An even more recent propensity score analysis involving 106 mucormycosis patients with hematological malignancies indicated no survival benefit for those starting on a combination antifungal regimen including i.v. liposomal-amphotericin B (AmB), posaconazole, and an echinocandin (OR = 0.8, 95%CI 0.3–2.4; p = 0.69) (30). Rajeev Soman and colleagues postulated that the outcomes of posaconazole or isavuconazole monotherapy were on par with amphotericin B treatment. Even in COVID-19-associated mycormycosis (31), the Vital trial further echoed this sentiment by stating that isavuconazole’s clinical efficacy and tolerability were comparable to AmB’s in mucormycosis cases (mortality 33.3% vs. 41.3%; p = 0.60). Mucormycosis treatment guidelines strongly support liposomal AmB 5–10 mg/kg per day as the first-line therapy, with isavuconazole and posaconzole carrying moderate and slight recommendations, respectively (10). Still, some prospective research involving small samples suggested that combination antifungal therapy (echinocandins + AmB) yielded promising results (32). We could not rule out the possibility that these combination therapies were implemented in more severe diseases with a worse prognosis. Future studies should investigate deeper into the antagonism or synergism between different anti-fungal drugs and whether AmB holds any incremental benefits over azoles at all.

Incidence rates for IFI could reach up to 5–8% following Hematopoietic Stem Cell Transplantation (HCT) (33). Such infections are particularly prevalent in patients under prophylactic, pre-emptive, and targeted antifungal therapy, especially those with immunodeficiency (34–36). An individual’s overall state of immunosuppression plays a vital role in determining their infection risk (33). Pedro Puerta-Alcalde found that invasive aspergillosis (45.5%) was the most common pathogen in breakthrough IFIs among hematological malignancy patients, followed by candidemia (19%) and mucormycosis (5.8%) (36). In this extensive, prospective, multi-center Spanish study on hematological malignancy patients with breakthrough IFI, the 100-day mortality rate was 47.1%, with breakthrough IFI was the contributing cause to death in 61.4% of these cases (36). Jin Yeong Hong et al. revealed that patients with myeloid malignancy receiving posaconazole tablet prophylaxis experienced a higher mortality rate (30.0%) in breakthrough IFI cases compared to non-IFI patients (1.9%; p < 0.001) (37). However, the high mortality rate associated with mucormycosis following voriconazole exposure mirrors that seen in patients without prior voriconazole use (38). Further examination of breakthrough IFIs and their outcomes is crucial.

Early diagnosis is crucial in preventing tissue invasion and dissemination, although it can be challenging due to the often-nonspecific symptoms that are typically associated with other infections. This complexity is further compounded by the limited awareness of pathogen identification among clinicians and the inadequate sophistication of reference laboratories and mycology technologists, which may contribute to the difficulty in timely diagnosis. However, despite these obstacles, histopathology, direct examination, and culture remain essential diagnostic tools. Furthermore, promising advancements have been made in the field of mucormycosis diagnosis. Methods focused on detecting Mucorales DNA in blood have shown potential, offering the possibility of quicker and earlier diagnosis (1, 39).

The case studies for this review were sourced from an exhaustive database search employing a systematic strategy, thereby enhancing the solidity of the evidence. There is an absence of publication bias, and the sensitivity remains steadfast. However, the study was not without shortcomings. The follow-up periods were not consistently documented across the selected cases. Similarly, the duration of antifungal treatment reported varied and relied largely on the treating physician’s discretion. It should be noted that all the incorporated studies were retrospective in nature, which typically indicates a relatively lower research quality. The data in some subgroups was sparse, preventing us from drawing reliable conclusions from the analysis.

This review offers the latest, most comprehensive snapshot of clinical presentations and mortality rates in mucor infected patients with hematological conditions. The collective mortality rate of hematological patients with mucormycosis stands at 61%. Notably, survival outcomes were better for patients receiving combined surgical and medical treatment and those with a singular infection site. Factors such as gender, breakthrough infections, pre-mucor infection use of mucor-active drugs, or multi-drug administration did not significantly impact the outcomes. The results of this meta-analysis underscore the need for future epidemiological studies on mucormycosis in hematological patients to better assess the role of various treatment regimens in reducing mortality risks.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

MS: Conceptualization, Data curation, Writing – original draft. JW: Data curation, Methodology, Writing – review & editing. ML: Formal analysis, Methodology, Writing – review & editing. ZW: Data curation, Writing – review & editing.