Keywords
pulmonary mucormycosis, pulmonary fungal infections, COVID-19 associated pulmonary mucormycosis, CAPM; management of pulmonary mucormycosis, management of pulmonary mucormycosis; mucormycosis, Mucorales.
-
Views
-
Downloads
How to cite this article
Fadelelmoula T, Ayyalil N and Doreswamy N. Management of Pulmonary Mucormycosis: A Systematic Review [version 2; peer review: 2 not approved]. F1000Research 2025, 13:1165 (https://doi.org/10.12688/f1000research.151564.2)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
Export Citation
Sciwheel
EndNote
Ref. Manager
Bibtex
ProCite
Sente
▬
✚
Systematic Review
Revised
Management of Pulmonary Mucormycosis: A Systematic Review
[version 2; peer review: 2 not approved]
PUBLISHED 28 Jul 2025
OPEN PEER REVIEW
REVIEWER STATUS
This article is included in the Global Public Health gateway.
This article is included in the Pathogens gateway.
Abstract
Corresponding author:
Tarig Fadelelmoula
Competing interests:
No competing interests were disclosed.
Grant information:
The author(s) declared that no grants were involved in supporting this work.
Copyright:
© 2025 Fadelelmoula T et al.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Fadelelmoula T, Ayyalil N and Doreswamy N. Management of Pulmonary Mucormycosis: A Systematic Review [version 2; peer review: 2 not approved]. F1000Research 2025, 13:1165 (https://doi.org/10.12688/f1000research.151564.2)
First published: 08 Oct 2024, 13:1165 (https://doi.org/10.12688/f1000research.151564.1)
Latest published: 28 Jul 2025, 13:1165 (https://doi.org/10.12688/f1000research.151564.2)
Revised Amendments from Version 1
Points from the first reviewer were carefully addressed regarding the confining the introduction to pulmonary Mucormycosis and balancing the management part with regards to cheating agents in the treatment of Mucormycosis.
To read any peer review reports and author responses for this article, follow the "read" links in the Open Peer Review table.
Introduction
Etiology
Humans usually contract mucormycosis by inhaling sporangiospores of Mucorales species leading to pulmonary mucormycosis (Ribes et al., 2000; Richardson, 2009). Mucorales species have significant angio-invasive characteristics, which results in rapid local progression and substantial morbidity (Lee et al., 1999; Moreira et al., 2016; Prakash et al., 2019).
Epidemiology
The most common clinical presentations of mucormycosis are rhino-orbito-cerebral (34%) and pulmonary (21%), the lungs being the second most common site of involvement in patients with mucormycosis (Jeong et al., 2019; Prakash et al., 2019). The incidence of mucormycosis is rising globally (Ambrosioni et al., 2010; Bitar et al., 2009; Pana et al., 2016; Torres-Narbona et al., 2007). Significant risk factors include uncontrolled diabetes mellitus in ketoacidosis, other forms of metabolic acidosis, treatment with glucocorticoids, organ or bone marrow transplantation, neutropenia, trauma and burns, malignant hematologic disorders, and deferoxamine therapy in patients receiving hemodialysis (Ibrahim et al., 2003; Spellberg et al., 2005; Sugar, 1990). For PM, haematological malignancy is the major risk factor (32–40%), followed by diabetes mellitus (32–56%), haematopoietic stem cell transplant (1–9.8%) and solid organ transplant (6.5–9%), and renal disease (13–18%) (Feng & Sun, 2018; Tedder et al., 1994). There are recent changes in the epidemiology of the disease, especially in Asia, where tuberculosis and chronic renal failure are emerging risks (Prakash & Chakrabarti, 2019).
Clinical presentation
Symptoms of PM include dyspnea, cough, chest pain, and fever is present in most reported cases (Tedder et al., 1994). Angioinvasion leads to the necrosis of the pulmonary parenchyma, which may lead to cavitation and hemoptysis. This can be fatal if a major blood vessel is involved (Harada et al., 1992; Watts, 1983). Although most patients with PM present with a fulminant and rapidly progressive disease, some patients only present with chronic symptoms (Agarwal et al., 2006).
Screening and diagnosis
Early diagnosis is a cornerstone of successful management (Fernandez et al., 2013). Clinical diagnostic methods have low sensitivity and specificity, which makes the diagnosis of PM challenging (Skiada et al., 2018). Therefore, diagnosis requires a high index of suspicion, recognition of host factors, and analysis of the clinical presentation. The prompt use of imaging, as well as histology, microbiology, and advanced molecular methods underpin successful diagnosis and management (Skiada et al., 2018).
Molecular diagnosis
In 2014, Gebremariam et al. investigated host immune responses to Mucorales. They discovered the genes for proteins that encode spore coatings – the CotH genes, which are only found in Mucorales (Gebremariam et al., 2014). A 2018 study by Baldin et al. showed that CotH could be used as a target for the early diagnosis of mucormycosis (Baldin et al., 2018). In this study, mice infected with Rhizopus delemar, Lichtheimia corymbifera, Cunninghamella bertholettiae, and Mucor circinelloides, were positive for CotH, detected through polymerase chain reaction (PCR), in 3/3, 1/3, 2/2, and 3/3 urine samples, respectively (Baldin et al., 2018).
Real-time qualitative polymerase chain reaction (qPCR) can now be used to detect Mucorales DNA in blood samples. qPCR is non-invasive and allows mucormycosis to be diagnosed up to eight days before mycological diagnosis (Bourcier et al., 2017; Millon et al., 2013, 2016; Springer et al., 2016). In 2022, Alinaghi et al. (2022) found that when mucormycosis occurred as a co-infection alongside COVID-19, the mortality rate was 33.6%. Furthermore, mucormycosis was diagnosed between 3 and 45 days after the diagnosis of COVID-19, and other co-infections such as aspregillosis occasionally occurred (Alinaghi et al., 2022).
Chest X-ray
Radiology may only show peribronchial ground-glass opacity in the early stages, but later, pulmonary nodules, isolated masses, lobar consolidation, or cavitation may be found (Kawakami et al., 2004; Lin et al., 2017; McAdams et al., 1997). Wedge-shaped pulmonary infarcts may also be found. These infarcts are usually seen when there is thrombosis of the pulmonary vessels, following fungal angioinvasion (Marchevsky et al., 1980).
Chest CT scan
High-resolution chest CT scans are the preferred method to detect the extent of PM. These scans may show evidence of a Mucorales infection earlier than a chest X-ray. If an expanding mass is found, or a consolidation across tissue planes, especially towards the great vessels of the mediastinum, it is highly suggestive of mucormycosis (Reimund & Ramos, 1994). Other suggestive findings include 10 or more nodules with pleural effusion (Skiada et al., 2018). When a reverse halo sign is found on CT, it is more suggestive of PM than IPA (Agrawal et al., 2020).
Bronchoscopy
The use of bronchoscopy in obtaining tissue biopsy for microscopic histological examination and culture seems to be safe in capitating lung lesions, despite its potential risk factors (e.g., pneumothorax) (Smith & Kauffman, 2012). Bronchoscopic guided Trans-Bronchial Lung Biopsy (TBLB) is the most common modality used to obtain lung tissue for diagnosis (Krishna et al., 2022). As far back as 1999, Lee, Mossad, and Adal undertook a 30-year review of patients with mucormycosis – of the 35 patients reviewed, bronchoscopy was required in more than 70% for a definitive diagnosis (Lee et al., 1999). Bronchoscopy remains a mainstay of diagnosis even today. In 2022, the Delphi panel recommended early bronchoscopy in all suspected cases of this life-threatening disease (Muthu et al., 2022).
Histology, Molecular Tests, and Biopsy
The diagnosis of mucormycosis is based on both histopathological findings of tissue invasion by hyphae and cultures isolating pathogens of the order Mucorales, most commonly Rhizopus, Mucor, and Rhizomucor species (Smith & Lee, 2022). Many molecular based tests can be used either for detection or identification of mucorales, these tests include polymerase chain reaction (PCR) (Hsiao et al., 2005), restriction fragment length polymorphism analyses (RFLP) (Kumar et al., 2022; Page et al., 2021), DNA sequencing of defined gene regions (Nyilasi et al., 2008; Springer et al., 2016), and melt curve analysis of PCR products (Kasai et al., 2008).
While transbronchial lung biopsy (TBLB) is the most common method of obtaining lung tissue for diagnosis, specimen tissue can also be obtained by video-assisted thoracoscopic surgery (VATS) and open lung biopsy in patients undergoing surgical treatment (Krishna et al., 2022). In patients with haematologic disease, it can be a challenge to perform a diagnostic biopsy early. In a study of 28 haematologic patients, Potenza et al. (2011) demonstrated that Mucorales-specific T cells were only detected in patients with proven invasive mucormycosis – these cells neither detected before the onset of infection nor after the infection was fully resolved. Therefore, when early diagnostic biopsy is a challenge, Mucorales-specific T cells can be an effective surrogate diagnostic marker.
Artificial intelligence (AI)
Syed-Abdul et al. (2022) showed that Artificial Intelligence-based models may be able to predict the risk of mucormycosis after COVID-19. AI models may be able to identify high-risk patients and flag predisposing factors such as obesity, anosmia, de novo diabetes, myalgia, and nasal discharge. Such models may enable protocols during and after COVID-19 that prevent co-infection with Mucorales (Agrawal et al., 2020).
Despite treatment with antifungal therapy and surgical debridement, the mortality rate is around 50% (Muthu, Singh, et al., 2021). The incidence of mucormycosis is rising globally (Ambrosioni et al., 2010; Bitar et al., 2009; Pana et al., 2016; Torres-Narbona et al., 2007). Although the mortality rate of this disease has improved over time, it is still high (Muthu, Agarwal, et al., 2021). Therefore, this systematic review aims to shed light on recent treatment protocols for PM.
This systematic review focuses on the pulmonary form of the disease, seeking to identify and map recent treatment protocols for PM. For PM, haematological malignancy is the major risk factor (32–40%), followed by diabetes mellitus (32–56%), haematopoietic stem cell transplant (1–9.8%) and solid organ transplant (6.5–9%), and renal disease (13–18%) (Feng & Sun, 2018; Tedder et al., 1994).
The clinical presentation, radiological presentation, and risk factors of PM are often very similar to acute Invasive Pulmonary Aspergillosis (IPA) (Agrawal et al., 2020).
One of the most remarkable signs of PM is tissue necrosis, which is often a result of vascular thrombosis. In immunocompromised hosts, the primary route of infection is the inhalation of sporangiospores, which leads to pulmonary infection (Roden et al., 2005). PM tends to occur in patients with high neutropenia (Roden et al., 2005). A definitive diagnosis of PM relies on histopathology of pulmonary tissue, culture of sputum secretions, bronchoalveolar lavage, fine needle aspiration, or a combination of these diagnostic methods (Mir et al., 2018).
The incidence of PM increased dramatically during the COVID-19 pandemic, with most cases seen in India. Uncontrolled diabetes and the use of glucocorticoids in India, and ICU stays elsewhere, are the main factors associated with this increase (Hoenigl et al., 2022). COVID-19-associated PM (CAPM) is difficult to diagnose because its clinical presentation is often the same as COVID-19 itself (Hoenigl et al., 2022). It is diagnosed at the same time as COVID-19 or within 3 months of virologically confirmed infection (Muthu et al., 2022). Any patient with COVID-19 who has haemoptysis, or expectorates brownish or black sputum, should be investigated for CAPM (Pruthi et al., 2022).
Before the advent of the antifungal amphotericin B deoxycholate (Am-B) in 1959, mucormycosis in all its forms carried a mortality of 84%, but the use of Am-B led to a dramatic improvement – by the 1990s, the mortality rate fell to 47% (Roden et al., 2005). A review conducted in 2021 shows how mortality from PM, specifically, has improved over time – before the year 2000, it was as high as 72.1%, dropping to 58.3% between 2000 and 2009, and decreasing even further, to 49.8%, between 2010 and 2020 (Muthu, Agarwal, et al., 2021).
While Am-B has been the mainstay of antifungal treatment for decades, its use has often been limited by a high degree of dose-dependent toxicity. It has now largely been replaced by liposomal amphotericin B, a lipid-based form of the drug, which has a significantly better toxicity profile. Other drugs, such as triazoles, have been found to be effective – posaconazole, introduced in 2006 (Brigmon et al., 2021), and isuvaconazole, approved for use in 2015 (Greenberg et al., 2006; van Burik et al., 2006) have not only been deployed as primary therapies, usually in combination with L-AmB, but also as stepdown, maintenance, and salvage therapies.
Adjunctive immune therapies have also looked promising in recent years – granulocyte transfusions, cytokines such as interferon-gamma (IFN-γ), and recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) (Spellberg & Ibrahim, 2010). Hyperbaric oxygen may also be a useful adjunct (John et al., 2021). In addition, there has been some debate about whether iron chelators and zinc have a role to play in the treatment of mucormycosis.
During the pandemic, there was a surge in mucormycosis in patients with COVID-19 and in those who recovered from COVID-19 (Ghazi et al., 2021). COVID-19-associated PM (CAPM) has been described in patients infected with SARS-CoV-2. Several factors have been implicated in the development of CAPM, including the use of glucocorticoids, poor glycaemic control, and viral-induced lymphopenia (Pal et al., 2021). Thromboembolic events are also seen in COVID-19, including pulmonary embolism, deep vein thrombosis (DVT), cerebrovascular accidents (CVA), and myocardial infarction (Abbas et al., 2021). The resultant hyper-coagulability and distal ischemia may well contribute to mucormycosis, although definitive proof for this remains elusive. The prime site of infection depends on the type of Mucorales and the comorbidity of the affected individual (Jeong et al., 2019; Lanternier et al., 2012; Skiada et al., 2011). Bone and joint infections, peritonitis, and nephritis are rare forms of mucormycosis (Serris et al., 2019). Endocarditis is also rare and is usually only seen in intravenous drug users (Serris et al., 2019).
Climate change
Climate change plays a role in the emergence of diseases (El-Sayed & Kamel, 2020). It may result in a surge in known fungal diseases and the emergence of new fungal diseases as well (Garcia-Solache & Casadevall, 2010). Climate change is defined by the United Nations Framework Convention on Climate Change (FCCC) as “a change of climate which is attributed directly or indirectly to human activity that alters the composition of the global atmosphere and which is in addition to natural climate variability observed over comparable time periods” (Pielke, 2004).
The geographic range of fungal pathogens is expanding because of the increase in temperature at higher latitudes (Gadre et al., 2022). Many fungal species are capable of developing thermotolerance and, as a result, fungi previously harmless to humans may become pathogenic (Gadre et al., 2022). Sivagnanam et al. (2017) reported patient clusters with sino-pulmonary mucormycosis associated with changes in climatic conditions, such as changes in precipitation and temperature. Extreme climate events may also exacerbate the incidence of fungal disease - for instance, there are reports of necrotizing fasciitis caused by mucormycosis after the Indian Ocean tsunami of 2004 (Andresen et al., 2005) and the Missouri tornado of 2011 (Neblett Fanfair et al., 2012).
The incidence of mucormycosis in India and Pakistan is a hundred times higher than the rest of the world combined (van Rhijn & Bromley, 2021). The higher incidence of co-morbidities such as diabetes mellitus accounts for some proportion of this significant difference in incidence (Ghazi et al., 2021). However, even before the advent of Covid-19, there was an increase in the number of cases of mucormycosis in these South Asian countries, and the higher incidence of diabetes mellitus alone does not account for the increase (van Rhijn & Bromley, 2021). Climate change in South Asia could be a contributing factor because fungi thrive at higher temperatures and in conditions of increasing humidity (Pörtner et al., 2022; Safdar et al., 2019; van Rhijn & Bromley, 2021).
Management
The effective management of depends on early suspicion or recognition of PM. Early diagnosis is critical to effective treatment. The essential components of the management of this disease include the reversal of underlying risk factors, such as correcting hyperglycemia or tapering glucocorticoids; early and aggressive surgical resection, if possible; and optimal anti-fungal therapy (Pandey et al., 2020; Patel et al., 2020). Amphotericin B is a reliable antifungal that is used for primary anti-fungal therapy, with L-AmB widely in use as a less toxic form of the drug. The triazoles posaconazole and isuvaconazole are also effective against mucormycosis, and are used as primary therapies and in stepdown, maintenance, and salvage therapies (Smith & Lee, 2022).
Surgical treatment
PM usually progresses rapidly. Surgery is often a necessity because of the massive amount of tissue necrosis that occurs during the disease. Treating the disease and killing these highly virulent fungi may not prevent or reverse the tissue necrosis (Ibrahim et al., 2005). While surgery and anti-fungal therapies are the primary modalities of treatment, clear-cut guidelines regarding the extent and timing of surgical resection are yet to be defined. However, a successful attempt at methodological management of PM was made by the authors in the previously reported surgical series (Pulle et al., 2021). Aggressive surgical resection with clear margins should be offered whenever feasible, as anti-fungal therapy alone may have sub-optimal outcomes. Surgical resection should be synergised with peri-operative anti-fungal therapy to improve long-term survival (Kumar et al., 2022).
Antifungal therapy
Amphotericin B (Am-B) has been in use from 1959, as a reliable antifungal that is effective in treating progressive and potentially fatal fungal infections (Cavassin et al., 2021). It is still an important option in the treatment of mucormycosis. However, Am-B has a high dose-dependent toxicity that can manifest as nephrotoxicity (Deray, 2002) or reactions to infusions (Cavassin et al., 2021). Am-B is only recommended now in settings where resources are limited, or it is the only treatment option available (Cornely et al., 2019).
There is sufficient evidence in the literature to merit the early initiation of the lipid-based amphotericin B formulation, liposomal amphotericin-B (L-AmB), instead of Am-B, as the first line of treatment, in doses of 5 to 10 mg per kilogram per day (Kontoyiannis & Lewis, 2006; Lewis & Wiederhold, 2003). Nephrotoxicity and infusion-related reactions are significantly less with L-AmB (Hamill, 2013). Its peak plasma level is much higher than Am-B and the area under the concentration-time curve is larger (Hamill, 2013). It is smaller in size and carries a negative charge, so it avoids substantial recognition and uptake by the mononuclear phagocyte system (Hamill, 2013).
Recently, posaconazole and isuvaconazole have been used as primary therapies, usually in conjunction with L-AmB. Intravenous isuvaconazole, intravenous posaconazole, or delayed release posaconazole tablets are also recommended as salvage treatments, in moderate doses (Cornely et al., 2019; Kohno et al., 2023). They are also used as stepdown or maintenance therapies, or as alternative therapies in patients who are unable to tolerate amphotericin B in any form (Smith & Lee, 2022). It is worth noting that fluconazole, voriconazole and itraconazole have no activity on Mucorales (Sun et al., 2002).
Iron chelating agents
Rhizoferrin is the most specific siderophore that Mucorales produce (Tahiri et al., 2023). A recent experimental study in a murine model showed that rhizoferrin may increase fungal virulence (Alejandre-Castañeda et al., 2022). Mucorales also produce permeases that have a high affinity for iron and make it available to the fungus (Stearman et al., 1996). Therefore, iron chelators may have a role to play in the management of mucormycosis (Boelaert et al., 1994; Symeonidis, 2009). Mucorales species have a very high affinity for iron. Therefore, iron chelators that do not capture and bind iron as efficiently as the pathogen, may “donate” iron to the fungus, thereby increasing a patient’s susceptibility to mucormycosis. Indeed, haemodialysis patients treated with the iron chelator deferoxamine (DFO) are more susceptible to mucormycosis (Mahalmani et al., 2021). However, there are new iron chelators, deferiprone and deferasirox, are even more efficient at binding iron than Mucorales fungi (Divakar Jose et al., 2021; Neufeld, 2006).
Deferiprone and deferasirox also have a stable chemical structure and low molecular mass – these properties render them impervious to fungal iron uptake systems (Boelaert et al., 1994; Symeonidis, 2009). There is anecdotal support as well – a case report in 2006 showed that salvage treatment with deferasirox had clear therapeutic benefits in rhino-cerebral mucormycosis (Reed et al., 2006). Further study is warranted to evaluate the role of iron chelators in the management of mucormycosis.
Cytokines, Granulocyte Transfusions and Hyperbaric Oxygen
Cytokines, granulocyte transfusions, and hyperbaric oxygen are promising new therapies. Cytokines such as IFN-γ, G-CSF, and GM-CSF enhance host immunity by activating granulocytes that damage fungal cells (Spellberg et al., 2009). IFN-gamma and GM-CSF are also known to enhance the activity of polymorphonuclear leukocytes to augment the damage to fungal hyphae (Gil-Lamaignere et al., 2005). In neutropenic hosts, granulocyte transfusions can help, as they can deliver polymorphonuclear leukocytes to the site of the infection (Spellberg et al., 2009). L-AmB acts synergistically with polymorphonuclear leukocytes to damage the hyphae of some Rhizopus species (Simitsopoulou et al., 2008).
Hyperbaric oxygen (HBO) enhances the oxidative action of amphotericin B by correcting lactic acidosis, at pressures over 10 atmospheres absolute (ATA) (Gebremariam et al., 2014; Siddiqui et al., 1997). HBO may enhance leukocyte-mediated phagocytoses and tissue repair (Chakrabarti & Singh, 2020). However, there is a paucity of data on the use of HBO in PM (Grigull et al., 2006; John et al., 2021; Spellberg et al., 2009). It has been used as adjunctive therapy for rhino-orbital-cerebral mucormycosis and soft tissue infections, but it is much less commonly used for PM and other manifestations of the disease (John et al., 2021). The recommended dose of hyperbaric oxygen therapy consists of two sessions of 90–120-min each, at 2–3 ATA, per day (Chakrabarti & Singh, 2020). HBO reportedly benefits patients with diabetes or in trauma, but is less effective in stem cell transplantation and in patients with haematological malignancies (Chakrabarti & Singh, 2020). Randomized controlled trials may prove the efficacy of HBO in mucormycosis (Brunet & Rammaert, 2020).
Methods
This systematic review identifies and maps recent treatment protocols for PM. It provides a clear, reproducible methodology (Sucharew & Macaluso, 2019) and is reported in accordance with the framework and recommendations by Peters et al. (2015). Although the mortality rate of this disease has improved over time, it is still high (Muthu, Agarwal, et al., 2021). The objective of this review is to systematically identify and map the management of pulmonary mucormycosis. Therefore, a systematic review is appropriate here.
Inclusion criteria
All articles relating to treatment protocols for PM were included. The concept is treatment protocols in the context of PM. The population of interest is the human population. The following inclusion criteria were applied:
Exclusion criteria
Articles that focus on limited treatment regimens or topics that are not relevant to the research question, were excluded. For example, articles focusing on the following topics were excluded:
Search strategy
Four electronic search systems were identified: Scopus, PubMed, ScienceDirect, and Web of Science. Scopus offers excellent coverage (Falagas et al., 2008; Kulkarni et al., 2009) and is the most effective search engine for the overview of a topic (Tober, 2011). ScienceDirect is also a highly effective, second only to Scopus as a search engine (Tober, 2011). PubMed, a subset of Scopus, is the optimal search system for biomedical topics - it is the most frequently updated and includes early releases of articles (Falagas et al., 2008; Kulkarni et al., 2009; Samadzadeh et al., 2013). PubMed was included for this reason, to ensure a more precise and in-depth search.
Science Direct is second only to PubMed in terms of precision, recall, and relevance of search results (Samadzadeh et al., 2013). Therefore, ScienceDirect was also selected as an appropriate search engine for this systematic review. Web of Science has a well-documented performance in tracking citation counts (Falagas et al., 2008; Kulkarni et al., 2009) and was therefore selected as a suitable search engine for this review. While Google Scholar is also effective in terms of recall and relevance, the search results it provides are inconsistent, and citation information is often inadequate or not updated (Falagas et al., 2008; Kulkarni et al., 2009). Therefore, Google Scholar was not selected for this systematic review.
For each of the four search systems selected, search strategy/search terms were defined ( Table 1). Within these search systems, all databases were included in the search. After the search results were assessed and articles relevant to the research question identified, citation tracking (snowball search) was also undertaken – a search of references within the relevant articles identified.
Data extraction
The second and third authors reviewed this. The extracted data was cross-checked by all authors to minimise personal bias (Page et al., 2021). Any disagreements on data extraction and the categorisation of articles were resolved through detailed discussions, leading to a consensus between the authors.
All three authors developed the concept and idea for this systematic review. The first author provided expert guidance on this review and verified the methods and results. The second and third authors conducted the search, identified, and removed duplicates from search results, and read the abstract and titles of the remaining articles, reading the full text of those articles where abstracts were unavailable. The second and third authors then applied the exclusion and inclusion criteria to the remaining articles, to ensure that only relevant articles were selected.
Results
The selected articles were reviewed in detail, with a focus on identifying and mapping treatment protocols for PM. The results span six years, from 2018 through 2023. Overall, 355 articles were identified in the four electronic search systems. 128 duplicates were removed. The titles and abstracts of the remaining 227 articles were screened and exclusion criteria applied. This process resulted in the exclusion of 202 articles. All the authors read the full text of the remaining 25 articles, applying the inclusion criteria. 19 articles were found to be relevant to the research question. Citation tracking was then undertaken – a snowball search of all references within these 19 articles. This process identified seven more relevant articles. Two more articles were identified by hand search. Thus, a total of 28 relevant articles were included.
Table 1 lists the search systems, databases and search terms used to identify relevant articles. Figure 1 (Fadelelmoula et al., 2024a) shows the PRISMA flow diagram of article screening and selection. Supplementary Table 1 (Fadelelmoula et al., 2024d) lists the key features of selected articles, listed by date of publication. Figure 2 (Fadelelmoula et al., 2024b) shows the treatment modalities for PM in diagrammatic form. Supplementary Table 2 (Fadelelmoula et al., 2024e) lists the co-morbidities mentioned in the articles selected and Figure 3 (Fadelelmoula et al., 2024c) illustrates these co-morbidities. Supplementary Table 3 (Fadelelmoula et al., 2024f) sets out the PRISMA checklist for this review.
Table 1. Search systems, databases and search terms used to identify relevant articles.
Search conducted on 1 December 2023.
Figure 1. Flow diagram based on the PRISMA-ScR.
Figure 2. Treatment modalities for PM.
Figure 3. Comorbidities and underlying conditions.
The key results relevant to the research question are presented below.
• Of the primary therapies recommended for PM, liposomal amphotericin B (L-AmB) was recommended in 21 articles, surgery in 20, amphotericin B in eight, posaconazole in 10, Isavuconazole in three, bronchoscopy or BAL in two, and antibiotics in one. Three articles mention echinocandins, but these antifungals had no therapeutic benefit in the treatment of PM.
• Stepdown, maintenance, or salvage therapy with posaconazole was mentioned in 10 articles, and isavuconazole in six articles.
• Combination therapy was recommended in eight articles, but the authors of three other articles did not find combination therapy helpful.
• Adjunctive therapies are recommended in four of the selected articles.
• Alternative therapies are mentioned in 12 articles – Am-B and Digital Subtraction Angiography in one article each, posaconazole and isavuconazole in four articles each, and iron chelators in five.
• Early diagnosis is underlined as the key to survival and low morbidity in 10 articles.
• Eight articles recommend the effective control of predisposing factors and co-morbidities.
• Multidisciplinary teams and a multimodal approach are recommended in four articles.
• Four articles mention the use of glucocorticoids such as dexamethasone in patients with COVID-19 but stress the need for caution.
• Two articles recommend checking for drug-drug interactions, particularly when triazoles are used for treatment.
• One article stated that combination therapy with L-AmB and NAB is not useful but recommends that nebulized amphotericin B (NAB) merits further investigation, as other doses and formulations may be of use.
• Two articles recommend against voriconazole.
• One article stated that zinc therapy may be protective, but another states that zinc does not have any therapeutic use in the treatment of this disease.
Discussion
The incidence of PM is rising globally, particularly since the advent of COVID-19. Climate change could also be a contributing factor, as fungi thrive at higher temperatures and in conditions of increasing humidity. Although survival and recovery from PM has improved over time, this disease still carries a high mortality – around 50%. Till the end of the twentieth century, the three mainstays of managing PM were surgery, where feasible; Am-B, the preferred first-line antifungal; and the control of underlying factors such as hyperglycaemia, ketoacidosis, and neutropenia. However, there seems to be a gradual but noticeable shift in the management of PM – not only because more efficacious antifungals are now available, but also because there is a more considered approach to diagnosis and therapy. An analysis of the articles included in this review point to four broad themes: early diagnosis; first-line or primary therapy; stepdown, maintenance, or salvage therapies; and adjunctive therapies.
Early diagnosis, early surgery, and a multidisciplinary approach: Early diagnosis may be the key to survival and low morbidity. However, as Wu states, early diagnosis may present a challenge – in many instances, patients with PM have nonspecific symptoms that may point to the possibility of COVID-19 or bacterial pneumonia, instead (Wu et al., 2023). Today, the emphasis is on a high index of suspicion, recognition of predisposing factors, and analysis of the clinical presentation. For instance, pleuritic pain in a patient with neutropenia should arouse the suspicion of PM. Urgent and early imaging, histology, microbiology, and advanced molecular methods can confirm the diagnosis early, and make all the difference to survival. In terms of the approach, multidisciplinary teams and a multimodal approach are important pieces of the puzzle that improve the chances of achieving early diagnosis and instituting effective therapy (Elgarten et al., 2018; Pruthi et al., 2022; Ramirez et al., 2018; Seifert et al., 2020).
Primary therapies: Surgery and L-AmB are the mainstays of primary therapy. Posaconazole also seems to be gaining traction as a first-line antifungal, either on its own or in combination with L-AmB. Posaconazole and isuvaconazole are the keys to successful stepdown, maintenance, or salvage therapy. While surgery remains a recommended first-line treatment, there seems to be a shift in thinking on whether, and when, surgery is required in PM. There is a growing recognition that early and aggressive surgical resection may significantly reduce mortality (Choi et al., 2019; Cornely et al., 2019; Dantis et al., 2021; Elgarten et al., 2018; Guo et al., 2019; Kanj et al., 2023; Liang et al., 2021; Mehta et al., 2022; Mills et al., 2018; Muthu et al., 2022; Muthu, Singh, et al., 2021; Pruthi et al., 2022; Pulle et al., 2021; Ramirez, 2018; Rana et al., 2021; Sipsas et al., 2018; Skiada et al., 2018; Yang et al., 2023). In addition, bronchoscopy and bronchoalveolar lavage (BAL) may be useful in removing retained secretions and necrotic tissue (Liang et al., 2021; Seifert et al., 2020).
Alongside early diagnosis, a multidisciplinary approach, and early and aggressive surgery, new antifungal drugs and formulations with a higher safety index are now preferred. The lipid-based L-AmB is the most widely used first-line antifungal, with the older and more toxic Am-B now reserved for use in settings where resources are limited. Posaconazole is being used in primary antifungal therapy as well, both in conjunction with L-AmB and as a monotherapy. Isuvaconazole is also being used as a primary therapy in clinical settings, but as it has only been available since 2015, it remains to be seen whether its clinical efficacy can be established more firmly, in time. Combination therapy with more than one antifungal was recommended by the authors of 11 articles (Choi et al., 2019; Cornely et al., 2019; Ding et al., 2020; Guo et al., 2019; Hanks et al., 2023; Hoenigl et al., 2022; Manjunath et al., 2018; Meena et al., 2023; Rana et al., 2021; Seifert et al., 2020; Yang et al., 2023). However, Kanj et al. (2023), Muthu et al. (2023) and Yuan et al. (2021), did not find combination therapy useful in the treatment of PM.
Stepdown, maintenance, salvage, and alternative therapies: For stepdown, maintenance, and salvage therapy, posaconazole is now the antifungal of choice (Elgarten et al., 2018; van Burik et al., 2006). However, based on a 2006 review of 91 patients treated with posaconazole as salvage therapy, Elgarten et al. (2018) concluded that while posaconazole can be effective, treatment failures are not unknown. Isuvaconazole can also be used for salvage. Posaconazole and isuvaconazole are also preferred alternative therapies for patients who cannot tolerate L-AmB.
Controlling co-morbidities and contributing factors: The control of co-morbidities continues to be a crucial aspect of effective treatment. Of the articles included, twenty-six mention co-morbidities – the details are listed in Supplementary Table 1 (Fadelelmoula et al., 2024d). Diabetes mellitus was the most common co-morbidity and is reported in fourteen articles, followed by COVID-19, which is stated in seven. Chronic kidney disease (CKD), hematological malignancies, immunosuppression, the use of glucocorticoids, hyperglycemia, and renal transplant are each mentioned in three or more articles. It is worth noting that in patients with COVID-19, glucocorticoids should be reserved for those with hypoxia, as these drugs can increase susceptibility to mucormycosis (Rana et al., 2021). Prolonged Intensive Care Unit (ICU) stays, ketoacidosis, chronic liver disease, a history of tuberculosis, pulmonary artery pseudoaneurysm (PAP), pulmonary compromise, high sequential organ failure assessment (SOFA) scores, and hypoproteinemia are some of the other contributing factors mentioned in the articles included in this review. Kontoyiannis and Lewis mention many of the same contributing factors in their recommendations for the treatment of mucormycosis, and state that the relative contribution of each of these factors is unknown (Kontoyiannis & Lewis, 2011).
Adjunctive therapies: Selected articles also mention promising new adjunctive therapies that may well improve the prognosis of this disease. Hanks et al. (2023) suggest that ECMO may be useful as an adjunctive therapy, while Yuan et al. (2021) state that mucolytic agents such as ambroxol may be helpful adjuncts. Sipsas et al. (2018) recommends monoclonal antibodies, GM-CSF, IFN-γ, and white blood cell transfusions. Skiada et al. (2018) suggest that hyperbaric oxygen, GM-CSF, IFN-γ, and ergosterol synthesis inhibitor (VT-1161) may be useful. Sipsas et al. (2018) also postulate that emerging therapies may offer promise in improving survival rates and decreasing the morbidity currently associated with PM – these authors state argue that targeted immunotherapy, reversal of tissue hypoxia, and host-specific immunological and metabolic profiling, all merit further study.
Potential therapies with insufficient or conflicting evidence: Five articles mention iron chelators, but there does not seem to be sufficient evidence or consensus, yet, of their efficacy in clinical practice. Meena et al. note that the DEFEAT Mucor study, a randomized trial, showed that combination therapy with the iron chelator, deferasirox, and L-AMB actually increased the 90-day mortality (Meena et al., 2023; Spellberg et al., 2012). However, Meena et al. (2023) still recommend that iron chelators merit consideration – larger studies may be required for definitive proof of therapeutic benefit or harm. In their view, diabetic patients with COVID-19 may benefit more from iron chelators than neutropenic patients with haematological malignancies. Skiada et al. (2018) note that the DEFEAT Mucor study had several limitations; they state that there are many case reports to show that deferasirox may be a useful adjunctive therapy in patients with diabetes. However, they state that its therapeutic role is yet to be established through prospective, randomized clinical trials (Skiada et al., 2018). Sipsas et al. (2018) state that the combination of deferasirox and L-AmB increases mortality in haematological malignancies, but may be beneficial in diabetic patients with mucormycosis, especially in ketoacidosis, where an acidic pH increases unbound tissue iron.
Muthu et al. (2023) state that adjunctive therapy with zinc supplements is helpful. However, Rana et al. (2021) state that zinc does not have any therapeutic use in this disease. Muthu et al. (2023) also found that NAB was not helpful as an adjunctive therapy, but postulate that a different dose or formulation may prove beneficial and warrants further investigation.
Therapies that are not recommended: Elgarten et al. (2018) and Manjunath et al. (2018) found no therapeutic benefit from echinocandins such as micafungin, used in combination with either L-AmB, or both L-AmB and posaconazole. Seifert et al. (2020) also used micafungin in combination with L-AmB to treat a patient with PM, but the patient did not survive. Yuan et al. (2021) does not recommend fluconazole or itraconazole because cultures from specimens obtained through bronchoscopy were not sensitive to these triazoles. There are clear recommendations against the use of voriconazole. Meena et al. (2023), Hanks et al. (2023), and Manjunath et al. (2018) state that PM does not respond to voriconazole. As early as 2007, a multicenter study (Trifilio et al., 2007) found that voriconazole-associated mucormycosis carried a 73% mortality rate. Pongas et al. (2009) state that the prophylactic use of voriconazole leads to selection pressure, which increases the risk of Mucorales infections and contributes to poorer outcomes. It is an open question as to whether there is a direct link between the hypervirulence of Mucorales and the use of voriconazole, or if is this a causal association (Meena et al., 2023).
Promising new therapies: Mucorales species are developing resistance to amphotericin B, posaconazole, and isavuconazole (Cornely et al., 2014; Dannaoui, 2017; Roden et al., 2005; Schwarz et al., 2019). There is an urgent need for new antifungal therapies that are effective and safe. There are innovative therapies emerging, currently, that hold great potential in the treatment of this disease. Among these novel therapies, the humanized clone VX01 may be the most promising. It is created by humanizing a mouse monoclonal antibody (C2 MAb). In the murine model, VX01 targets CotH3, a spore coat protein specific to Mucorales species. VX01 has an affinity for this protein and binds it, resulting in the loss of CotH3. Therefore, the fungus is rendered non-invasive, and its virulence is attenuated. Other promising therapies for PM include nanoemulsions such as NB-201, silver nanoparticles (AgNPs), and zirconium oxide nanoparticles (ZrO2NPs) (León-Buitimea et al., 2021). These nanomaterials are currently in the experimental, in vitro phase of development (George et al., 2011).
Transparency: The authors of this systematic review have endeavoured to use transparent and robust methods. The framework described by Peters et al. (2015) guided this review. The authors undertook an initial exploration to identify appropriate search systems, which had disciplines and subjects relevant to the research question. Four electronic search systems were thus identified, and the search strategy consisted of searching all available databases within each of these four systems, as well as citation tracking (snowball search) and a hand search.
Limitations: There are limitations to this review. It only includes peer-reviewed journal articles published between 2018 and 2023, in English. A search of other databases and systems may have provided additional results. But still relevant papers may have been missed because of these limitations.
Conclusion
The objective of this systematic review was to identify and map the management of pulmonary mucormycosis. Four broad themes were identified, that are not only critical to survival, but also to lowering the burden of morbidity associated with this disease. The four themes are: early diagnosis; first-line or primary therapy; stepdown, maintenance, or salvage therapies; and adjunctive therapies. Recommended approaches and modalities of treatment were identified and mapped within each of these themes.
The results indicate that early diagnosis, and early and aggressive surgery, may hold the key to effective management. The results also indicate that a multidisciplinary, multimodal approach may improve the chances of achieving an early diagnosis and a prompt decision to operate. In addition, the results show that there has been a shift away from the use of Am-B as an antifungal, except in resource-limited settings. There is a clear preference for L-AmB as a first-line antifungal, with posaconazole used either in combination with L-AmB or as a first-line monotherapy. Posaconazole and isavuconazole are the drugs of choice for stepdown, maintenance, and salvage therapy, and as alternatives for patients who are unable to tolerate L-AmB. The control of co-morbidities such as diabetes continues to be a crucial aspect of effective management.
The results highlight new adjunctive therapies that may well improve the chances of surviving this deadly disease – immunomodulators such as IFN-γ and GM-CSF, hyperbaric oxygen, and ergosterol synthesis inhibitor (VT-1161). The results also highlight potential therapies such as iron chelators, zinc, and NAB that do not, yet, have sufficient evidence for their use, or have conflicting evidence. The results indicate that there is considerable debate about the role of iron chelators such as deferasirox, but no broad consensus yet for their use in clinical settings. However, as many Mucorales species depend on iron for both growth and virulence, iron chelators seem to offer substantial promise as future therapies.
Author contributions
All three authors were responsible for developing the concept of this systematic review. The first author provided expert guidance, provided critical revisions of intellectual content, and verified methods and results. The second and third authors conducted the search, extracted the data, performed the analysis, and drafted the manuscript. All the authors read and approved the final version of the manuscript for publication.
Author note
This review has not been published and is not under consideration for publication elsewhere. Correspondence concerning this article should be addressed to Tarig Fadelelmoula, Head of the Department of Internal Medicine, College of Medicine and Health sciences, National University of Science and Technology, Sohar, Sultanate of Oman. Email: tarigeltoum@nu.edu.om
Download
Export To
metrics
| Views | Downloads | |
|---|---|---|
| F1000Research | - | - |
|
PubMed Central
Data from PMC are received and updated monthly.
|
- | - |
Citations
CITE
how to cite this article
Fadelelmoula T, Ayyalil N and Doreswamy N. Management of Pulmonary Mucormycosis: A Systematic Review [version 2; peer review: 2 not approved]. F1000Research 2025, 13:1165 (https://doi.org/10.12688/f1000research.151564.2)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
track
receive updates on this article
Track an article to receive email alerts on any updates to this article.
Open Peer Review
Current Reviewer Status:
Key to Reviewer Statuses
VIEW
HIDE
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations
A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 2
VERSION 2
PUBLISHED 28 Jul 2025
Revised
Views
1
How to cite this report:
Drogari-Apiranthitou M. Reviewer Report For: Management of Pulmonary Mucormycosis: A Systematic Review [version 2; peer review: 2 not approved]. F1000Research 2025, 13:1165 (https://doi.org/10.5256/f1000research.175240.r400950)
The direct URL for this report is:
https://f1000research.com/articles/13-1165/v2#referee-response-400950
https://f1000research.com/articles/13-1165/v2#referee-response-400950
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 19 Aug 2025
Maria Drogari-Apiranthitou,
Infectious Diseases Research Laboratory, 4th Department of Internal Medicine, Attikon General University, National and Kapodistrian University of Athens, Athens, Greece
Not Approved
VIEWS 1
I am afraid the issues I
... Continue reading
CITE
HOW TO CITE THIS REPORT
Drogari-Apiranthitou M. Reviewer Report For: Management of Pulmonary Mucormycosis: A Systematic Review [version 2; peer review: 2 not approved]. F1000Research 2025, 13:1165 (https://doi.org/10.5256/f1000research.175240.r400950)
The direct URL for this report is:
https://f1000research.com/articles/13-1165/v2#referee-response-400950
https://f1000research.com/articles/13-1165/v2#referee-response-400950
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Version 1
VERSION 1
PUBLISHED 08 Oct 2024
Views
6
How to cite this report:
Drogari-Apiranthitou M. Reviewer Report For: Management of Pulmonary Mucormycosis: A Systematic Review [version 2; peer review: 2 not approved]. F1000Research 2025, 13:1165 (https://doi.org/10.5256/f1000research.166217.r334217)
The direct URL for this report is:
https://f1000research.com/articles/13-1165/v1#referee-response-334217
https://f1000research.com/articles/13-1165/v1#referee-response-334217
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 28 Nov 2024
Maria Drogari-Apiranthitou,
Infectious Diseases Research Laboratory, 4th Department of Internal Medicine, Attikon General University, National and Kapodistrian University of Athens, Athens, Greece
Not Approved
VIEWS 6
In the submitted manuscript titled “Management of Pulmonary Mucormycosis: A Systematic Review,” the authors state their objective as identifying and mapping the management of PM through a systematic review approach. While the study tackles an important subject, it exhibits several
... Continue reading
CITE
HOW TO CITE THIS REPORT
Drogari-Apiranthitou M. Reviewer Report For: Management of Pulmonary Mucormycosis: A Systematic Review [version 2; peer review: 2 not approved]. F1000Research 2025, 13:1165 (https://doi.org/10.5256/f1000research.166217.r334217)
The direct URL for this report is:
https://f1000research.com/articles/13-1165/v1#referee-response-334217
https://f1000research.com/articles/13-1165/v1#referee-response-334217
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Views
11
How to cite this report:
Dannaoui E. Reviewer Report For: Management of Pulmonary Mucormycosis: A Systematic Review [version 2; peer review: 2 not approved]. F1000Research 2025, 13:1165 (https://doi.org/10.5256/f1000research.166217.r334224)
The direct URL for this report is:
https://f1000research.com/articles/13-1165/v1#referee-response-334224
https://f1000research.com/articles/13-1165/v1#referee-response-334224
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 19 Nov 2024
Not Approved
VIEWS 11
In this article, the authors present a systematic review of pulmonary mucormycosis. They start with an extended introduction that encompasses general information of all forms of mucormycosis. The methods section outlines the article selection process and specifies the main review
... Continue reading
CITE
HOW TO CITE THIS REPORT
Dannaoui E. Reviewer Report For: Management of Pulmonary Mucormycosis: A Systematic Review [version 2; peer review: 2 not approved]. F1000Research 2025, 13:1165 (https://doi.org/10.5256/f1000research.166217.r334224)
The direct URL for this report is:
https://f1000research.com/articles/13-1165/v1#referee-response-334224
https://f1000research.com/articles/13-1165/v1#referee-response-334224
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Comments on this article Comments (0)