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A peek behind the curtain in the diagnosis and management of COVID‑19‑Associated Mucormycosis (CAM)


Coronavirus disease 2019 (COVID-19)-associated mucormycosis (CAM) is responsible for a high mortality rate due to its unique and severe host-pathogen interactions. Critically ill or immunocompromised COVID-19 patients are more prone to suffer from aggressive mycoses. Probable victims include those with uncontrolled diabetes mellitus (DM), metabolic acidosis, prolonged neutropenia, increased ferritin levels, hypoxia, and prolonged hospitalization with/without mechanical ventilators and corticosteroids administration. The current review aims to outline the journey of patients with CAM as well as the advantages and disadvantages of the currently available diagnostic techniques. It also discussed the current status of treatment options and caveats in the management of mucormycosis. Multidisciplinary team, early diagnosis, controlling the predisposing condition(s), complete surgical debridement, effective antifungal therapies (e.g., amphotericin B, isavuconazole, and posaconazole), and implementing antifungal stewardship programs are imperative in CAM cases.

1 Introduction

Mucormycosis leads to poor survival rates regardless of the notable understanding of its pathophysiology, enhanced diagnostic tools, and different treatment options [1, 2]. Mucormycosis or the ‘black fungus’ infection (‘black fungus’ is a metaphoric, not scientifically accurate, nomenclature) is a member of the order Mucorales and is a very rare but serious angioinvasive disease, with 11 genera and approximately 27 species that can cause human infections [3]. Mucormycosis is a noncontagious disease (human-to-human transmission does not occur in normal conditions); humans mainly acquire the infection through inhalation of the sporangiospores, and occasionally through traumatic inoculation or ingestion of contaminated food. Rhizopus oryzae (R. oryzae) fungus accounts for nearly 60% of mucormycosis in humans around the world, being responsible for 90% of the rhino-orbital-cerebral mucormycosis (ROCM) type [4]. Lichtheimia, Apophysomyces, Cunninghamella, Rhizomucor, and Mucor species are less common types [5]. Mucorales along with other moulds invade airways, disrupt mucosal and skin barriers and natural host defenses, and have common histopathological and clinical features [6, 7]. For instance, R. oryzae, Lichtheimia, Rhizomucor, and Mortierella spp. can infect patients with diabetic ketoacidosis (DKA) or other types of acidosis. With their distinctive host-pathogen interactions, Mucorales evade the host immune system and facilitate disease progression regardless of treatment, increasing the mortality rate [8].

According to the World Health Organization (WHO) statistics, mucormycosis occurs with a global incidence rate of 0.005-1.7 per million population with a case fatality rate of 46%. In India and China, the incidence of mucormycosis predominantly increases among patients with uncontrolled diabetes mellitus (DM) [9,10,11,12]. In India only, the prevalence of mucormycosis is roughly 80 times (about 0.14 cases/1000 population) higher than that in developed countries, because India ranks second with more than 77 million people with DM, which might be the most important factor (followed by the inadequate infection prevention and control measures in hospitals) for the high prevalence of cases there [12,13,14]. Critically ill or immunocompromised coronavirus disease 2019 (COVID-19) patients are more liable to suffer from aggressive mycoses [15]. Examples for coexisting conditions that aggravate the aggressiveness of mycoses are the uncontrolled DM, metabolic acidosis and DKA, prolonged neutropenia, increased ferritin levels, hypoxia, prolonged hospitalization with/without mechanical ventilators, trauma, use of corticosteroids, hemopoietic malignancy, immunosuppression associated with a reduced phagocytic activity of white blood cells (WBCs), solid organ transplantation, and allogeneic hematopoietic stem cell transplantation [16,17,18].

Recent global medical reports have documented that the rate of mucormycosis increases in COVID-19 patients and the cases are suffering from significantly poor prognoses [18]. In a recent systematic review, 93% of 41 COVID-19 patients with confirmed mucormycosis were diabetic, while 88% received corticosteroids [19]. Similarly, Singh et al. have confirmed the diagnosis of mucormycosis in 95% of COVID-19 patients, whereas 80% had DM, and about 76% received corticosteroids [18, 19]. Forty-six percent of confirmed mucormycosis cases already received corticosteroids within one month prior to diagnosis [13]. Prakash et al. also reported that 57% of patients had uncontrolled DM while 18% had DKA in the 2019 nationwide multicenter study of 388 suspected or confirmed cases of mucormycosis in India before COVID-19 [9]. Moreover, Ahmadikia et al. highlighted that COVID-19-associated mucormycosis (CAM) is more serious than influenza-associated mucormycosis, irrespective of an intense therapeutic approach [20]. Retrospective analysis of severe acute respiratory syndrome (SARS), global data, and other reports from China concerning influenza revealed that COVID-19-related fungal coinfections may be under/misdiagnosed [15]. The present review article highlights the main diagnostic criteria and the proper therapeutic options in COVID-19 patients who are confirmed with mucormycosis. Figure 1 outlines the COVID-19 patient's journey with mucormycosis, including patient's criteria, diagnostic tools, and management.

Fig. 1
figure 1

A schematic chart summarizing the complete pathogenic, diagnostic, and therapeutic journey of CAM patients

2 Current Challenges in Diagnosis of Mucormycosis

The nonspecific and confusing clinical presentation of mucormycosis remains burdensome, making its diagnosis and treatment more difficult [21]. Mucormycosis can virtually affect any organ (e.g., central nervous system [CNS] in general, brain, nose, sinuses, jaw bones, skin, joints, heart, kidneys, lungs, gastrointestinal tract, and invasive mediastinum) [22, 23]. Just prior to the emergence of COVID-19 pandemic, the recent global guidelines for the diagnosis and management of mucormycosis in 2019 highlighted that diagnosis of mucormycosis is usually delayed with the rapid disease progression [16, 24]. This delayed diagnosis worsens in CAM cases due to many reasons, such as the difficulty in taking invasive tissue biopsies and the unease of aerosol-generating procedures in oral and maxillofacial surgery in COVID-19. Moreover, the laboratory diagnosis of mucormycosis is difficult since blood cultures are negative and their assessment is often feasible only after a relatively long period of time [25]. Unfortunately, although blood culture, histopathology, and direct examination are essential to diagnose mucormycosis, they are insensitive and time-consuming [26]. These low-sensitivity and slow procedures are certainly more apparent in COVID-19 cases.

Rapid diagnosis is usually deterred due to the relative lack of specific agents that detect mucormycosis in the cerebrospinal fluid [27]. In addition, early and rapid diagnosis of mucormycosis is relatively unusual from the historic point of view and according to the literature, since about half of the cases with mucormycosis were diagnosed only in the postmortem autopsy examination (i.e., after death) [28]. Namely, a 12-hour delay in the diagnosis of mucormycosis could be deadly. Hence, a timely diagnosis upon suspicion of mucormycosis, a proper referral to a top-level health care facility, and initiation of prompt antifungal treatment (specially, antimucormycosis therapies) would prevent tissue invasion and its damaging sequelae in COVID-19 patients [27]. Subsequently, this would minimize the impact of corrective surgery and improve survival and outcome [10, 29].

2.1 The Clinical Criteria of Mucormycosis in COVID-19 Patients

Patients with COVID-19 exhibit ROCM as the most common clinical presentation seen worldwide in clinical microbiology [20, 23]. Thrombosis, eosinophilic necrosis of the underlying tissue, and giant cell invasion are hallmarks of mucormycosis, but diagnosis based on inconsistent symptoms/signs and clinical presentation is insensitive and nonspecific [15, 18, 30, 31]. Smith and Krichner established the gold standard criteria for the clinical diagnosis of mucormycosis in a report of three cases in 1958 (Table 1) [21]. Song et al. suggested to assess the risk factors, clinical settings, forms of invasive mycosis, advantages and limitations of diagnostic techniques, and demand for individualized or standard treatment options in patients with COVID-19 [15].

Table 1 The pathognomonic criteria for the clinical diagnosis of mucormycosis established by Smith and Krichner (Smith-Krichner's mucormycosis pathognomonic criteria) [21]

Depending on the involved organ, ROCM ranges from a limited invasion to sinonasal tissue and rhino-orbital disease to a diffuse rhino-orbital-cerebral (ROC) disease that involves CNS [31]. For instance, patients with uncontrolled DM and DKA frequently present with ROCM, whereas those with neutropenia, organ and bone marrow transplant, and hematological malignancies usually exhibit pulmonary involvement. Diagnosis of mucormycosis relies on different integrative factors, such as the availability of imaging techniques (e.g., magnetic resonance imaging and computed tomography), comprehensive mycological and histological assessments, and qualified personnel [16]. Several studies suggested that real-time polymerase chain reaction (RT-PCR), radiological imaging, and culture used for invasive aspergillosis (IA) are also applicable if mucormycosis is suspected [32,33,34,35,36,37].

2.2 Diagnostic Techniques in Mucormycosis: Strengths and Limitations

The United States Food and Drug Administration (FDA) has not yet approved serological assays that identify Mucorales compared to Aspergillus galactomannan index and β1,3-D-glucan (BDG) assays that can diagnose IA and other hyalohyphomycetes [35, 38]. Direct microscopy and/or fluorescent brighteners from clinical specimens (e.g., skin lesions, sputum, and bronchoalveolar lavage fluid [BALF]) usually suspect mucormycosis [26]. Microbiological identification (e.g., irregular and ribbon-like, 6–25 μm, nonseptate/pauci-septate, and branching pattern) of the Mucor hyphae distinguishes it from other fungi (i.e., invasive cryptococcosis, aspergillosis, and candidiasis) [15, 18, 31, 39]. Importantly, the ribbon-like and broader identity of the Mucorales hyphae are more authentic than its branching angle and septations [39]. However, data remain scarce to confirm the accuracy of using these criteria to distinguish Mucorales from other moulds. Furthermore, molecular/in-situ identification methods or culture of specimens are highly advocated to diagnose tissue mucormycosis [16].

Stains of fixed sections showing invasive nonpigmented hyphae, such as periodic acid-Schiff, hematoxylin-eosin, and Grocott-Gomori’s methenamine-silver stain, are confirmatory of mucormycosis [39]. Moreover, separate culture of specimens at 30 °C and 37 °C is highly recommended to identify genus and species, showing cottony white or greyish-black colony. Then, the morphological identification of fungi or DNA sequencing could be performed [35]. Nevertheless, Gomez et al. suggested that PCR should be restricted to tissues showing Mucorales hyphae upon staining to avoid the false positive results [40].

2.2.1 Lateral Flow Immunoassay (LFIA)

Lateral flow immunoassay (LFIA) is an essential serological assay for large-scale screening of immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), being used for national and regional seroprevalence surveys in Europe and the USA [41, 42]. LFIA is a rapid, specific, accurate, cheap, and an easy-to-use test that early detects cell wall fucomannan of Mucorales in clinical samples, such as serum, urine, BALF, and tissue [43]. Furthermore, LFIA can be either performed by qualified health care professionals or self-administered. Despite some reports of high sensitivity and specificity, use of LFIA is relatively limited to date due to its variable degree of sensitivity (the high degree of sensitivity is broadly changeable and is not always constant to a certain reliable value among all cases) [44,45,46,47,48,49].

2.2.2 PCR of Fresh Tissues

The PCR of fresh tissues is highly sensitive and specific with PCR-restriction fragment length polymorphism that confirms the diagnosis to the genus or species level. The European Confederation of Medical Mycology (ECMM) states that the fresh tissue is more advantageous than those embedded in paraffin because formalin damages DNA [16]. However, lack of matching controls and DNA extraction and contamination of the specimen might lead to false negative results, whereas false positive results may arise due to fungal contamination of the PCR master mixture [4, 50,51,52]. Besides, obtaining a tissue biopsy might not be always feasible in vulnerable patients [35].

2.2.3 RT-PCR of Blood/Serum

The PCR of blood/serum samples can early identify circulating fungal DNA, help follow up and assess treatment response, and indicate angioinvasive disease. However, low quantities of fungal DNA, heterogeneity of internal transcribed spacer regions, and lack of both comprehensive database and species-specific probes provide false negative result. False positive results occurring due to amplification of DNA contaminating the sample are less likely compared to other samples [53,54,55,56,57,58,59].

3 The Treatment of Mucormycosis: What We Already Know

Although investigators have evaluated numerous therapeutic regimens, mainly systemic glucocorticoids are proven to improve survival in hypoxemic COVID-19 patients [60]. Recognizing disease patterns upon early detection, rapid control or the possible discontinuation of predisposing factors (e.g., hyperglycemia), the fast surgical debridement of infected tissues, the early administration of the optimal dose of active antifungal agents (i.e., liposomal amphotericin B), and using adjuvant therapies are mainstay in the effective management of mucormycosis [16, 37, 61]. Management of mucormycosis during COVID-19 has encountered several hurdles, including multiorgan failure, the difficulty of controlling the hyperglycemia, lack of manpower in operating rooms, and the shortage in departmental resources. Moreover, angioinvasion with hematogenous dissemination, vessel thrombosis, and necrotic tissues impede the needed penetrability of immune cells and antifungal drugs [8, 16, 62,63,64]. Evaluation of antifungal response relies on clinical course, imaging, the patient's immune status, and kinetics of biomarkers (e.g., cytokines) [16, 65]. It is worth mentioning that severe COVID-19 patients often develop acute respiratory distress syndrome (ARDS), with significant elevations of C-reactive protein (CRP) and diverse inflammatory/immune cytokines like interleukins (ILs) 5, 6, 8, 10, 13, 17, and 22, as a result of hyperactivation of the innate and adaptive immune responses (cytokine release storm) [66]. Thus, regaining immune system balance and repressing markedly elevated inflammatory cytokines are very necessary for effectively treating severe COVID-19 patients and the accompanying mucormycosis infection.

Upon suspicion of mucormycosis, the ECMM and Mycoses Study Group Education and Research Consortium (MSG-ERC) in 2019 strongly recommended an appropriate imaging, followed by an immediate complete surgical intervention whenever possible, and systemic antifungal drugs. Surgical debridement for both necrotic tissue and neighboring healthy-looking infected tissues should be aggressive when needed. Surgery is helpful in soft tissue and ROC infections, and it may be valuable in a single localized pulmonary lesion. Table 2 outlines the latest ECMM/MSG-ERC treatment recommendations. Data are still somewhat insufficient to support the use of antifungal combination therapy (i.e., polyenes/azoles or polyenes/echinocandins) [16, 48, 67, 68]. Treating physicians should quickly taper CAM predisposing/aggravating drugs (e.g., corticosteroids and immunosuppressive drugs) to the lowest possible dose. Combined with antifungal therapy, hyperbaric oxygen as an adjunctive therapy provides an oxygen-rich cellular environment with cytokines. For instance, interferon-γ and/or granulocyte-macrophage colony-stimulating factor might improve the immune system against certain Mucorales in vitro [69, 70].

Table 2 The updated ECMM/MSG-ERC treatment guidelines for mucormycosis [16]

Among other antifungal therapies, amphotericin B possesses the highest activity except for some Cunninghamella and Apophysomyces isolates. A minimum inhibitory concentration (MIC) of ≤0.5 μg/mL amphotericin B significantly resulted in better outcomes over six weeks in humans [71]. Moreover, in patients with probable or confirmed mucormycosis, a combination of surgery with liposomal amphotericin B (10 mg/kg/day) for the first month of treatment, resulted in overall response rates of 36% and 45% at week 4 and week 12, respectively [67]. Similarly, isavuconazole and posaconazole are active, while some strains show a certain degree of susceptibility to terbinafine and itraconazole [72,73,74,75,76]. For instance, posaconazole had higher efficacy against strains of R. oryzae in infected mice [77]. Oral formulations of isavuconazole and posaconazole are favored because they can be administered for a long period (e.g., several months), if required. Based on the findings of some recent studies that proved the roles and effects of prior excessive zinc intake (even from multivitamins taken during COVID-19 treatment) and higher blood glucose level in the severity of CAM cases [18, 78], a new additive therapeutic hypothesis for CAM can be established in the current work. This hypothesis states that zinc ion-sequestering agents and blood glucose-lowering agents (e.g., most antidiabetic medicines) may have indirect positive roles in managing and accelerating the cure and recovery, along with reducing the mortality rates, of CAM. In Table 3, we have enumerated some of the obstacles that might face management of mucormycosis in COVID-19 patients.

Table 3 Caveats in the management of mucormycosis (including CAM)

4 Conclusion and Take-home Messages

Multidisciplinary team preparedness, early diagnosis, controlling the predisposing condition(s), applying complete surgical debridement, using systemic and local antifungal therapies, and implementing antifungal stewardship programs are imperative for CAM patients. Further research is mandatory to explore other noxious prognostic factors in COVID-19 associated mucormycosis and methods to reduce their influence on morbidity and mortality along with finding more effective medications.

Availability of data and materials

Not applicable.



Bronchoalveolar lavage fluid




COVID-19-associated mucormycosis


Central nervous system


Coronavirus disease 2019


Diabetic ketoacidosis


Diabetes mellitus


European Confederation of Medical Mycology


Graft-versus-host disease


Invasive aspergillosis


Lateral flow immunoassay


Minimum inhibitory concentration


Mycoses Study Group Education and Research Consortium


Corrected QT




Rhino-orbital-cerebral mucormycosis


Real-time polymerase chain reaction


Severe acute respiratory syndrome


Severe acute respiratory syndrome coronavirus 2


White blood cells


  1. Petrikkos G, Tsioutis C. Recent advances in the pathogenesis of mucormycoses. Clin Ther. 2018;40(6):894–902.

    Article  CAS  PubMed  Google Scholar 

  2. Zaman K, Rudramurthy SM, Das A, Panda N, Honnavar P, Kaur H, et al. Molecular diagnosis of rhino-orbito-cerebral mucormycosis from fresh tissue samples. J Med Microbiol. 2017;66(8):1124–9.

    Article  CAS  PubMed  Google Scholar 

  3. Richardson M. The ecology of the Zygomycetes and its impact on environmental exposure. Clin Microbiol Infect. 2009;15(Suppl. 5):2–9.

    Article  PubMed  Google Scholar 

  4. Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. Clin Microbiol Rev. 2000;13(2):236–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41(5):634–53.

    Article  PubMed  Google Scholar 

  6. Roilides E, Antachopoulos C, Simitsopoulou M. Pathogenesis and host defence against Mucorales: the role of cytokines and interaction with antifungal drugs. Mycoses. 2014;57(s3):40–7.

    Article  CAS  PubMed  Google Scholar 

  7. Netea MG, Van der Meer JWM, Kullberg B-J. Role of the dual interaction of fungal pathogens with pattern recognition receptors in the activation and modulation of host defence. Clin Microbiol Infect. 2006;12(5):404–9.

    Article  CAS  PubMed  Google Scholar 

  8. Gebremariam T, Liu M, Luo G, Bruno V, Phan QT, Waring AJ, et al. CotH3 mediates fungal invasion of host cells during mucormycosis. J Clin Invest. 2014;124(1):237–50.

    Article  CAS  PubMed  Google Scholar 

  9. Prakash H, Ghosh AK, Rudramurthy SM, Singh P, Xess I, Savio J, et al. A prospective multicenter study on mucormycosis in India: Epidemiology, diagnosis, and treatment. Med Mycol. 2019;57(4):395–402.

    Article  PubMed  Google Scholar 

  10. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B–based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis. 2008;47(4):503–9.

    Article  PubMed  Google Scholar 

  11. Jeong W, Keighley C, Wolfe R, Lee WL, Slavin MA, Kong DCM, et al. The epidemiology and clinical manifestations of mucormycosis: a systematic review and meta-analysis of case reports. Clin Microbiol Infect. 2019;25(1):26–34.

    Article  CAS  PubMed  Google Scholar 

  12. Prakash H, Chakrabarti A. Epidemiology of Mucormycosis in India. Microorganisms. 2021;9(3):523.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Prattes J, Wauters J, Giacobbe D, Lagrou K, Hoenigl M, Koehler P, et al. Diagnosis and treatment of COVID-19 associated pulmonary apergillosis in critically ill patients: results from a European confederation of medical mycology registry. Intensive Care Med. 2021;47(10):1158–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. IDF Diabetes Atlas. Demographic and geographic outline. Available from:

  15. Song G, Liang G, Liu W. Fungal co-infections associated with global COVID-19 pandemic: a clinical and diagnostic perspective from China. Mycopathologia. 2020;185(4):599–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cornely OA, Alastruey-Izquierdo A, Arenz D, Chen SCA, Dannaoui E, Hochhegger B, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019;19(12):e405–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Spallone A, Moran C, Wurster S, Axell-House D, Kontoyiannis D. Taking a closer look: clinical and histopathological characteristics of culture-positive versus culture-negative pulmonary mucormycosis. J Fungi. 2022;8(4):380.

    Article  Google Scholar 

  18. Singh AK, Singh R, Joshi SR, Misra A. Mucormycosis in COVID-19: a systematic review of cases reported worldwide and in India. Diabetes Metab Syndr. 2021;15(4):102146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. John TM, Jacob CN, Kontoyiannis DP. When uncontrolled diabetes mellitus and severe COVID-19 converge: the perfect storm for mucormycosis. J Fungi. 2021;7(4):298.

    Article  CAS  Google Scholar 

  20. Ahmadikia K, Hashemi SJ, Khodavaisy S, Getso MI, Alijani N, Badali H, et al. The double-edged sword of systemic corticosteroid therapy in viral pneumonia: a case report and comparative review of influenza-associated mucormycosis versus COVID-19 associated mucormycosis. Mycoses. 2021;64(8):798–808.

  21. Smith HW, Kirchner JA. Cerebral mucormycosis: a report of three cases. AMA Arch Otolaryngol. 1958;68(6):715–26.

    Article  CAS  PubMed  Google Scholar 

  22. Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh TJ, Kontoyiannis DP. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis. 2012;54(Suppl. 1):S23–34.

    Article  PubMed  Google Scholar 

  23. Sugar AM. Mucormycosis. Clin Infect Dis. 1992;14(Suppl. 1):S126–9.

    PubMed  Google Scholar 

  24. Klimko NN, Khostelidi SN, Volkova AG, Popova MO, Bogomolova TS, Zuborovskaya LS, et al. Mucormycosis in haematological patients: case report and results of prospective study in Saint Petersburg, Russia. Mycoses. 2014;57(s3):91–6.

    Article  PubMed  Google Scholar 

  25. Vehreschild JJ, Koehler P, Lamoth F, Prattes J, Rieger C, Rijnders BJA, et al. Future challenges and chances in the diagnosis and management of invasive mould infections in cancer patients. Med Mycol. 2021;59(1):93–101.

    Article  CAS  PubMed  Google Scholar 

  26. Skiada A, Lass-Floerl C, Klimko N, Ibrahim A, Roilides E, Petrikkos G. Challenges in the diagnosis and treatment of mucormycosis. Med Mycol. 2018;56(Suppl. 1):S93–101.

    Article  CAS  PubMed Central  Google Scholar 

  27. Rana N. COVID-19 Associated rhino-orbital-cerebral mucormycosis - an institutional series. J Clin Otorhinolaryngol. 2022;4(1):1–9.

    Article  Google Scholar 

  28. Sanguinetti M, Posteraro B, Beigelman-Aubry C, Lamoth F, Dunet V, Slavin M, et al. Diagnosis and treatment of invasive fungal infections: looking ahead. J Antimicrob Chemother. 2019;74(Suppl. 2):ii27–37.

    Article  CAS  PubMed  Google Scholar 

  29. Walsh TJ, Gamaletsou MN, McGinnis MR, Hayden RT, Kontoyiannis DP. Early clinical and laboratory diagnosis of invasive pulmonary, extrapulmonary, and disseminated mucormycosis (Zygomycosis). Clin Infect Dis. 2012;54(Suppl. 1):S55–60.

    Article  PubMed  Google Scholar 

  30. Aggarwal D, Chander J, Janmeja AK, Katyal R. Pulmonary tuberculosis and mucormycosis co-infection in a diabetic patient. Lung India. 2015;32(1):53–5.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Peterson KL, Wang M, Canalis RF, Abemayor E. Rhinocerebral mucormycosis: evolution of the disease and treatment options. Laryngoscope. 1997;107(7):855–62.

    Article  CAS  PubMed  Google Scholar 

  32. Legouge C, Caillot D, Chrétien M-L, Lafon I, Ferrant E, Audia S, et al. The reversed halo sign: pathognomonic pattern of pulmonary mucormycosis in leukemic patients with neutropenia? Clin Infect Dis. 2014;58(5):672–8.

    Article  CAS  PubMed  Google Scholar 

  33. Patterson TF, Thompson GR III, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1–60.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Millon L, Herbrecht R, Grenouillet F, Morio F, Alanio A, Letscher-Bru V, et al. Early diagnosis and monitoring of mucormycosis by detection of circulating DNA in serum: retrospective analysis of 44 cases collected through the French Surveillance Network of Invasive Fungal Infections (RESSIF). Clin Microbiol Infect. 2016;22(9):810.e1–8.

    Article  CAS  Google Scholar 

  35. Dadwal SS, Kontoyiannis DP. Recent advances in the molecular diagnosis of mucormycosis. Expert Rev Mol Diagn. 2018;18(10):845–54.

    Article  CAS  PubMed  Google Scholar 

  36. Ullmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll AH, Lagrou K, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018;24(Suppl. 1):e1–38.

    Article  PubMed  Google Scholar 

  37. Tissot F, Agrawal S, Pagano L, Petrikkos G, Groll AH, Skiada A, et al. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2017;102(3):433–44.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Angebault C, Lanternier F, Dalle F, Schrimpf C, Roupie A-L, Dupuis A, et al. Prospective evaluation of serum β-glucan testing in patients with probable or proven fungal diseases. Open Forum Infect Dis. 2016;3(3):ofw128.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Guarner J, Brandt ME. Histopathologic diagnosis of fungal infections in the 21st century. Clin Microbiol Rev. 2011;24(2):247–80.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Gomez CA, Budvytiene I, Zemek AJ, Banaei N. Performance of targeted fungal sequencing for culture-independent diagnosis of invasive fungal disease. Clin Infect Dis. 2017;65(12):2035–41.

    Article  CAS  PubMed  Google Scholar 

  41. Pollán M, Pérez-Gómez B, Pastor-Barriuso R, Oteo J, Hernán MA, Pérez-Olmeda M, et al. Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. Lancet. 2020;396(10250):535–44.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Bendavid E, Mulaney B, Sood N, Shah S, Bromley-Dulfano R, Lai C, et al. COVID-19 antibody seroprevalence in Santa Clara County, California. Int J Epidemiol. 2021;50(2):410–9.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Burnham-Marusich AR, Hubbard B, Kvam AJ, Gates-Hollingsworth M, Green HR, Soukup E, et al. Conservation of mannan synthesis in fungi of the zygomycota and ascomycota reveals a broad diagnostic target. mSphere. 2018;3(3):e00094-18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pallett SJC, Rayment M, Patel A, Fitzgerald-Smith SAM, Denny SJ, Charani E, et al. Point-of-care serological assays for delayed SARS-CoV-2 case identification among health-care workers in the UK: a prospective multicentre cohort study. Lancet Respir Med. 2020;8(9):885–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Asselah T, Lee SS, Yao BB, Nguyen T, Wong F, Mahomed A, et al. Efficacy and safety of glecaprevir/pibrentasvir in patients with chronic hepatitis C virus genotype 5 or 6 infection (ENDURANCE-5,6): an open-label, multicentre, phase 3b trial. Lancet Gastroenterol Hepatol. 2019;4(1):45–51.

    Article  PubMed  Google Scholar 

  46. Whitman JD, Hiatt J, Mowery CT, Shy BR, Yu R, Yamamoto TN, et al. Evaluation of SARS-CoV-2 serology assays reveals a range of test performance. Nat Biotechnol. 2020;38(10):1174–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lassaunière R, Frische A, Harboe ZB, Nielsen ACY, Fomsgaard A, Krogfelt KA, et al. Evaluation of nine commercial SARS-CoV-2 immunoassays. medRxiv. 2020;2020.04.09.20056325.

  48. Kontoyiannis DP, Yang H, Song J, Kelkar SS, Yang X, Azie N, et al. Prevalence, clinical and economic burden of mucormycosis-related hospitalizations in the United States: a retrospective study. BMC Infect Dis. 2016;16(1):730.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Adams ER, Ainsworth M, Anand R, Andersson MI, Auckland K, Baillie JK, et al. Antibody testing for COVID-19: a report from the National COVID Scientific Advisory Panel [version 1; peer review: 2 approved]. Wellcome Open Res. 2020;5:139.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Legrand M, Gits-Muselli M, Boutin L, Garcia-Hermoso D, Maurel V, Soussi S, et al. Detection of circulating Mucorales DNA in critically ill burn patients: preliminary report of a screening strategy for early diagnosis and treatment. Clin Infect Dis. 2016;63(10):1312–7.

    Article  CAS  PubMed  Google Scholar 

  51. Salehi E, Hedayati MT, Zoll J, Rafati H, Ghasemi M, Doroudinia A, et al. Discrimination of aspergillosis, mucormycosis, fusariosis, and scedosporiosis in formalin-fixed paraffin-embedded tissue specimens by use of multiple real-time quantitative PCR assays. J Clin Microbiol. 2016;54(11):2798–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Balajee SA, Borman AM, Brandt ME, Cano J, Cuenca-Estrella M, Dannaoui E, et al. Sequence-based identification of Aspergillus, Fusarium, and Mucorales species in the clinical mycology laboratory: where are we and where should we go from here? J Clin Microbiol. 2009;47(4):877–84.

    Article  CAS  PubMed  Google Scholar 

  53. Caillot D, Valot S, Lafon I, Basmaciyan L, Chretien ML, Sautour M, et al. Is it time to include CT “reverse halo sign” and qPCR targeting Mucorales in serum to EORTC-MSG criteria for the diagnosis of pulmonary mucormycosis in leukemia patients? Open Forum Infect Dis. 2016;3(4):ofw190.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Bernal-Martínez L, Buitrago MJ, Castelli MV, Rodriguez-Tudela JL, Cuenca-Estrella M. Development of a single tube multiplex real-time PCR to detect the most clinically relevant Mucormycetes species. Clin Microbiol Infect. 2013;19(1):E1–7.

    Article  CAS  PubMed  Google Scholar 

  55. Kasai M, Harrington SM, Francesconi A, Petraitis V, Petraitiene R, Beveridge MG, et al. Detection of a molecular biomarker for Zygomycetes by quantitative PCR assays of plasma, bronchoalveolar lavage, and lung tissue in a rabbit model of experimental pulmonary zygomycosis. J Clin Microbiol. 2008;46(11):3690–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Baldin C, Soliman SSM, Jeon HH, Alkhazraji S, Gebremariam T, Gu Y, et al. PCR-based approach targeting Mucorales-specific gene family for diagnosis of mucormycosis. J Clin Microbiol. 2018;56(10):e00746-18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Baldin C, Ibrahim AS. Molecular mechanisms of mucormycosis—The bitter and the sweet. PLoS Pathog. 2017;13(8):e1006408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Millon L, Larosa F, Lepiller Q, Legrand F, Rocchi S, Daguindau E, et al. Quantitative polymerase chain reaction detection of circulating DNA in serum for early diagnosis of mucormycosis in immunocompromised patients. Clin Infect Dis. 2013;56(10):e95–101.

    Article  CAS  PubMed  Google Scholar 

  59. Dolatabadi S, Najafzadeh MJ, de Hoog GS. Rapid screening for human-pathogenic Mucorales using rolling circle amplification. Mycoses. 2014;57(s3):67–72.

    Article  CAS  PubMed  Google Scholar 

  60. Garg D, Muthu V, Sehgal IS, Ramachandran R, Kaur H, Bhalla A, et al. Coronavirus Disease (Covid-19) Associated Mucormycosis (CAM): case report and systematic review of literature. Mycopathologia. 2021;186(2):289–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Katragkou A, Walsh TJ, Roilides E. Why is mucormycosis more difficult to cure than more common mycoses? Clin Microbiol Infect. 2014;20(Suppl. 6):74–81.

    Article  PubMed  Google Scholar 

  62. Bakshi SS, Kalidoss VK. COVID 19 infection and mucormycosis—a dangerously increasing combination. Egypt J Otolaryngol. 2021;37(1):53.

    Article  Google Scholar 

  63. Ben-Ami R, Luna M, Lewis RE, Walsh TJ, Kontoyiannis DP. A clinicopathological study of pulmonary mucormycosis in cancer patients: extensive angioinvasion but limited inflammatory response. J Infect. 2009;59(2):134–8.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Chamilos G, Lewis RE, Lamaris G, Walsh TJ, Kontoyiannis DP. Zygomycetes hyphae trigger an early, robust proinflammatory response in human polymorphonuclear neutrophils through Toll-like receptor 2 induction but display relative resistance to oxidative damage. Antimicrob Agents Chemother. 2008;52(2):722–4.

    Article  CAS  PubMed  Google Scholar 

  65. Heinz WJ, Vehreschild JJ, Buchheidt D. Diagnostic work up to assess early response indicators in invasive pulmonary aspergillosis in adult patients with haematologic malignancies. Mycoses. 2019;62(6):486–93.

    Article  PubMed  Google Scholar 

  66. Chandley P, Subba P, Rohatgi S. COVID-19-associated mucormycosis: a matter of concern amid the SARS-CoV-2 pandemic. Vaccines. 2022;10(8):1266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lanternier F, Poiree S, Elie C, Garcia-Hermoso D, Bakouboula P, Sitbon K, et al. Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis. J Antimicrob Chemother. 2015;70(11):3116–23.

    Article  CAS  PubMed  Google Scholar 

  68. Kara IO, Tasova Y, Uguz A, Sahin B. Mucormycosis-associated fungal infections in patients with haematologic malignancies. Int J Clin Pract. 2009;63(1):134–9.

    Article  CAS  PubMed  Google Scholar 

  69. Roilides E, Kontoyiannis DP, Walsh TJ. Host defenses against Zygomycetes. Clin Infect Dis. 2012;54(Suppl. 1):S61–6.

    Article  PubMed  Google Scholar 

  70. Gil-Lamaignere C, Simitsopoulou M, Roilides E, Maloukou A, Winn RM, Walsh TJ. Interferon-γ and granulocyte-macrophage colony-stimulating factor augment the activity of polymorphonuclear leukocytes against medically important zygomycetes. J Infect Dis. 2005;191(7):1180–7.

    Article  CAS  PubMed  Google Scholar 

  71. Lamoth F, Damonti L, Alexander BD. Role of antifungal susceptibility testing in non-Aspergillus invasive mold infections. J Clin Microbiol. 2016;54(6):1638–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Perkhofer S, Lechner V, Lass-Flörl C; European Committee on Antimicrobial Susceptibility Testing. In vitro activity of Isavuconazole against Aspergillus species and zygomycetes according to the methodology of the European Committee on Antimicrobial Susceptibility Testing. Antimicrob Agents Chemother. 2009;53(4):1645–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Alastruey-Izquierdo A, Castelli MV, Cuesta I, Monzon A, Cuenca-Estrella M, Rodriguez-Tudela JL. Activity of posaconazole and other antifungal agents against Mucorales strains identified by sequencing of internal transcribed spacers. Antimicrob Agents Chemother. 2009;53(4):1686–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Almyroudis NG, Sutton DA, Fothergill AW, Rinaldi MG, Kusne S. In vitro susceptibilities of 217 clinical isolates of zygomycetes to conventional and new antifungal agents. Antimicrob Agents Chemother. 2007;51(7):2587–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Salas V, Pastor FJ, Calvo E, Sutton DA, Chander J, Mayayo E, et al. Efficacy of posaconazole in a murine model of disseminated infection caused by Apophysomyces variabilis. J Antimicrob Chemother. 2012;67(7):1712–5.

    Article  CAS  PubMed  Google Scholar 

  76. Alvarez GS, Hélary C, Mebert AM, Wang X, Coradin T, Desimone MF. Antibiotic-loaded silica nanoparticle–collagen composite hydrogels with prolonged antimicrobial activity for wound infection prevention. J Mater Chem B. 2014;2(29):4660–70.

    Article  CAS  PubMed  Google Scholar 

  77. Rodríguez MM, Pastor FJ, Sutton DA, Calvo E, Fothergill AW, Salas V, et al. Correlation between invitro activity of posaconazole and invivo efficacy against Rhizopus oryzae infection in mice. Antimicrob Agents Chemother. 2010;54(5):1665–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kumar S, Acharya S, Jain S, Shukla S, Talwar D, Shah D, et al. Role of zinc and clinicopathological factors for COVID-19-Associated Mucormycosis (CAM) in a rural hospital of central India: a case-control study. Cureus. 2022;14(2):e22528.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Alvarez E, Stchigel AM, Cano J, Sutton DA, Fothergill AW, Chander J, et al. Molecular phylogenetic diversity of the emerging mucoralean fungus Apophysomyces: proposal of three new species. Rev Iberoam Micol. 2010;27(2):80–9.

    Article  PubMed  Google Scholar 

  80. Mellinghoff SC, Bassetti M, Dörfel D, Hagel S, Lehners N, Plis A, et al. Isavuconazole shortens the QTc interval. Mycoses. 2018;61(4):256–60.

    Article  CAS  PubMed  Google Scholar 

  81. Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10020):760–9.

    Article  CAS  PubMed  Google Scholar 

  82. DiPippo AJ, Rausch CR, Kontoyiannis DP. Tolerability of isavuconazole after posaconazole toxicity in leukaemia patients. Mycoses. 2019;62(1):81–6.

    Article  CAS  PubMed  Google Scholar 

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The authors gratefully thank anyone who helped to make this new review article coming out to light.


This review work did not receive any external funding.

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Authors and Affiliations



NAO and MMA are the leading first authors of this work, responsible for conceptualizing the research idea and had a share in writing the manuscript holistically. BS and GKG almost equally contributed in editing different parts of this manuscript. BS designed the conceptual diagram (Fig. 1), and GKG wrote the Abstract section. AMR is the leading corresponding author of this paper, wrote the major part of the "The Treatment of Mucormycosis" section along with having a share in writing some parts of the manuscript, and was also responsible for supervising, proofreading, and revising the whole final article. All authors read and approved the final manuscript.

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Dr. Amgad M. Rabie (the supervisor of this review work) is a senior drug discovery pharmacist and he is also the head of the Drug Discovery & Clinical Research Department at Dikernis General Hospital (DGH) in Egypt. Information of other authors (professors and lecturers) is as indicated in their affiliations.

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Correspondence to Amgad M. Rabie.

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Osman, N.A., Anwar, M.M., Singh, B. et al. A peek behind the curtain in the diagnosis and management of COVID‑19‑Associated Mucormycosis (CAM). J. Egypt. Public. Health. Assoc. 98, 4 (2023).

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