Mucormycosis infection in patients with COVID-19: A systematic review.

INTRODUCTION: Several reports previously described mucormycosis co-infection in patients with COVID-19. As mucormycosis and COVID-19 co-infection might adversely affect patients' outcomes, we aimed to systematically review the related evidence and the subsequent outcomes.
METHODS: We conducted a systematic review of relevant articles searching the keywords in the online databases of PubMed, Scopus, Embase, Cochrane, and Web of Science. All the records from the start of the pandemic until June 12th, 2021 underwent title/abstract and then full-text screening process, and the eligible studies were included. We did not include any language or time restrictions for the included studies.
RESULTS: We found 31 eligible studies reporting 144 total cases of COVID-19 and mucormycosis co-infection. The nose, cranial sinuses, and orbital cavity were the most commonly involved organs, although the cerebrum, lungs, and heart were also involved in the studies. Pre-existing diabetes mellitus (DM), as well as corticosteroid use, were the most commonly identified risk factors, but other underlying conditions and immunomodulatory drug use were also present in several cases. Aspergillus was the most commonly reported micro-organism that caused further co-infections in patients with concurrent COVID-19 and mucormycosis. As most of the studies were case reports, no reliable estimate of the mortality rate could be made, but overall, 33.6% of the studied cases died.
CONCLUSION: Early diagnosis of mucormycosis co-infection in COVID-19 patients and selecting the right treatment plan could be a challenge for physicians. Patients with underlying co-morbidities, immunocompromised patients, and those receiving corticosteroids are at higher risk of developing mucormycosis co-infection and it is crucial to have an eye examination for early signs and symptoms suggesting a fungal infection in these patients.

INTRODUCTION

The coronavirus disease 2019 (COVID‐19) pandemic emerged as a new health crisis worldwide and affected millions of people. , , , COVID‐19 causes several symptoms and can precipitate severe multiorgan involvements, acute respiratory distress syndrome (ARDS), and death. , ,

Cases of bacterial or fungal co‐infections or super‐infections have been reported in previous studies and can increase the mortality rates and complications of COVID‐19. , Several reports of COVID‐19 and mucormycosis co‐infection exist. Although antibiotics and systemic corticosteroids could reduce the risk of severe COVID‐19 complications and bacterial co‐ or super‐infection, they can provide a favorable condition for opportunistic infections, such as mucormycosis. , , Mucormycosis, also commonly knowns as the disease caused by the black fungus, is a rare and life‐threatening fungal infection with various ranges of involvement. , A previous systematic review reported an enormous 33.6% mortality rate in patients co‐infected with mucormycosis and COVID‐19.

This potentially deadly black fungus can affect various organs and systems. , Rhino‐orbital, pulmonary, oral, cerebral, sinonasal, and gastrointestinal mucormycosis are some of the sites of involvement in mucormycosis. , , Underlying diseases such as poorly controlled diabetes mellitus (DM), hematological malignancies, or immunocompromised state are predisposing factors to mucormycosis infection. , ,

Early diagnosis and treatment can reduce the mortality rate and improve the outcome. Understanding this condition may improve the diagnosis and quality of care of the COVID‐19 patients co‐infected with mucormycosis. Therefore, we aimed to systematically review mucormycosis co‐infection in patients with COVID‐19 and its subsequent outcomes. This systematic review was conducted to establish the risk factors for mucormycosis co‐infection in patients with COVID‐19, the target organs for mucormycosis in the co‐infected patients, the diagnosis time between the COVID‐19 and mucormycosis infection, the provided treatments and the mortality of the co‐infected patients, and other further co‐infections in the patients co‐infected with COVID‐19 and mucormycosis.

METHODS

This is a comprehensive review to shed light on the incidence of fungus mucormycosis in COVID patients based on the current evidence. To authenticate the end results this investigation benefits from the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) checklist.

Search strategy

We systematically searched the keywords in the online databases of PubMed, Scopus, Embase, Web of Science, and Cochrane and extracted all relevant publications and reports from December 2019 to June 12th, 2021. All the searches were conducted as title/abstract, in all the databases, and PubMed is mentioned as an example in the query below:

[COVID‐19] OR [SARS‐CoV‐2] OR [SARS‐CoV2] OR [2019‐nCoV] OR [Novel coronavirus]

[Mucormycosis] OR [Mucormycose] OR [Mucorales] OR [Black fungus]

[A] AND [B]

Study selection

We aimed to include the original studies that reported mucormycosis co‐infection in patients with COVID‐19. We downloaded the records into the EndNote software and then excluded the duplicate records using the software. Then, the remaining duplicates were excluded manually and the records got ready to enter the two‐phase screening process. To select and include pertinent literature, two of our research staff read and selected the eligible studies based on their titles and abstracts. At the next step, we inspected the full texts of these studies carefully, and finally, the studies that adhered to the inclusion criteria were included in the qualitative synthesis.

Inclusion/exclusion criteria

Original studies published in any language that met the aim of our study, that is, those including COVID‐19 patients with confirmed or suspected mucormycosis co‐infection, were included. We did not include any language or time restrictions for the included studies. We included all the peer‐reviewed original studies, case reports and case series.

The exclusion criteria for this study were as follows:

Non‐original studies, such as reviews, systematic reviews, meta‐analyses, or editorials without original reports.

Studies lacking available full texts, such as abstracts and conference abstracts.

Any pure laboratory or animal studies without mentioning human subjects.

Patients with mucormycosis that did not have previously suspected or diagnosed COVID‐19, that is, sole mucormycosis without co‐infection.

Data extraction

After summarizing the literature, two independent investigators assembled and transferred the relevant information and findings including first author (reference) information, study type (eg, original article), country of origin, study population (N), patient mean age, male proportion, comorbidities, affected organ, day of mucormycosis detection after preliminary COVID‐19 diagnosis, other opportunistic and bacterial co‐infection, treatments received (for COVID‐19 and mucormycosis), mortality rate, and summary of findings into a table. To avoid duplications and/or overlaps, other investigators double‐checked the selected literature as well.

RESULTS

In this study, 162 documents were retrieved using a systematic search strategy. After a primary review of retrieved articles, 94 duplicates were removed. The title and abstract of the remaining articles were reviewed and 19 studies were excluded. After applying the eligibility criteria and full‐text check, 18 articles were excluded, and only 31 articles met the inclusion criteria and were included in the final review (Figure 1). These studies were from India (n = 8), USA (n = 7), Iran (n = 2), Egypt (n = 2), France (n = 2), UK (n = 2), Spain (n = 1), Turkey (n = 1), Brazil (n = 1), the Netherlands (n = 1), Italy (n = 1), China (n = 1), Mexico (n = 1), and Austria (n = 1). In total, 144 cases were identified.

FIGURE 1

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram of the study's selection process

The nose, cranial sinuses, and orbital cavity were the most commonly involved organs, although cerebrum, lungs, and heart were also reported. Pre‐existing DM (in many cases concurrent with diabetic ketoacidosis [DKA]) as well as corticosteroid use were the most commonly identified risk factors, but other underlying conditions and immunomodulatory drug use were also present in several cases. The most common underlying conditions were DM and hypertension, with the prevalence of 89/134 (66.4%) and 46/134 (34.3%) among the studies that reported the underlying conditions, respectively. The period between diagnosis of COVID‐19 and mucormycosis ranged from 3 to 90 days in the included studies, with a mean duration of 25.6 ± 21 days.

Aspergillus was the most commonly reported micro‐organism that caused further co‐infection in the COVID‐19 patients with concurrent mucormycosis. This aspergillus co‐infection was reported mainly by two studies in Egypt in 30.6% and 12.5% the patients with COVID‐19 and mucormycosis (the sample size of these studies were 36 and eight), , and four case reports from France (two studies), India, and the United States. , , ,

Amphotericin B was the most prescribed treatment given in 92% of the patients. As many of the studies were case reports and patients either died or recovered, the mortality rates ranged from 0% to 100% (Table  1). However, overall, 45/134 (33.6%) of the studied patients with COVID‐19 and mucormycosis co‐infection died (excluding a post‐mortem study by Hanley et al).

TABLE 1

Summary of findings of the included studies

Author (reference)	Type of study	Country	Study population (N)	Mean age	Male no. (%)	Comorbidities	Affected organ	Day of mucormycosis detection after COVID‐19 diagnosis	Co‐infection	Treatments received (for COVID‐19 and mucormycosis	Mortality rate	Summary of findings
Alekseyev et al 9	Case report	USA	1 patient	41	100%	Type 1 diabetes mellitus (DM), hypertension, coronary artery disease	Heart, lungs, palate	—	—	Steroids, hydroxychloroquine, Intravenous (IV) fluids, cefepime, amphotericin B, IV heparin, sphenoidotomy, and ethmoidectomy maxillary antrostomy	0%	The severity of mucormycosis infection is due to its rapid disease progression and angio‐invasive character
Arana et al 10	Case report	Spain	2 patients	55	100%	Type 2 DM (n = 1), hypertension (n = 2), end‐stage renal disease with kidney transplant (n = 2), hypothyroidism (n = 1), ischemic heart disease (n = 1)	Respiratory system	7 and 21 days	—	Dexamethasone, prednisone, ceftriaxone, hydroxychloroquine, azithromycin, lopinavir/ritonavir, tocilizumab, liposomal amphotericin B, isavuconazole, posaconazole, maxillectomy, mechanical ventilation	0%	—
Ashour, Manar et al 13	Case series	Egypt	8 patients	53.6	62.5	DM type 2 (n = 6), chronic kidney disease (n = 2), hyperlipidemia (n = 2), hypertension (n = 2), ischemic heart disease (n = 1), cerebral infarction (n = 1)	Respiratory system, orbital cavities, ethmoidal and maxillary sinuses, nasal cavity, nasopharynx, carotid artery, hard palate, skin	14 days	Aspergillosis (12.5%)	Amphotericin B, ambisome, itraconazole, surgical debridement, orbital enucleation, mechanical ventilation	37.5%	—
Bayram et al 11	Prospective observational study	Turkey	11 patients with rhino‐orbital mucormycosis	73.1	81.8%	Uncontrolled DM type 2 (n = 9), hypertension (n = 8), acute and chronic renal failure (n = 5), coronary artery disease (n = 2), chronic obstructive pulmonary disease (n = 1), myelodysplastic syndrome (n = 1), hyperthyroidism (n = 1), atrial fibrillation (n = 1)	Paranasal sinuses, orbital cavities	Mean of 14.4	—	Amphotericin B, voriconazole, surgical debridement, mechanical	63.6%	The risk of coinfections in patients with acute respiratory distress syndrome (ARDS), receiving broad‐spectrum antibiotics, corticosteroids, and supported by invasive or non‐invasive ventilation is higher
Bellanger et al 22	Case report	France	1 patient	55	100%	Follicular lymphoma	Lungs	20 days	Aspergillus fumigatus and Rhizopusmicrosporus, Cytomegalovirus (CMV) and HHV6 viremia	Amphotericin B, mechanical ventilation	100%	A hematologic malignancy was independently associated with high SARS‐CoV‐2 viral load and the SARS‐CoV‐2 infection itself may induce an immunosuppressive state exposing the patient to invasive mold disease
Buil et al 24	Case series	The Netherlands	4 patients	65.2	100%	DM (n = 2), chronic lymphocytic lymphoma (n = 1), Obesity (n = 1)	Lungs, rhino orbital cavity, kidney, sinus, eye, cranium	17 days 22 days 35 days 45 days	Rhizopus microsporus, Lichtheimia Ramosa, A. fumigatus, R. arrhizus	Tocilizumab, dexamethasone, prednisone, amphotericin B, posaconazole, voriconazole, isavuconazole, surgical debridement, interferon‐γ, mechanical ventilation	75%	—
Dallalzadeh et al 17	Case report	USA	2 patients	42	100%	Type 2 DM (n = 2)	Cranium, sinonasal cavity, orbit, lungs,	6 days	Rhizopus	Lateral canthotomy, IV amphotericin, isavuconazole, micafungin, remdesivir, dexamethasone, surgical debridement,	50%	—
do Monte et al 18	Case report	Brazil	1 patient	86	100%	Arterial hypertension	GI system, respiratory system, blood,	—	—	Ceftriaxone, azithromycin, oseltamivir, hydrocortisone, vasopressors, mechanical ventilation, red blood cells units, omeprazole	100%	Depending on the anatomic site involved, mucormycosis can present as a variety of different syndromes, including rhino‐orbital‐cerebral, pulmonary, cutaneous, and less often GI, renal, and disseminated diseases
El‐Kholy et al 21	Longitudinal prospective study.	Egypt	36 patients	52.92	52.8%	DM (n = 10), hypertension (n = 6), uncontrolled leukemia (n = 1), pancreatic cancer (n = 1), CKD (n = 3), asthma (n = 3), cardiac (n = 1), hypothyroidism (n = 1), systemic lupus erythematosus (n = 2)	Sinonasalcavity, cerebrum, orbit, palate, skin	17.82 days	Aspergillus species (30.6%)	Amphotericin B, voriconazole, posaconazole, surgical debridement, mechanical ventilation	36.1%	—
Fekkar et al 23	Case report	France	2 patients with probable/putative invasive pulmonary aspergillosis and mucormycosis co‐infection	62.5	100%	Obesity (n = 2), kidney transplantation (n = 1), hypertension (n = 1), dyslipidemia (n = 1)	Lungs	Not mentioned, diagnosis made 3 and 21 days after ICU admission	Both patients had invasive pulmonary aspergillosis co‐infection	One had no specific antifungal or COVID‐19 treatments (died later). One received no specific COVID‐19 therapies, but voriconazole, amphotericin B, caspofungin, and isavuconazole for fungal infections (alive)	50%	The risk of pulmonary fungal infection is low in the COVID‐19 patients without underlying immunosuppression
Garg et al 14	Case study	India	1 patient	55	100%	Type 2 DM, hypertension, ischemic cardiomyopathy, end‐stage renal disease, severe anemia	Interstitial opacities, heart, lungs	3	Escherichia coli, Aspergillus fumigatus	IV dexamethasone, remdesivir, O2 supplement thromboprophylaxis, maintenance hemodialysis, liposomal amphotericin B, right upper lobectomy	0%	For critically diagnosed COVID‐19 patients, doctors must be aware of serious infections that can complicate the course of COVID‐19. A high degree of clinical suspicion is required to diagnose pulmonary mucormycosis. Early diagnosis and timely management are completely necessary to improve outcomes in pulmonary mucormycosis
Hanley et al 15	Cohort study/case series	UK	10 patients	73	70%	Not available	Hilar lymph nodes, heart, brain, lungs (DAD), pancreas			4 patients on ventilator	100%	Invasive secondary mucormycosis was confirmed by Mucorales‐specific PCR in one patient during the autopsy. He was a 22‐year‐old man with necrotic hemorrhagic pancreatitis and no fungal hyphae in his pancreas. Suggesting all human fungal pathogens can complicate COVID‐19‐associated infections
Johnson et al 20	Case report	USA	1 patient	79	100%	Diabetes, hypertension	Lungs, brain	19	Aspergillosis, methicillin‐resistant Staphylococcus aureus, Klebsiella pneumoniae	IV ceftriaxone, azithromycin, remdesivir and dexamethasone, norepinephrine, IV L‐AmB, tracheostomy endoscopic gastrotomy	0%	The combined risk factors of DM, COVID‐19, and recent corticosteroid treatment contributed to both mucormycosis and aspergillosis infections in the patient
Kanwar et al 25	Case reports	USA	1 patient	56	100%	End‐stage renal disease	Lungs	16	Vancomycin‐resistant Enterococcus spp. Bacteroides fragilis	Methylprednisolone, tocilizumab, convalescent plasma, IV vancomycin, piperacillin‐tazobactam, robotic decortication surgery with LAmB	100%	In this patient, receipt of two commonly used immunosuppressants likely contributed to mucormycosis risk, suggesting the need for vigilance in hospitalized patients with COVID‐19. He was readmitted 5 days after his discharge (16 days after initial positive SARS) with shortness of breath, fatigue, and hemoptysis, which lead to the diagnosis of both mucormycosis and rhizopus infections. On day 17, the patient developed a cardiac arrest and died
Karimi‐Galougahi et al 26	Case reports	Iran	1 patient	61	0%	None	Facial nerve, eyes, skin, nose, sinus	21		Remdesivir, interferon‐alpha, systemic corticosteroid, insulin, systematic anti‐fungal endonasal endoscopic debridement	0%	Invasive mucormycosis was noted in one patient (PM5, Figure 1) and confirmed with Mucorales‐specific PCR. The mucormycosis was vasculocentric and disseminated, involving the hilar lymph nodes, heart, brain, and kidney in the same patient. Macroscopic (two [23%] of nine patients) and microscopic (eight [89%] of nine) pulmonary thromboemboli were frequent observations. Invasive mucormycosis was noted in one patient (PM5, Figure 1) and confirmed with Mucorales‐specific PCR. The mucormycosis was vasculocentric and disseminated, involving the hilar lymph nodes, heart, brain, and kidney in the same patient. Macroscopic (two [23%] of nine patients) and microscopic (eight [89%] of nine) pulmonary thromboemboli were frequent observations. The new‐onset glucocorticoid‐induced diabetes and immunosuppression by steroids may have predisposed this patient to invasive mucormycosis. There may be a contribution by COVID‐19, which was present at the time of readmission, to susceptibility to mucormycosis. Clinicians should be familiar with the manifestation of invasive mucormycosis in patients with COVID‐19 who received corticosteroids during the pandemic
Khatri et al 27	Case reports	USA	1 patient	68	100%	CAD/heart transplant, diabetes type II, hypertension, chronic kidney disease, obstructive sleep apnea	Lungs, GI tract, brain, joints, chest wall, right axilla	90	Morganellamorganni, Enterobacter cloacae, vancomycin‐resistant Enterococcus faecium bacteremia, multidrug‐resistant Klebsiella variicola, coagulase‐negative Staphylococcus bacteremia, deptomycin resistant E. faecium	Oral hydroxychloroquine, amiodarone IV vancomycin and meropenem, debridement and surgery of sternal wound, mechanical ventilation, cyclosporine, nystatin, tracheostomy, omental flap, split thickness skin graft, IV L‐AmB, resection of subclavian artery, infected prosthetic graft	100%	We describe a case of mucormycosis occurring after COVID‐19, in an individual who received a recent heart transplant for severe heart failure and was diagnosed with COVID‐19 2 months later. Approximately 3 months after the COVID‐19 diagnosis, he developed cutaneous mucormycosis at an old intravascular device site. He underwent extensive surgical interventions, combined with broad‐spectrum antifungal therapy. Despite a lot of aggressive therapeutic measures, he died after a prolonged (175 days) hospital stay
Sai Krishna et al 28	Case reports	India	2 patients	42	100%	Type 2 DM (n = 2), hypertension (n = 1)	Midface, 1/4 teeth maxillary sinus and bone, zygomatic bone	60	Fungal osteomyelitis	Insulin, IV L‐AmB, surgical resection, itraconazole, extraction of URQ teeth, posaconazole	0%	COVID‐19 patients are predisposed to developing various fungal infections during the course and in later stages of this disease, especially severely ill cases, due to a decrease of CD4 + T cells and CD8 + T cells leading to immune suppression. So the main objective of this case report is to document cases of oral and maxillofacial pathologies which are associated with COVID‐19 infection
Krishna et al 29	Case reports	UK	1 patient	22	100%	Hypothyroidism, steatohepatitis, thrombo‐embolic disease	Lungs, heart, hilar nodes, brain, pharynx, nasal mucosa, trachea		Pericarditis	Mechanical ventilation, aspirin, LMW‐heparin, hydroxychloroquine, azithromycin, meropenem, teicoplanin, argatroban, noradrenaline, vasopressin, gentamicin, tracheostomy, bronchoalveolar lavage	100%	A young obese Asian male was admitted with an acute anterior cerebral artery (ACA) territory infarct and severe COVID‐19 pneumonitis to the ICU. He had a complicated stay with recurrent episodes of vasoplegic shock and multiorgan dysfunction. At autopsy, he was confirmed to have disseminated mucormycosis. In our belief, this is the first documented case of disseminated mucormycosis in an immunocompetent host with COVID‐19. The lack of modalities and biomarkers to diagnose mucormycosis, along with the extremely high mortality in untreated cases, present a unique challenge to clinicians dealing with critically ill COVID‐19 patients
Maini et al 30	Case reports	India	1 patient	38	100%	None	Lungs, eye, maxillary and ethmoidal sinus	18	—	IV remdesivir, methylprednisolone, dexamethasone, FESS surgery, metronidazole, fluconazole, tocilizumab, tobramycin, nepalact, lateral canthotomy, inferior cantholysis, monocef	0%	The patient was diagnosed with COVID‐19 and treated according to the persisting protocols. Following recovery, the patient developed chemosis and pain in the left eye. A diagnosis of mucormycosis was established after MRI and FESS. Initially, conservative management was done and later on surgical debridement. The patient recovered with minimal residual deformity after 38 days hospitalization
Mehta et al 31	Case report	India	1 patient	60	100%	DM	Lungs, eye, midface, sinuses	11	—	Meropenem, oseltamivir, methylprednisolone, dexamethasone, enoxaparin, ventilator, tocilizumab, sitagliptin/metformin, topical moxifloxacin, vancomycin, L‐AmB, steroid therapy	100%	Extensive use of steroids and monoclonal antibodies, also broad‐spectrum antibiotics may lead to the development or exacerbation of pre‐existing fungal diseases. Physicians should be aware of the possibility of secondary invasive fungal infections in COVID‐19 patients, especially in patients with existing risk factors. It should enable early diagnosis and treatment with the subsequent reduction of mortality and morbidity. The use of therapeutic agents should be monitored to achieve the effect at the lowest dose and shortest duration. The use of broad‐spectrum antibiotics, especially in the absence of infection, should be re‐evaluated
Mekonnenet al 19	Case report	USA	1 patient	60	100%	Diabetes, asthma, hypertension, hyperlipidemia	Lungs, eye, sinuses, nerve	(24) 4	Angioinvasion	Remdesivir, intranasal biopsy and endoscopy, vancomycin, cefepime, L‐AmB, caspofungin, dexamethasone, convalescent plasma, endoscopic debridement, posaconazole	100%	Acute invasive fungal rhinosinusitis is a rare but highly morbid infection, primarily affecting immunosuppressed individuals. The same is at particularly high risk of complications and mortality in the setting of coronavirus‐related ARDS. The authors present a case of acute invasive fungal rhino‐orbital mucormycosis in a patient with COVID‐19. Prompt recognition, initiation of therapy, and consideration of the challenges of rapidly evolving COVID‐19 therapy guidelines are important for improving patient survival
Rao et al 32	Case report	India	1 patient	66	100%	Poorly controlled diabetic	Eyes	12	—	Systemic steroids for COVID‐19, functional endoscopic sinus surgery, IV liposomal amphotericin.	0%	The patient had orbital infarction syndrome secondary due to rhino‐orbital mucormycosis
Ravani et al 33	Retrospective cohort	India	31 patients	56.3 years	64.5%	Uncontrolled diabetes (n = 30), Hypertension (n = 17), Ischemic heart disease (n = 1), Kidney disease (n = 2)	Eyes	60	—	IV liposomal amphotericin B and debridement of local necrotic tissue	9.6%	Rhino‐orbital cerebral mucormycosis and HbA1c ≥8 mmol/mol must be treated aggressively
Revannavar, et al 34	Case report	Italy	1	Middle‐aged	0%	Uncontrolled diabetes	Eyes	—	—	Amphotericin B and antibiotics functional endoscopic sinus procedure	0%	Early diagnosis and treatment are essential to prevent further end‐organ damage
Saldanha et al 35	Case report	India	1	32 years	0%	Uncontrolled diabetes	Eyes, nose, and paranasal sinus	—	—	emergency endoscopic surgery with or without debridement conventional amphotericin B 25 mg/day	0%
Sarkar et al 36	Case report	China	10	Middle‐aged	Unknown	DM (n = 10), DKA (n = 9)	Rhino‐orbital	—	Bacterial and fungal coinfections	IV dexamethasone for COVID‐19 disease, liposomal amphotericin B for mucormycosis, debridement	40%	Should be mindful of the probability of development of fungal infections such as mucormycosis in patients with COVID‐19 illness, especially in those with comorbidities and on immunosuppressive agents in the coming future
Sen et al 37	retrospective, interventional study	India	6	60.5	100%	Type 2 DM (n = 6), hypertension (n = 3), coronary artery disease (n = 2)	Rhino‐orbito‐cerebral	15.6	—	IV dexamethasone or oral prednisolone in n = 5	0%	The incidence of rhino‐orbito‐cerebral Mucormycosis is likely to rise, both as a coinfection and as a sequela of COVID‐19. Early diagnosis and management with appropriate and aggressive antifungals and surgical debridement can improve survival
Veisi et al 12	Case report	Iran	2	40‐54	50%	DM (n = 1)	Orbit and paranasal sinuses	After 8 days	—	IV remdesivir, levofloxacin, dexamethasone for COVID‐19 disease (n = 2),endoscopic debridement, IV Amphotericin B for mucormycosis, mechanical ventilation	50%
Waizel‐Haiat et al 38	Case report	Mexico	1	24	0%	Uncontrolled diabetes	Rhino‐orbital mucormycosis	—	—	Aggressive surgical debridement and liposomal amphotericin B, mechanical ventilation	100%	Severe immunosuppressive state secondary to diabetic ketoacidosis without previous treatment made the patient susceptible to both severe COVID‐19 and mucormycosis
Werthman‐Ehrenreich et al 39	Case report	USA	1	33	0%	Hypertension, asthma	Orbital	—	—	Sinus debridement and amphotericin B, remdesivir and convalescent plasma for covid‐19	0%	—
Zurl et al 40	Case report	Austria	1	53	100%	Myelodysplastic syndrome, obesity	Pulmonary	—	—	Tocilizumab and high‐dose glucocorticoids for covid‐19, piperacillin/tazobactam plus linezolid for pulmonary infection	100%

DISCUSSION

Findings outline

Based on the findings from 31 included studies, the mucormycosis co‐infection in COVID‐19 patients, the infected organs, mortality rate, diagnosis interval, treatment plan, and further co‐infections were reviewed. The most commonly affected site of mucormycotic co‐infections in COVID patients are the nose, sinuses, and orbits. The mucormycosis co‐infection was often diagnosed between 3 and 45 days after COVID‐19 diagnosis, with a mean interval of 25.6 days. In addition, a co‐infection with a third micro‐organism was occasionally reported, mainly with aspergillosis. We found a mortality rate of 45/134 (33.6%). However, as many of the included studies were case reports, the mortality rate was either not reported or described as 0% for those who survived or 100% for those who died due to mucormycosis co‐infection; therefore, the mean mortality rate is not reliable. Among the underlying conditions of patients infected with both COVID‐19 and mucormycosis, diabetes was the most abundant with 66.4%. The main findings, such as the most commonly affected site and the most important risk factors, were in line with other systematic reviews. ,

Mucormycosis and COVID‐19 co‐infection

DM was present in an enormous 66.4% of the patients. Several studies have indicated DM and DKA as significant risk factors of mucormycosis in the pre‐pandemic era. , In India, a multicenter study revealed higher odds of contracting Rhino‐orbito‐cerebral mucormycosis (odds ratio: 7.55, P = .001) in DM patients. In the post‐COVID time, a recent systematic review consisting of 105 cases of COVID‐19 with mucormycosis co‐infection reported DM and corticosteroid intake in 80% and 76.3% of cases, respectively. Similarly, in another systematic review by John et al DM, corticosteroid intake, and DKA were present in 93%, 88%, and 14.9% of cases, respectively. These findings are consistent with our results, as pre‐existing DM and corticosteroid use were present in most included studies. Hypertension was also present in a remarkable 34.3% of the patients; however, this number might be overestimated due to the high prevalence of DM, as hypertension and DM co‐exist together in many patients, such as those with metabolic syndrome. Unfortunately, the design of the studies could not yield any possible assessment of whether hypertension is a risk factor for mucormycosis co‐infection or not; therefore, more robust studies are required.

COVID‐19 can exacerbate pre‐existing DM and precipitate DKA in patients, known risk factors for mucormycosis. Hyperglycemic conditions in DM and hyper acidemic state in DKA can predispose patients to mucormycosis due to increasing free iron levels, discussed later in the text.

Currently, corticosteroids are the mainstay of treatment in severe COVID‐19 patients. They have been shown to effectively increase survival and reduce mortality in COVID‐19 patients. However, corticosteroid intake eliminates the phagocytic capability of WBCs, predisposing patients to fungal infections. In addition, new‐onset corticosteroid‐induced DM or exacerbated previous DM might enhance the growth of mucormycosis.

COVID‐19 itself commences a chain of events that might make patients prone to secondary fungal infections, namely mucormycosis. Here are possible mechanisms through which SARS‐CoV‐2 infection might give rise to mucormycosis susceptibility:

Dramatic decrease in the total number of T‐cells including both CD4+ and CD8+ groups in severe cases of COVID‐19 causes an immunocompromised state and thus predisposition to mucormycosis.

In severe COVID‐19 infection, inflammatory markers such as IL‐6, IL‐2R, IL‐10, and TNF‐alpha rise and lead to a term called “cytokine storm”. Cytokine storm elevates ferritin levels and reduces iron export. As a result, iron accumulates in the cells. Iron overload causes tissue damage and necrosis, leading to cell death and free iron release into the circulation. A perfect iron‐rich environment is ideal for mucormycosis since the fungus needs iron to grow and spread through the body. ,

A study in the UK reported a higher prevalence of DM and DKA in COVID‐19 patients than in the general population. The SARS‐CoV‐2 infection might exhibit new‐onset DM features either due to corticosteroid therapy or the disease itself similar to the SARS‐CoV‐1. Expression of angiotensin‐converting enzyme two receptors in pancreatic islets in COVID‐19, along with increased insulin resistance due to cytokine storm, might explain the diabetogenic nature of COVID‐19. Excessive glucose occupies the iron‐binding site of ferritin and transferrin in hyperglycemia. Subsequently, free iron levels and thus mucormycosis susceptibility increase. Also, DKA can lead to an acidemic state, allowing more free iron available for fungal growth and elevating the risk of mucormycosis co‐infection.

Endothelialitis is another sequela of COVID‐19 that might explain the risk of mucormycosis co‐infection in COVID‐19 patients. , Endothelial damage facilitates angio‐invasion and dissemination of mucormycosis. Additionally, COVID‐associated low ph, hyperglycemia, and high iron levels contribute to the expression of glucose‐regulator protein 78 (GRP‐78) of endothelium cells and fungal ligand spore coating homolog (CotH) protein. These two receptors mediate the adhesion and penetration of mucorales into the tissues. ,

In addition to systemic corticosteroids, our studies described immunomodulatory drugs (such as tocilizumab) and voriconazole intake among their cases. In this matter, immunomodulatory drugs such as tocilizumab increased the co‐infection susceptibility in one study. Also, published studies have demonstrated an increased risk of mucormycosis in patients who received voriconazole.

Some of our studies reported lymphoma, leukemia, and solid organ transplant cases in table. , , , , , , , , These observations are consistent with previous publications. Based on the existing evidence, malignancies, organ transplantation, and hemopathies are known risk factors for mucormycosis infection. , Moreover, in an observational study by Patel et al, malignancy and organ transplant were the most significant risk factor after DM.

Target organs

Mucormycosis may target the nasal cavity, paranasal sinuses, orbit fossa, central nervous system (CNS), lung (pulmonary), gastrointestinal tract, skin, jawbones, joints, heart, kidney, and mediastinum. We observed similar findings to the systematic review by Singh et al that suggested nasal cavity and paranasal sinuses are the most common site of involvement (88.9%), followed by rhino‐orbital involvement (56.7%). To determine the site of mucormycosis infection, several variables are important. For example, the site of involvement depends on the underlying cause of mucormycosis. Rhino‐cerebral form of the infection is associated with uncontrolled DM and DKA, while the pulmonary form is associated with neutropenia, organ transplant, and hematological malignancies. Besides, critical lung damage in severe cases of COVID‐19 might increase the risk of imposed pulmonary mucormycosis infection since mucormycosis can share an airborne route and primary pulmonary entry with COVID‐19.

Mortality

As a rare invasive fungal infection, mucormycosis inflicts high morbidity and mortality on patients. In the COVID‐19 setting, Singh et al reported a mortality rate of 30.7% in patients with COVID‐19 and mucormycosis co‐infection. This study comes very close to the 33.6% we found in this study. However, the lack of larger studies makes the reported rate unreliable. Since most of our studies were case reports consisting of only one patient, their mortality rates were either 0% or 100%. Subsequently, due to the diverse demographic backgrounds and features of the cases, combining their mortality rates seems inconclusive.

Diagnosis time

The early diagnosis of mycosis and pursuant treatment is crucial for a propitious outcome and prognosis. The mean day of diagnosis was 25.6 ± 21. A systematic review of 34 studies and 275 cases by Muthu et al reported the mean diagnosis time 19.5 days from COVID‐19 onset. The Earliest times to diagnose mucormycosis infection in COVID‐19 patients were reported on days 3, 4, and 6, respectively, in one, one, and two patients. In contrary, in four studies, it was diagnosed late; after 45 days in one patient, after 60 days in 33 patients, , and after 90 days in one patient ; the patient, who was diagnosed 90 days after the infection, had a heart transplant.

Co‐infections

The most common co‐infection of mucormycosis reported pulmonary invasive aspergillosis in COVID‐19 patients, which raises concerns about increased mortality. Cases of mucormycosis and aspergillosis co‐infection have been reported in hospitalized COVID‐19 patients in two studies with the sample sizes of 36 and eight patients from Egypt, respectively, representing 30.6% and 12.5%. , Also, this co‐infection was reported in four case reports; two of which in France and the others in India and the United States. , , , One study reported pericarditis in two patients. This finding was consistent with the findings of other systematic review studies; aspergillus has been reported to be the most opportunistic concomitant infection in these studies. ,

Treatment

The poor outcome of mucormycosis infections is rather dependent on the severe invasiveness, vigorous of the mycotic infections, and severe suppression of the immune system. The precise comprehensive treatment is radical debridement and incision of infected tissue, alongside therapy with high‐dose amphotericin B. As expected, amphotericin B as the most common drug used for the management of COVID‐19 patients with mucormycosis was observed in 92% of the cases. In addition, the use of antifungals has been reported regularly in studies, mostly voriconazole (17.3%). Also, for treatment of COVID‐19, the use of hydroxychloroquine (18.5%), dexamethasone (16%), and tocilizumab (8.3%) were reported. The use of high‐dose corticosteroid had been reported in most of the studies to manage COVID‐19 disease; since the systematic steroids barricade the immune system as well as negatively affects glycemic control, its use should be further investigated. Other systematic review studies have also reported the use of corticosteroids in many cases of mucormycosis. , Of the 144 patients studied in the surveys, more than half of them (52%) had debridement of infected tissue. Furthermore, 23.2% underwent mechanical ventilation due to respiratory problems caused by COVID‐19. Proper actions to reduce the incidence of this fungal infection include early detection of patients with mucormycosis, the timely start of medical treatment and surgical operations to debride the infected tissue and proper and adequate use of corticosteroids in COVID‐19 patients.

LIMITATIONS

As the new coronavirus gained mainstream attention among infectious diseases, less and less attention has been given to fungal infections. Meanwhile, the diversity of COVID‐19 symptoms overshadowed the other probable pathological conditions of COVID‐19 patients, due to which the diagnosis of many fungal co‐infections has been delayed. Thus, the relatively small number of published studies reporting mucormycosis co‐infection in COVD‐19 patients was the main limitation concerning the aim of this paper. In addition, the small sample size in each study and extreme mortality rates in case reports and case series hindered a comparison between the mortality rate of single COVID‐19 infection and mucormycosis co‐infection. Furthermore, most studies were case reports or small case series that may introduce biases to the study, for example, they may report specific circumstances that occur rarely in the real world but are emphasized in case reports.

CONCLUSION

The mucormycosis co‐infection in COVID‐19 patients is of great concern as it raises mortality and delay diagnosis is probable in the setting of COVID‐19. In addition, the lung involvement caused by the COVID‐19 infection could often worsen by the mucormycosis fungal infection and the patient, therefore, has a higher risk of mortality or developing a serious medical condition. Furthermore, the diagnosis of mucormycosis co‐infection plays an important role in determining the patient's treatment plan, as corticosteroids, a treatment choice for COVID‐19, is simultaneously a risk factor for mucormycosis infection. To manage both infections at the same time, one may consider debridement of the tissue infected with mucormycosis, mechanical ventilation, and proper use of corticosteroids, which could be a challenge in cases of mucormycosis co‐infection; especially in critically ill patients with diffused lung involvement and receiving high doses of corticosteroids. To avoid the problems arising from mucormycosis, we should have the patients' hyperglycemia under control and use corticosteroid only when needed, and suspect the clinical findings pointing to a mucormycosis co‐infection earlier with the aim of a quicker diagnosis leading to a better prognosis.

Overall, we recommend considering the co‐infection with mucormycosis when the patient's symptoms do not completely match up with a single COVID‐19 infection, especially in those receiving corticosteroids as COVID‐19 treatment or else wise, patients with underlying co‐morbidities such as diabetes and immunocompromised patients. Avoiding high‐dose corticosteroids through the early stages of COVID‐19 would also help to prevent mucormycosis co‐infection. Finally, providing an early diagnosis of mucormycosis, through an adequate follow‐up of patients, who have recently received corticosteroids as COVID‐19 treatment, would give the physician an advantage in timely managing the patient.

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest

AUTHOR CONTRIBUTIONS

The conception and design of the study: Esmaeil Mehraeen, SeyedAhmad SeyedAlinaghi.

Methodology: Esmaeil Mehraeen, SeyedAhmad SeyedAlinaghi, Amirali Karimi.

Acquisition of data: Amirali Karimi, Alireza Barzegary, Zahra Pashaei.

Analysis and interpretation of data: Nazanin Janfaza, Alireza Shojaei, Fatemeh Afroughi, Parsa Mohammadi, Yasna Soleimani, Newsha Nazarian.

Writing—Original Draft Preparation: Amir Masoud Afsahi, Sanam Alilou, Nazanin Janfaza, Alireza Shojaei, Fatemeh Afroughi, Parsa Mohammadi, Yasna Soleimani, Newsha Nazarian, Ava Amiri, Marcarious M. Tantuoyir, Shahram Oliaei.

Writing—Review and Editing: SeyedAhmad SeyedAlinaghi, Omid Dadras.

Validation: Esmaeil Mehraeen, Omid Dadras, SeyedAhmad SeyedAlinaghi.

All authors have read and approved the final version of the manuscript. Esmaeil Mehraeen had full access to all of the data in this study and takes complete responsibility for the integrity of the data.

TRANSPARENCY STATEMENT

Esmaeil Mehraeen affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.