Abstract
Objectives
Studies reviewing orofacial mycoses in coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) infection are sparse. Here we review the major oral and maxillofacial mycoses of COVID-19, the associated comorbidities, and the probable precipitating factors.
Methods
English-language manuscripts published between March 2020 and October 2021 were searched using PubMed, OVID, SCOPUS, and Web of Science databases, using appropriate keywords.
Results
We identified 30 articles across 14 countries, which met the inclusion criteria of PRISMA guidelines. These yielded a total of 292 patients with laboratory-confirmed COVID-19, 51.4% (n = 150) of whom presented with oral and maxillofacial fungal infections, mainly comprising candidosis, mucormycosis, and aspergillosis. Candida infections were the most prevalent, present in 64% (n = 96), followed by mucormycosis, and only a single case of aspergillosis was noted. Oral and maxillofacial mycoses were predominantly seen in those with comorbidities, especially in those with diabetes (52.4%). Oral mucormycosis was noted in 8.6% (n = 13) and mainly manifested on the hard palate. An overall event rate of oral/maxillofacial mucormycosis manifestation in patients with COVID-19 with diabetes mellitus type 1/2 was about 94% (49/52; 95% confidence interval, 0.73%-0.89%), implying a very high association between diabetes mellitus and the latter condition. All fungal infections appeared either concurrently with COVID-19 symptoms or during the immediate recovery period.
Conclusions
SARS-CoV-2 infection–related immunosuppression, steroid therapy, as well as comorbidities such as diabetic hyperglycemia appear to be the major predisposing factors for the onset of oral and maxillofacial mycoses in patients with COVID-19 across all age groups.
Key words: Orofacial, Mycoses, COVID-19, Systematic review, Candidosis, Aspergillosis, Mucormycosis
Introduction
The coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a wide range of opportunistic bacterial and fungal coinfections.1 The triad of the most common secondary oral fungal coinfections seen in COVID-19 comprises candidosis, mucormycosis, and aspergillosis.2
Candida species are generally found as oral commensals in approximately one-half of the general population. They metamorphose into opportunistic pathogens when adverse conditions supervene, as in SARS-CoV-2 infection, causing both localised and systemic infections.3 COVID-19 itself and/or the associated contributory factors including corticosteroid therapy, lymphocytopenia, mechanical ventilator support, and other localised factors such as poor oral hygiene, xerostomia, and denture-wearing appear to favour Candida proliferation in the oral cavity.4
On the contrary, mucormycosis (previously called zygomycosis) is an uncommon, angio-invasive disease caused by the fungi belonging to the group of molds called mucormycetes. The most common species that cause mucormycosis are Mucor and Rhizopus species.5 They are rarely isolated in health from the oral cavity, and their usual transmission mode is through inhalation of fungal spores common in air and dust.6 Recent data suggest a number of possible reasons that facilitate germination of mucorales spores in patients with SARS-CoV-2 infection. These include hypoxic conditions, diabetes-related conditions, and/or steroid-induced hyperglycemia and ketoacidosis, immune suppression, and several other risk mediators such as prolonged hospitalisation and mechanical ventilation.7, 8, 9 In addition, numerous reports of oral and maxillofacial mucormycosis in patients with COVID-19, particularly from the Indian subcontinent, with devastating outcomes leading to blindness are now available.10 Recently, Singh et al7 in a comprehensive review of oral and maxillofacial mucormycoses reported more than 100 such cases in patients with COVID-19.
The last of the COVID-19–associated triad of common oral and maxillofacial mycoses is aspergillosis. Some studies note that as many as 15% of patients with COVID-19 hospitalised in an intensive care unit experience aspergillus infection.11 For instance, a German report observed COVID-19–associated invasive pulmonary aspergillosis in 5 of 19 (26.3%) patients with moderate to severe acute respiratory distress syndrome.12
Despite the relative commonality of oral and maxillofacial mycoses in COVID-19, there are no systematic reviews, to our knowledge, that specifically address the prevalence or aetiopathogenesis of these diseases, and there is a need for clinically relevant information. Therefore, the aim of this systematic review was to identify the prevalence, aetiopathogenesis, oral and maxillofacial manifestations, and management these infections either directly linked to COVID-19 per se or secondary to their treatment protocols.
Methods
Data sources
Three reviewers (L.P.S., K.S.F., and H.C.N.) executed an electronic data search using PubMed via OVID, SCOPUS, and Web of Science databases for the English-language manuscripts. Published reports were accessed between March 1, 2020, and October 1, 2021, to identify case series, observational studies, or case reports.
Study selection
Inclusion criteria
-
a.
Study design: Case series, case reports, observational studies
-
b.
Population: Laboratory-confirmed cases with asymptomatic, mild, moderate, or severe SARS-CoV-2 infection
-
c.
Setting: Any health care setting (hospitals, dental clinics) that provides consultation or treatment for SARS-CoV-2 infection
-
d.
Date or country enforced no limitations
Exclusion criteria
-
a.
Review articles
-
b.
Reports that present incomplete outcome details
-
c.
Studies evaluating systemic fungal coinfection without data on oral or maxillofacial yeast manifestation
-
d.
Studies that do not meet the set study objectives, grey literature, abstract only
Search terms
A particular search string was set up for each of the databases, which included the following search terms: COVID-19 OR coronavirus 19 OR novel coronavirus disease 19 OR nCoV-19 OR SARS-CoV-2 OR SARS-CoV-2 infection AND oral lesions OR oral manifestations OR oral fungal lesion OR oral yeast presentation OR oral mucormycosis OR oral black fungus OR oral aspergillosis OR orofacial manifestations OR orofacial fungal presentation OR orofacial yeast manifestation OR maxillofacial yeast manifestation AND mucormycosis AND Candida infection OR Candida infection AND aspergillosis.
Summary measure
The intended outcome was to review the prevalence, clinical presentation, temporality, and the likely etiology of oral and maxillofacial fungal coinfections in patients with COVID-19.
Electronic data search and analysis
The present review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for a systematic and comprehensive approach. During the first stage of the 3-staged electronic data search and analysis, 2 reviewers (L.P.S. and K.S.F.) examined the titles and abstracts of all published relevant reports that were in line with our set inclusion criteria. Next, a full-text review of all the related articles was performed to explore the data comprehensively during stage 2 of the review process. A detailed analysis of the full text of the selected literature ensured that the eligibility standards were met and the reported outcomes were in accordance with the preset outcome measures. In addition, references of the included reports were examined as a backward search. Finally, the reviewers (L.P.S. and K.S.F.) extracted and assessed the data during stage 2.
Upon completion of the full-text review, specific points linked to the characteristics of each individual included study were mapped and recorded. This assisted in classifying the study design, setting, intervention, and reporting jurisdiction. In addition, the sample size, assessment time, evaluation methods, and study conclusions were systematically analysed. Finally, the third reviewer (H.C.N.) cross-checked the data to validate its accuracy. Relevant reports with case presentations of oral and maxillofacial mucormycosis were evaluated. The frequency of occurrence of the mucormycosis manifestation amongst patients with COVID-19 with and without comorbid diabetic conditions was analysed with random-effects meta-analysis using a comprehensive meta-analysis tool (CMA v.3). The identified manuscripts were listed using a bibliographic software tool, Endnote version 20 (Clarivate Analytics). Summarised characteristics of the included reports are provided in Table 1.
Table 1.
Characteristics of the included studies with risk of bias assessment.
| Study(country) | Number of patients | Age/sex | Comorbid conditions | Fungal test | Oral-maxillofacial manifestationCandidosis | Oral-maxillofacial manifestationAspergillosis | Oral -maxillofacial manifestationMucormycosis | Risk of bias |
|---|---|---|---|---|---|---|---|---|
| Asymptomatic/mild COVID-19 cases | ||||||||
|
Corchuelo J et al 2020 (Colombia) |
1 | Female = 40 y | An atopic patient with mostly on analgesics and antibiotics | NM |
+ |
_ | _ | L |
|
Glavina A et al 2020 (Croatia) |
1 | Female = 40 y | None | NM |
+ |
_ | _ | M |
|
Mirabela D et al (2020) (Romania) |
3 | Neonates (n = 3) Female (n = 1) Male (n = 2) |
None | NM |
+ |
_ | _ | L |
|
Riad A et al (2020) (Czech Republic) |
1 | Female = 47 y | Mild hypothyroidism and on oral levothyroxine | NM |
+ |
_ | _ | L |
|
Diwakar J et al (2021) (India) |
2 | Male = 11 y Female = 13 y |
Type 1 diabetes mellitus | Fungal culture showing Rhizopus arrhizus | _ | _ |
+ |
L |
|
Pauli MA et al (2021) (Brazil) |
1 | Female = 50 y | Type 2 diabetes | Histopathologic findings confirmed mucormycosis | _ | _ |
+ |
L |
|
Revannavar SM et al (2021) (India) |
1 | Female (Middle-aged, age not specified) |
Uncontrolled type 2 diabetes without ketosis | Fungal culture-confirmed Rhizopus species | _ | _ |
+ |
M |
|
Saldanha M et al (2021) (India) |
1 | Female = 32 y | Uncontrolled type 2 diabetes | Histopathologic examination | _ | _ |
+ |
M |
|
Verma V et al (2021) (India) |
2 | Female = 44 y Male = 35 y |
Healthy patients | NM |
+ |
_ | _ | M |
|
Moderate/severe COVID-19 cases | ||||||||
|
Amorim dos Santos et al (2020) (Brazil) |
1 | Male = 67 y | Type 2 diabetes, hypertensive | Fungal culture |
+ |
_ | _ | L |
|
Baraboutis IG et al (2020) (Greece) |
49 patients, 2 of whom experienced a yeast infection | Female (n = 19) Male (n = 30) |
NM | NM |
+ |
_ | _ | L |
|
Díaz Rodríguez M et al 2020 (Spain) |
1 | Female = 78 y | NM | There was a burning mouth sensation and pain |
+ |
_ | _ | M |
|
Salehi et al (2020) (Iran) |
53 | Sex = NM Age = NM |
Cardiovascular diseases (52.83%), and type 2 diabetes (37.7%) | C albicans (70.7%); C glabrata (10.7%), C dubliniensis (9.2%), C parapsilosis (4.6%), C tropicalis (3%), and C krusei (1.5%) |
+ |
_ | _ | M |
|
Alekseyev K et al (2021) (US) |
1 | Male = 41 y | Type 1 diabetes mellitus | Fungal culture shows Rhizopus |
_ | _ |
+ |
L |
|
Ashour MM et al (2021) (Egypt) |
8 | Male (n = 5); ages 42-67 y Female (n = 3); ages 41-65 y |
Cases 1-2; 4, 5, 6, and 8: Uncontrolled type 2 diabetes mellitus Case 3: CRD Case 7: Uncontrolled diabetes mellitus, hypertension, and dialysis |
Case 1: histopathology and culture revealed invasive Aspergillus species Case 2-8: histopathology and culture shows Rhizopus |
_ |
+ |
+ |
L |
|
Bayram N et al (2021) (Turkey) |
11 | Female (n = 2) Male (n = 9) Mean age = 73.1 ± 7.7 y |
Eight patients had uncontrolled type 2 diabetes mellitus | NM | _ | _ |
+ |
L |
|
Dallalzadeh LO et al (2021) (US) |
2 | Male = 36 y Male = 48 y |
Type 2 diabetes | Fungal culture shows Rhizopus |
_ | _ |
+ |
L |
|
Favia G et al 2021 (Italy) |
123 |
Female (n = 53) Male (n = 70) Median age 72 y |
NM | Histopathology and culture |
+ |
_ | _ | L |
|
Farid HA et al (2021) (Iraq) |
1 | Male = 53 y | Uncontrolled type 2 diabetes on oral hypoglycemic Diabetic ketoacidosis at hospital admission |
Fungal culture consistent with mucormycosis | _ | _ |
+ |
L |
|
Karimi-Galougahi M et al (2021) (Iran) |
1 | Female = 61 y | No reported comorbidity | Histopathology and culture | _ | _ |
+ |
M |
|
Mahan KM et al (2021) (US) |
1 | Male = 13 y | Type 1 diabetes mellitus | NM | _ | _ |
+ |
M |
|
Mehta S et al (2020) (India) |
1 | Male = 60 y | Diabetic (on oral hypoglycemic) | _ | _ |
+ |
M | |
|
Mekonnen ZK et al (2021) (US) |
1 | Male = 60 y | Uncontrolled insulin-dependent diabetes, asthma, hypertension, hyperlipidaemia | Fungal cultures show Rhizopus species | _ | _ |
+ |
L |
|
Mishra N et al (2021) (India) |
10 | Female (n = 1) Male (n = 9) Age = 55.8 y (range = 37-78 y) |
Case 1-3: type 2 diabetes mellitus Case 4; CKD; Case 5: diabetes mellitus, hypertension, and IHD; Case 6: diabetes mellitus and CLD; Case 7: diabetes mellitus and hypertension; Case 8: diabetes mellitus, hypertension, hypothyroidism, and CKD; Case 9: diabetes mellitus and hypothyroidism; Case 10: no comorbidity |
Fungal culture consistent with mucormycosis | _ | _ |
+ |
L |
|
Mohammadi F et al (2021) (Iran) |
1 | Male = 59 y | Healthy | PCR test demonstrated Rhizopus oryzae | _ | _ |
+ |
M |
|
Riad A et al (2021a) (Czech Republic) |
3 | Female (n = 3) Case 1: 70 y Case 2: 25 y Case 3: 56 y |
Case 1: peripheral neuropathy, urinary incontinence, and vascular disease Case 2 & 3: healthy |
NM |
+ |
_ | _ | L |
|
Riad A et al (2021b) (Czech Republic) |
7 | Female (n = 2) Male (n = 5) |
Case 1, 2, and 5: diabetes mellitus Case 3, 4, and 6: diabetes mellitus with hypertension, CVD, stable angina Case 7: healthy |
RT-PCR | _ | _ |
+ |
L |
|
Veisi A et al (2021) (Iran) |
2 | Female (n = 1); age 40 y Male (n = 1); age 54 y |
Case 1: no comorbidity Case 2: well-controlled type 2 diabetes mellitus |
Histopathology and culture | _ | _ |
+ |
L |
|
Waizel Haiat S et al (2021) (Mexico) |
1 | Female = 24 y | Uncontrolled diabetes (severe diabetic ketoacidosis) | Direct exam (Sabouraud media isolating Lichteimia (Absidia) spp | _ | _ |
+ |
L |
|
Werthman-Ehrenreich A et al (2021) (US) |
1 | Female = 33 y | Hypertension and asthma | Fungal culture consistent with mucormycosis | _ | _ |
+ |
L |
CKD, chronic kidney disease; CLD, chronic liver disease; CRD, chronic renal disease; CVD, cardiovascular disease; IHD, ischemic heart disease; NM, not mentioned; PCR, polymerase chain reaction; RT-PCR, reverse transcription-polymerase chain reaction.
Joanna Briggs Institute critical appraisal tool for CR (Case Reports): low (L) risk of bias = >70% scores; moderate (M) risk of bias = scores between 50% and 69%; and high (H) risk of bias = scores <49%.
Quality and the overall risk of bias assessment of the included reports
During stage 3 of the systematic assessment of the available records, 2 reviewers (L.P.S. and K.S.F.) independently performed the quality valuation of the eligible studies employing the Joanna Briggs Institute Critical Appraisal Checklist for (i) case reports, (ii) case series, and (iii) analytical cross-sectional studies’ critical appraisal checklists.13 The third and fourth reviewers (Y.Y.L. and M.H.M.N.B.) were referred to in case of any conflict. They evaluated reports were recorded as low-, moderate-, or high-risk, as shown in Table 1. Any case reports or case series with a high risk of bias were omitted from the present review. All the involved reviewers discussed decisions based on the cumulative scores. The report was deemed low-risk when the “yes” score was ≥70%, moderate-risk, when the score was between 50% and 69%, and high-risk when the score was ≤49%.
Results
Of the 108 full texts reviewed, 30 reported cases or case series were included in the present review, and they represented a total of 292 patients with COVID-19, of whom only 150 had fungal manifestations14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 (Figure 1). These 30 articles met the PRISMA criteria and encompassed a single descriptive observational study, 6 case series, and 23 case reports.
Fig. 1.
PRISMA flowchart of the literature search and study selection.
All 150 patients with confirmed COVID-19 experienced one or more of the following predominant oral fungal infections: candidosis, aspergillosis, or mucormycosis (Table 1). These patients were either asymptomatic or presented with mild, moderate, or severe COVID-19. In addition, a significant age diversity was noted in the cohort, ranging from 3 COVID-19–positive neonates15 who experienced oral Candida infections to adults older than 75 years old with other mycoses. Interestingly, 3 children aged 11 to 16 years with insulin-dependent type 1 diabetes were noted with rhinocerebral mucormycosis.35,42
Of the cohort of patients with fungal infections, 92.6% (139/150) had comorbidities, with only a small minority without recorded comorbidity. The predominant comorbidity noted was diabetes mellitus, reported in 43.3% (65/150)21,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,35, 36, 37, 38,40, 41, 42 together with or without other comorbidities, such as cardiovascular diseases, renal ailments, and liver diseases. A few other patients exhibited an atopic immune condition,14 asthma,26,37 and mild hypothyroidism.16,38
Overall, 8.7% of patients with asymptomatic/mild COVID-19 and 91.3% with moderate to severe COVID-19 were affected by candidosis, aspergillosis, or mucormycosis. In addition, none of the patients displayed simultaneous oral coinfection with two different mycoses (Table 1).
In terms of the time of appearance of the fungal infections, 95.8% (92/96) experienced candidosis with their COVID-19 symptoms and 4.2% during the post–COVID-19 recovery period (Table 2). The time span of presentation of candidosis ranged from a few days to 1 month after initial COVID-19 symptom appearance. All patients with candidosis were on either antibiotic, antiviral, and/or steroidal therapy.
Table 2.
Oral and maxillofacial manifestation of (I) mucormycosis and (II) candidosis and their respective management modalities in the reviewed studies.
| I Mucormycosis | |||||||
|---|---|---|---|---|---|---|---|
| Study(No. of patients) | Ambulatory/hospitalised patient | Length of stay in the hospital | COVID-19 therapies | Symptoms at the time of presentation | Fungal manifestation (time of onset) | Mucormycosis manifestation | Treatment for fungal infection |
| Oral mucormycosis in asymptomatic/mild COVID-19 cases | |||||||
|
Pauli MA et al (2021) (n = 1) |
Quarantined patient for mild symptoms of SARS-CoV-2 infection | 1.5 months for the treatment of fungal infection | Antibiotics, NSAIDs, and tramadol for intense pain | A painful deep ulcerated lesion in the hard palate (near midline) | A week after COVID diagnosis | Mucormycosis in the hard palate | IV amphotericin B and hydrocortisone |
| Maxillofacial mucormycosis in asymptomatic/mild COVID-19 cases | |||||||
|
Diwakar J et al (2021) (n = 2) |
Ambulatory Post-COVID patients with hyperglycemia and diabetic ketoacidosis |
None | No exposure to systemic steroids or antibiotics |
Case 1: pain and swelling of an eye for a week with high-grade fever for 3 days Case 2: pain, swelling, and diplopia in the eye |
Mucormycosis manifestation at the time of COVID-19 diagnosis | Rhino-orbital-cerebral mucormycosis | Liposomal amphotericin B (LAMB) and systemic antibiotics |
|
Revannavar SM et al (2021) (n = 1) |
Ambulatory COVID-positive case with the history of type 2 diabetes | None | No exposure to systemic steroids or antibiotics | Complete ptosis and fever of short duration | Mucormycosis manifestation at the time of COVID-19 diagnosis | Left pansinusitis, ophthalmoplegia, and acute infarct in the left parieto-occipital region | Amphotericin B and antibiotics |
|
Saldanha M et al (2021) (n = 1) |
Ambulatory COVID-positive case with uncontrolled diabetes | None | No exposure to systemic steroids or antibiotics | Left eye ptosis and facial pain for 5 days | Mucormycosis manifestation at the time of COVID-19 diagnosis | Nose, paranasal sinus, and orbital apex mucormycosis | Amphotericin B |
| Oral mucormycosis in moderate/severe COVID-19 cases | |||||||
|
Alekseyev K et al (2021) (n = 1) |
Hospitalised | NM | Steroids and hydroxychloroquine IV insulin for diabetic ketoacidosis |
Ageusia, dry cough, deep aching pain in the nose radiating down to the throat | With COVID-19 diagnosis | Black eschar on the hard palate | Echinocandins and amphotericin B |
|
Ashour MM et al (2021) (n = 6) |
Hospitalised | 2 weeks to about a month | NM | Symptoms of SARS-CoV-2 infection | Amongst all cases, invasive fungal disease within 12–35 days from initial presentation of COVID-19 infection | In 6 patients, there was hard-palate involvement |
Case 1: amphotericin B and ambisome Case 2-8: amphotericin B |
|
Riad A et al (2021b) (Of n = 7, 1 has palatal mucormycosis involvement) |
Hospitalised | NM | NM | A painful lesion in the hard palate for 4 days, also fever and neurological symptoms | After recovery from COVID-19 infection | Case 1: ulcerative and necrotic lesion in the left side of the hard palate | Liposomal amphotericin B |
|
Veisi A et al (2021) (n = 2) |
Hospitalised | NM |
Case 1 and 2: Remdesivir and levofloxacin day 1-6 On day 7 IV dexamethasone |
Symptoms of SARS-CoV-2 infection | A week later of the COVID-19 infection, yeasts manifestation occurred | Case 1: black necrotic tissues in hard palate | Systemic amphotericin B |
|
Waizel Haiat S et al (2021) (n = 1) |
Hospitalised | NM | Imipenem/linezolid | Pain in the left midface region left lid edema with extension to the upper lip and malar area | With COVID-19 diagnosis | Pallor of hard palate mucosa | Amphotericin B |
|
Werthman-Ehrenreich A et al (2021) (n = 1) |
Hospitalised | 26 days | No exposure to systemic steroids or antibiotics | Altered mental status, left eye ptosis, afebrile, mild tachycardia, hypertension, and tachypnea | With COVID-19 diagnosis | Dry oral mucosa, with brown, dry secretion on the palate | Vancomycin and piperacillin-tazobactam with amphotericin B |
| Maxillofacial mucormycosis in moderate/severe COVID-19 cases | |||||||
|
Bayram N et al (2021) (n = 11) |
Hospitalised | 6 weeks | Broad-spectrum antibiotics and corticosteroids | Symptoms of SARS-CoV-2 infection | The mean time interval between COVID-19 symptom and fungal manifestation was 14.4 ± 4.3 days | 7 rhino-orbital and 3 patients of rhino-orbital-cerebral mucormycosis | IV and retrobulbar liposomal amphotericin B |
|
Dallalzadeh LO et al (2021) (n = 2) |
Hospitalised | NM |
Case 1: Antibiotics and corticosteroids Case 2: Remdesivir and IV dexamethasone |
Case 1: Atraumatic left facial swelling and sinusitis Case 2: COVID-19 pneumonitis. |
Case 2: Patient experienced diabetic ketoacidosis after COVID-19 therapy. On day 6, right periorbital edema with purulent discharge | Rhino-orbital-cerebral mucormycosis |
Case 1: amphotericin, isovuconazole, and micafungin Case 2: IV amphotericin B and isovuconazole |
|
Farid HA et al (2021) (n = 1) |
Hospitalised | 10 days |
Before hospital admission: Injectable steroids and antibiotics, without medical prescription At hospital admission: Favipiravir, anticoagulants, and antibiotics |
Symptoms of SARS-CoV-2 infection | After 2 days of hospital admission, the patient developed swelling around the right eye with ptosis and right-sided facial palsy | Rhinofacial-orbital-cerebral mucormycosis | Amphotericin B |
|
Karimi-Galougahi M et al (2021) (n = 1) |
Hospitalised | 2 weeks | Remdesivir, interferon-alpha, and systemic corticosteroid | Symptoms of SARS-CoV-2 infection | Readmitted for fungal infection after 1 week of hospital discharge Black eschar on the skin on the right lateral nasal wall and malar and periorbital regions |
Rhino-orbital-cerebral mucormycosis | Insulin (raised blood sugar without ketoacidosis) and systemic antifungals |
|
Mahan KM et al (2021) (n = 1) |
Hospitalised | NM | Vancomycin, cefepime, IV insulin, and azithromycin | Disoriented, hypothermic, hypotensive, hyperglycemic, with lips and nares featured dark crusting | Mucormycosis manifestation at the time of COVID-19 diagnosis | Rhinosinusitis, cerebral mucormycosis | Micafungin, isavuconazomiun |
|
Mehta S et al (2020) (n = 1) |
Hospitalised | 10 days | For COVID-19: IV meropenem and oral oseltamivir with parenteral methylprednisolone | Severe breathlessness, pyrexia, tachypnea, and generalised malaise | On the 10th day of hospitalisation, patient developed sinusitis, bilateral lid edema, and right-eye prominence | Rhinosinusitis, cerebral mucormycosis | Amphotericin B was added |
|
Mekonnen ZK et al (2021) (n = 1) |
Visit 1: Tested negative for SARS-CoV-2 given antibiotics for bronchitis At visit 2: Hospitalised, patient tested positive for SARS-CoV2 at 1 week |
31 days | Antibiotic for a week on suspicion of bronchitis After COVID-19 infection confirmation, remdesivir initially. Later, IV vancomycin, cefepime, and dexamethasone |
After one week, pt. presented with ARDS and hyperglycemia | 1 day after hospitalisation | Rhinosinusitis with orbital involvement | Antifungal (liposomal amphotericin B), caspofungin |
|
Mishra N et al (2021) (n = 10) |
Hospitalised | NM |
Cases 4-9: Steroid treatment Case 10: Both remdisivir and tocilizumab Cases 1, 2, 8 and 9: remdisivir |
Nasal blockage, eye, and facial pain | NM | Rhino-orbital-cerebral mucormycosis | IV amphotericin B |
|
Mohammadi F et al (2021) (n = 1) |
Visit 1: Hospitalised for SARS-CoV-2 infection | NM | Visit 1: Remdesivir and methylprednisolone |
Visit two: Nasal obstruction and left side facial and orbital swelling |
After 10 days of hospital discharge after COVID-19 treatment | Rhino-orbital-cerebral mucormycosis | IV liposomal amphotericin B |
|
Riad A et al (2021b) (Of n = 7, 6 cases had rhinocerebral mucormycosis) |
Hospitalised | 4-6 weeks | Azithromycin; dexamethosone; salbutamol; enoxaparin sodium; zinc | Symptoms of SARS-CoV-2 infection | From a few days to a month of COVID-19 diagnosis/recovery | Rhino-cerebral mucormycosis | Liposomal amphotericin B |
| II Candidosis | |||||||
|
Study (No. of patients) |
Ambulatory/hospitalised patient | Length of stay in the hospital | COVID-19 therapies | Fungal manifestation (Time of onset) | Oral fungal manifestation | Treatment for fungal infection | |
| Asymptomatic/mild COVID-19 cases | |||||||
|
Corchuelo J et al 2020 (n = 1) |
Ambulatory COVID case | None | Ibuprofen and azithromycin twice for 5 days (1st and 3rd week) | 3 weeks post–lab confirmation of COVID-19 infection | Whitish plaque at the back of the tongue and the attached gingiva near the first lower premolar | Nystatin for 2 weeks Use of CHX 0.12% |
|
|
Glavina A et al (2020) (n = 1) |
Ambulatory COVID case | None | Systemic acyclovir | After a week of COVID-positive symptoms | White lesion on the ventral side of the tongue | Local therapy with nystatin, panthenol, local anesthesia | |
|
Mirabela D et al (2020) (n = 3; neonatal cases) |
Case 1 and 2: asymptomatic but hospitalised for care Case 3: symptomatic and hospitalised |
2-3 weeks |
Case 1: vitamin D Case 2: vitamins, eye drops, topical cream for erythema Case 3: ampicillin, gentamicin, human immunoglobulins, aminophylline |
During hospitalisation | Oral candidosis on the tongue; erythematous lesions |
Case 1 and 2: topical nystatin Case 3: IV fluconazole and topical nystatin |
|
|
Riad A et al (2020) (n = 1) |
Ambulatory COVID case | None | Azithromycin, linezolid, and ceftriaxone | A few days post-SARS-CoV-2 infection | Multiple pseudo-membranous lesions with white plaques over the dorsal surface of the tongue | NM | |
|
Verma V et al (2021) (n = 2) |
Case 1 and 2: hospitalised with mild COVID-19 symptoms | A week for fungal infection | Case 1 and 2: antiviral therapy | Presented with dysphagia. Upon investigation, SARS-CoV-2 infection was confirmed |
Case 1: whitish patch on the back and lateral surface of the tongue Case 1: whitish patch on the dorsal surface of the tongue |
Case 1: oral fluconazole and antiviral Case 2: oral fluconazole and antiviral (remdesivir) |
|
| Moderate/Severe COVID-19 cases | |||||||
|
Amorim dos Santos et al (2020) (n = 1) |
Hospitalised | 24 days | Initially: hydroxychloroquine, ceftriaxone, and azithromycin. Later: meropenem, sulfamethoxazole, trimethoprim, immunosuppressants, and anticoagulants |
After 24 days of ICU admission, opportunistic fungal infection | The white plaque on the tongue dorsum | Systemic fluconazole and oral nystatin | |
|
Baraboutis IG et al (2020) (n = 2) |
Hospitalised | NM | Azithromycin, teicoplanin, dexamethasone | At 7-10 days of hospital admission | Oral candidosis | NM | |
|
Díaz Rodríguez M et al 2020 (n = 1) |
Hospitalised | NM | NM | Since hospital admission for SARS-CoV-2 symptoms | Pseudo-membranous candidosis and angular cheilitis | Nystatin for 2 weeks Use of CHX 0.12% |
|
|
Salehi et al (2020) (n = 53) |
Hospitalised | NM | Antiviral, antibacterial, and corticosteroids | During hospital stay for SARS-CoV-2 infection treatment | Oropharyngeal candidosis | Fluconazole, nystatin, and caspofungin | |
|
Favia G et al 2021 (Italy) |
Hospitalised | NM | Antiviral and cortisones | During hospital stay for COVID-19 treatment |
Moderate COVID: candidosis (18) Severe COVID: candidosis (4) Critical cases: candidosis (6) |
Miconazole nitrate | |
|
Riad A et al (2021) (n = 3) |
Case 1: hospitalised Case 2 and 3: home quarantined |
2-3 weeks |
Case 1: azithromycin, levofloxacin, rivaroxaban, and lactoferrin Case 2: moxifloxacin, pantoprazole, and multivitamins Case 3: azithromycin |
Case 1: 3 days after release from the hospital for COVID-19 treatment Case 2: 2 weeks Case 3: After 2 weeks |
Case 1: white membranous patches on the tongue dorsum, mouth floor, soft palate, oropharynx region, and buccal mucosa Case 2: erythematous candidosis on the tongue dorsum Case 3: white membranous patches on labial mucosa, soft palate, and tongue dorsum |
Case 1: nystatin and 0.2% CHX Case 2: topical miconazole Case 3: systemic fluconazole and topical miconazole |
|
ARDS, acute respiratory distress syndrome; CRD, chronic renal disease; CHX, chlorhexidine; ICU, intensive care unit; IV, intravenous; NM, not mentioned; NSAIDs, nonsteroidal anti-inflammatory drugs.
As for the sites of candidal manifestations, the tongue was the most common focus of infection, followed by the soft palate, oropharynx, and the buccal/labial mucosa (Figure 2). Finally, all the candidal infections were managed with oral nystatin, miconazole, or systemic fluconazole therapy (Table 2).
Fig. 2.
Schematic illustration of the reviewed data on oral-fungal manifestations related to COVID-19.
As regards oral mucormycosis, we noted 13 cases of the disease predominantly manifesting as pallor or dry palatal mucosa with dry brown secretion to brownish-black ulcerative necrotic lesions, mainly on the hard palate (Table 2). Three patients with mucormycosis presenting with oral lesions were simultaneously diagnosed with COVID-19 symptoms.25, 26, 27 In addition, a number of other cases were fortuitous, incidental findings when examined for moderate/severe SARS-CoV-2 infection.42, 43, 44
Furthermore, all moderate/severe cases of COVID-19 with the maxillofacial manifestation of mucormycosis were in hospitalised patients, mostly with comorbidities, and all were receiving systemic antibiotics, antiviral, and steroidal therapies for SARS-CoV-2 infection (Table 2). A noteworthy commonality amongst all patients with COVID-19 with oral/maxillofacial mucormycosis was their uncontrolled hyperglycemic condition. Thus, the overall event rate of mucormycosis was 94% (49/52; 95% confidence interval, 0.73%-0.89%) amongst patients with known diabetic type 1/2 conditions (Figure 3). The mucormycosis in the reviewed cohort was essentially managed with liposomal amphotericin B and surgical debridement of the necrotic tissue (Table 2). A single patient24 who had diabetes and mild COVID-19 presented with a painful deep-ulcerated lesion caused by Rhizopus species—belonging to the mucorales group. Additionally, only a single patient presented with histopathologically confirmed oral aspergillosis.
Fig. 3.
Prevalence and a 95% confidence interval of oral-maxillofacial mucormycosis manifestations in patients with/without type 1/2 diabetes comorbid conditions.
Discussion
Orofacial opportunistic mycotic coinfections are reported with increasing frequency at various stages of COVID-19. To our knowledge, the current review is the first report on the prevalence and aetiopathogenesis of the major opportunistic, mycotic coinfections specific to the orofacial region in laboratory-confirmed COVID-19 cases. The available data clearly indicate that such coinfections in COVID-19 are due to 3 major fungal groups, Candida spp, Aspergillus spp, and mucorales, a group of common zygomycotic fungi. These infections manifest with a spectrum of clinical presentations, ranging from erythematous and edematous mucosae to pseudo-membranous lesions and, on occasions, to extensive focal tissue necrosis involving the alveolar bone.
Candidosis
Oral candidosis due to several pathogenic candidal species is perhaps the commonest human fungal infections seen in debilitated individuals.43,44 C albicans, the most common agent of oral candidosis, as well as several non-albicans Candida species have been reported in our cohort of COVID-19 cases, especially in hospital-bound patients.20,23 In general, these manifestations could be explicable in terms of diabetic ketoacidosis that promotes yeast growth and lymphocytopenia, especially the T lymphocytes, due to SARS-CoV-2 infection. Other causative factors include the use of broad-spectrum antibiotics and steroid therapy and neglected and poor oral hygiene.45
It is known that oral candidal infections are common amongst the “very young, the very old, and the very sick”,44 and this aphorism has been, once again, proven to be the case in COVID-19. For instance, candidosis was present in 3 full-term neonatal patients with COVID-19 infection, with no history of receiving antibiotics.15 Characteristically, neonates exhibit immature cellular immune responses, resulting in increased susceptibility to infection,46 and this, together with the SARS-CoV-2 infection, are the likely causes for such manifestations. Nevertheless, more comprehensive studies are needed to better understand the oral mycoses of COVID-19 in the neonatal population.
Aspergillosis
It is now known that bronchopulmonary aspergillosis is the another common opportunistic systemic infection seen in COVID-19.47,48 In general, it is frequently seen in those who are immunosuppressed and may lead to life-threatening complications.49 A solitary case of aspergillosis with maxillary sinus invasion in a patient with uncontrolled diabetes with severe COVID-19 was noted in our review.29.
The disease usually ensues after inhalation of Aspergillus spores, and their subsequent germination and proliferation in the bronchopulmonary system.50 However, on occasions, the infection may manifest in nasal sinuses, the oral cavity, and the eyes.51 The most common agent of the disease known to cause invasive oral and maxillofacial lesions is A flavus.50 In the absence of a robust immune response, the angioinvasive hyphal elements of Aspergillus species usually cause thrombosis, leading to tissue infarction and necrosis. The other virulence traits of the fungus include the production of hemolysins, proteases, phospholipases, and the toxins, aflatoxin and gliotoxin.52, 53, 54
Mucormycosis
Mucorales that cause mucormycosis are common saprophytic fungi found in air, dust, and wet, organic materials.6 They cause infection predominantly in patients with poorly controlled diabetes mellitus or those who are immunocompromised due to disease or drugs. Hence, it is not surprising that the prevalence of mucormycosis has increased during the COVID-19 pandemic. Oral mucormycosis was reported in 7 reviewed cases of mild to moderate SARS-CoV-2 infection, and most of them involved patients with either controlled or uncontrolled diabetes.24, 25, 26, 27, 28, 29, 30 Their clinical presentation included malaise, facial pain, swelling, irregular black eschar, exudation of pus from the eye and nose, and low-grade fever.
As noted above, mucormycosis is the third most reported opportunistic fungal infection in patients with SARS-CoV-2 infection.55 It has 4 to 5 categories: rhinocerebral, cutaneous, disseminated, gastrointestinal, or pulmonary, depending on the infected tissues.56 Of these, rhinocerebral mucormycosis is relevant in the current context as it affects the oral cavity, sinuses, nasal passages, and brain. The infection usually begins in the nasal mucosa or palate and spreads via nearby vessels to the paranasal sinuses, often involving the maxillary and ethmoidal sinuses.57 Previous literature from the pre–COVID-19 era also indicates that rhinocerebral mucormycosis affects patients with poorly controlled diabetes and immunosuppressed patients.58 Many of the cases in our review had documented mucor invasion of cranial nerves III, IV, and VI, leading to ptosis, pupillary dilatation, proptosis, and vision loss. In addition, hematogenous spread to the cavernous sinus led to fatal cavernous sinus thrombosis in a few cases.59, 60, 61
In cases in which mucormycosis is suspected, prompt diagnosis and treatment are critical because of the angioinvasive nature of the fungus and its rapid systemic dissemination. A number of recent cases, particularly from the Indian subcontinent, report fungal invasion seeded in the maxillary sinus and progressing into maxillary alveolar bony tissues and then the oral cavity as well as the orbits, with eventual blindness of the individual.57 Late diagnosis of the disease with orbital invasion needs to be managed by radical surgery of the affected regions and removal of the orbital contents.
Apart from the Mucor genus, other disease-causing genera in this group include Rhizopus and Absidia.62,63 In the oromaxillofacial region, Mucor and Rhizopus species account for most of the oral and rhinocerebral mucormycosis in COVID-19 cases. In contrast, a single case from Mexico reported isolating Absidia (Lichteimia) spp (belonging to mucorales) from the biopsy of a young female patient with severe diabetic ketoacidosis secondary to steroidal therapy for COVID-19 treatment.27
In clinical terms, it should be noted that most oral mycoses in COVID-19 may present as innocuous red patches on the hard palate or the buccal mucosa, as shown by incidental findings in SARS-CoV-2 infection.42, 43, 44 However, as some of these lesions may lead to impairment of vision and/or even removal of the affected bony tissues and eventual disfigurement, all clinicians examining the oral cavity should maintain a high index of suspicion and be cognisant of the oral and maxillofacial mycoses that may pose a threat to the long-term health and the quality of life of these patients, particularly after recovery from SARS-CoV-2 infection. Indeed, oral and maxillofacial mycoses in COVID-19 could be construed as a little-known silent manifestation of the pandemic.
Study limitations
Our review has a few limitations. First is the disparate and heterogeneous nature of the reported cases emanating from various geographic locales, a significant proportion with limited and incomplete data. For instance, only a few case reports or case series included microbiological or histopathologic data of the fungal lesions confirming the diagnoses, and mere clinical observations were reported. In addition, most reports documenting oral candidosis did not elaborate on the species differentiation of Candida species. Additionally, it should be noted that the majority of fungal infections reported thus far have been diagnosed in hospitalised patients with severe COVID-19, and the data presented cannot be extrapolated for all patients with COVID-19 who mostly have mild symptoms.
Conclusions
Patients with SARS-CoV-2 infection are susceptible to oral fungal superinfections. The most likely reasons for this could be the impaired immune defenses due to the underlying viral infection, immunosuppressive and steroid therapy for COVID-19, ventilator-associated fungal infection, xerostomic conditions, and/or extant diabetes mellitus. Oral and maxillofacial mycoses, when present, appeared either concurrently with COVID-19 symptoms or during the immediate postrecovery period. Attending clinicians must maintain a high degree of suspicion of the possibility of these mycoses, particularly in patients with underlying comorbidities such as diabetes. A full and complete oral examination of patients with COVID-19 leading to early identification and treatment of secondary oral and maxillofacial mycoses can considerably reduce morbidity and improve their long-term health and quality of life.
Author contributions
All authors equally contributed to this work, through data computation and analysis, writing, and editing the manuscript. The final approval for publication was given by all authors after review of the final edited version of the manuscript.
Funding
No funding from any source was received for this research compilation.
Conflict of interest
None disclosed.
Footnotes
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.identj.2022.02.010.
Appendix. Supplementary materials
REFERENCES
- 1.Lai C-C, Wang C-Y, Hsueh P-R. Co-infections among patients with COVID-19: The need for combination therapy with non-anti-SARS-CoV-2 agents? J Microbiol Immunol Infect. 2020;53(4):505–512. doi: 10.1016/j.jmii.2020.05.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Samaranayake L, Fakhruddin KS, Bandara N. Oral manifestations of coronavirus disease 2019 (COVID-19): an overview. Dent Update. 2021;48(5):418–422. doi: 10.12968/denu.2021.48.5.418. [DOI] [Google Scholar]
- 3.Samaranayake L. 5th ed. Elsevier; Edinburgh: 2018. Essential microbiology for dentistry. [Google Scholar]
- 4.Jerônimo LS, Esteves Lima RP, Suzuki TYU, Discacciati JAC, Bhering CLB. Oral candidiasis and COVID-19 in users of removable dentures: is special oral care needed? Gerontology. 2022;68:80–85. doi: 10.1159/000515214. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Eucker J, Sezer O, Graf B, Possinger K. Mucormycoses. Mycoses. 2001;44(7-8):253–260. [PubMed] [Google Scholar]
- 6.Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. Clin Microbiol Rev. 2000;13(2):236–301. doi: 10.1128/CMR.13.2.236. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.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) doi: 10.1016/j.dsx.2021.05.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Rodriguez-Morales AJ, Sah R, Millan-Oñate J, et al. COVID-19 associated mucormycosis: the urgent need to reconsider the indiscriminate use of immunosuppressive drugs. Ther Adv Infect Dis. 2021;8 doi: 10.1177/20499361211027065. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.John TM, Jacob CN, Kontoyiannis DP. When uncontrolled diabetes mellitus and severe COVID-19 converge: the perfect storm for mucormycosis. J Fungi (Basel) 2021;7(4) doi: 10.3390/jof7040298. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Selarka L, Sharma S, Saini D, et al. Mucormycosis and COVID-19: an epidemic within a pandemic in India. Mycoses. 2021;64(10):1253–1260. doi: 10.1111/myc.13353. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Kuehn BM. Aspergillosis is common among COVID-19 patients in the ICU. JAMA. 2021;326(16):1573. doi: 10.1001/jama.2021.17973. [DOI] [PubMed] [Google Scholar]
- 12.Koehler P, Cornely OA, Böttiger BW, et al. COVID-19 associated pulmonary aspergillosis. Mycoses. 2020;63(6):528–534. doi: 10.1111/myc.13096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Moola S, Munn Z, Tufanaru C, et al. Chapter 7: Systematic reviews of etiology and risk. In: Aromataris E, Munn Z, editors. JBI Manual for Evidence Synthesis. JBI; 2020. Available from: https://synthesismanual.jbi.global. Accessed 28 March 2022.
- 14.Corchuelo J, Ulloa FC. Oral manifestations in a patient with a history of asymptomatic COVID-19: case report. Int J Infect Dis. 2020;100:154–157. doi: 10.1016/j.ijid.2020.08.071. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Dima M, Enatescu I, Craina M, Petre I, Iacob ER, Iacob D. First neonates with severe acute respiratory syndrome coronavirus 2 infection in Romania: three case reports. Medicine. 2020;99(33) doi: 10.1097/MD.0000000000021284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Riad A, Gad A, Hockova B, Klugar M. Oral candidiasis in non-severe COVID-19 patients: call for antibiotic stewardship. Oral Surg. 2020 doi: 10.1111/ors.12561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Baraboutis IG, Gargalianos P, Aggelonidou E, Adraktas A. Initial real-life experience from a designated COVID-19 centre in Athens, Greece: a proposed therapeutic algorithm. SN Compr Clin Med. 2020:1–5. doi: 10.1007/s42399-020-00324-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Glavina A, Biočina-Lukenda D, Mravak-Stipetić M, Markeljević J. Oral symptoms and lesions in SARS-CoV-2-positive patient. Oral Dis. 2020 doi: 10.1111/odi.13596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Verma V, Talwar D, Kumar S, Acharya S, Verma A. Oral candidiasis as rare complication of COVID-19: a case series. Med Sci. 2021;25(112):1397–1401. [Google Scholar]
- 20.Favia G, Tempesta A, Barile G, et al. Covid-19 symptomatic patients with oral lesions: clinical and histopathological study on 123 cases of the University Hospital Policlinic of Bari with a purpose of a new classification. J Clin Med. 2021;10(4) doi: 10.3390/jcm10040757. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Amorim Dos Santos J, Normando AGC, Carvalho da Silva RL, et al. Oral mucosal lesions in a COVID-19 patient: new signs or secondary manifestations? Int J Infect Dis. 2020;97:326–328. doi: 10.1016/j.ijid.2020.06.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Díaz Rodríguez M, Jimenez Romera A, Villarroel M. Oral manifestations associated with COVID-19. Oral Dis. 2020 doi: 10.1111/odi.13555. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Salehi M, Ahmadikia K, Mahmoudi S, et al. Oropharyngeal candidiasis in hospitalised COVID-19 patients from Iran: species identification and antifungal susceptibility pattern. Mycoses. 2020;63(8):771–778. doi: 10.1111/myc.13137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Pauli MA, Pereira LdM, Monteiro ML, de Camargo AR, Rabelo GD. Painful palatal lesion in a patient with COVID-19. Oral Surg Oral Med Oral Pathol Oral Radiol. 2021;131(6):620–625. doi: 10.1016/j.oooo.2021.03.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Alekseyev K, Didenko L, Chaudhry B. Rhinocerebral mucormycosis and COVID-19 pneumonia. J Med Cases. 2021;12(3):85–89. doi: 10.14740/jmc3637. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Werthman-Ehrenreich A. Mucormycosis with orbital compartment syndrome in a patient with COVID-19. Am J Emerg Med. 2021;42:264. doi: 10.1016/j.ajem.2020.09.032. e5–e8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Waizel-Haiat S, Guerrero-Paz JA, Sanchez-Hurtado L, Calleja-Alarcon S, Romero-Gutierrez L. A case of fatal rhino-orbital mucormycosis associated with new onset diabetic ketoacidosis and COVID-19. Cureus. 2021;13(2):e13163. doi: 10.7759/cureus.13163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Veisi A, Bagheri A, Eshaghi M, Rikhtehgar MH, Rezaei Kanavi M, Farjad R. Rhino-orbital mucormycosis during steroid therapy in COVID-19 patients: a case report. Eur J Ophthalmol. 2021 doi: 10.1177/11206721211009450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Ashour MM, Abdelaziz TT, Ashour DM, Askoura A, Saleh MI, Mahmoud MS. Imaging spectrum of acute invasive fungal rhino-orbital-cerebral sinusitis in COVID-19 patients: a case series and a review of literature. J Neuroradiol. 2021;48(5):319–324. doi: 10.1016/j.neurad.2021.05.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Riad A, Shabaan AA, Issa J, et al. COVID-19-associated mucormycosis (CAM): case-series and global analysis of mortality risk factors. J Fungi (Basel) 2021;7(10):837. doi: 10.3390/jof7100837. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Dallalzadeh LO, Ozzello DJ, Liu CY, Kikkawa DO, Korn BS. Secondary infection with rhino-orbital cerebral mucormycosis associated with COVID-19. Orbit. 2021:1–4. doi: 10.1080/01676830.2021.1903044. [DOI] [PubMed] [Google Scholar]
- 32.Bayram N, Ozsaygılı C, Sav H, et al. Susceptibility of severe COVID-19 patients to rhino-orbital mucormycosis fungal infection in different clinical manifestations. Jpn J Ophthalmol. 2021;65(4):515–525. doi: 10.1007/s10384-021-00845-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Farid HA, Hashim AR, Hasrat NH. Rhinocerebral mucormycosis as a COVID-19-related complication: a case report from Basra City, Southern Iraq. J Glob Sci Res. 2021;6(5):1369–1374. [Google Scholar]
- 34.Karimi-Galougahi M, Arastou S, Haseli S. Fulminant mucormycosis complicating coronavirus disease 2019 (COVID-19) Int Forum Allergy Rhinol. 2021;11(6):1029–1030. doi: 10.1002/alr.22785. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Mahan KM, Molina MF, Coffey ECC, Manchanda ECC. New-onset pediatric diabetes complicated by diabetic ketoacidosis and invasive rhinocerebral mucormycosis with internal carotid artery occlusion. J Emerg Med. 2022;62(1):95–100. doi: 10.1016/j.jemermed.2021.07.024. [DOI] [PubMed] [Google Scholar]
- 36.Mehta S, Pandey A. Rhino-orbital mucormycosis associated with COVID-19. Cureus. 2020;12(9):e10726. doi: 10.7759/cureus.10726. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Mekonnen ZK, Ashraf DC, Jankowski T, et al. Acute invasive rhino-orbital mucormycosis in a patient with COVID-19-associated acute respiratory distress syndrome. Ophthalmic Plast Reconstr Surg. 2021;37(2):e40–e80. doi: 10.1097/iop.0000000000001889. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Mishra N, Mutya VSS, Thomas A, et al. A case series of invasive mucormycosis in patients with COVID-19 infection. Int J Otorhinolaryngol Head Neck Surg. 2021;7(5) [Google Scholar]
- 39.Mohammadi F, Badri M, Safari S, Hemmat N. A case report of rhino-facial mucormycosis in a non-diabetic patient with COVID-19: a systematic review of literature and current update. BMC Infect Dis. 2021;21(1):906. doi: 10.1186/s12879-021-06625-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Saldanha M, Reddy R, Vincent MJ. Paranasal mucormycosis in COVID-19 patient. Indian J Otolaryngol Head Neck Surg. 2021:1–4. doi: 10.1007/s12070-021-02574-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Revannavar SM, SS P, Samaga L, VK V. COVID-19 triggering mucormycosis in a susceptible patient: a new phenomenon in the developing world? BMJ Case Rep. 2021;14(4) doi: 10.1136/bcr-2021-241663. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Diwakar J, Samaddar A, Konar SK, et al. First report of COVID-19-associated rhino-orbito-cerebral mucormycosis in pediatric patients with type 1 diabetes mellitus. J Mycol Med. 2021;31(4) doi: 10.1016/j.mycmed.2021.101203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Akpan A, Morgan R. Oral candidiasis. Postgrad Med J. 2002;78(922):455–459. doi: 10.1136/pmj.78.922.455. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Samaranayake LP, MacFarlane TW. Oral candidosis. London: Wright; 1990.
- 45.Ng S. Managing patients with oral candidiasis. J Can Dent Assoc. 2013;79:d122. [PubMed] [Google Scholar]
- 46.Garcia AM, Fadel SA, Cao S, Sarzotti M. T cell immunity in neonates. Immunol Res. 2000;22(2-3):177–190. doi: 10.1385/ir:22:2-3:177. [DOI] [PubMed] [Google Scholar]
- 47.Hartwick RW, Batsakis JG. Sinus aspergillosis and allergic fungal sinusitis. Ann Otol Rhinol Laryngol. 1991;100(5,):427–430. doi: 10.1177/000348949110000515. pt 1. [DOI] [PubMed] [Google Scholar]
- 48.Mitaka H, Kuno T, Takagi H, Patrawalla P. Incidence and mortality of COVID-19-associated pulmonary aspergillosis: a systematic review and meta-analysis. Mycoses. 2021;64(9):993–1001. doi: 10.1111/myc.13292. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Samaranayake LP, Leung WK, Jin L. Oral mucosal fungal infections. Periodontol 2000. 2009;49(1):39–59. doi: 10.1111/j.1600-0757.2008.00291.x. [DOI] [PubMed] [Google Scholar]
- 50.Dreizen S, Keating MJ, Beran M. Orofacial fungal infections. Nine pathogens that may invade during chemotherapy. Postgrad Med. 1992;91(5) doi: 10.1080/00325481.1992.1170129. 349–50, 53–4, 57–60 passim. [DOI] [PubMed] [Google Scholar]
- 51.Emmanuelli JL. Infectious granulomatous diseases of the head and neck. Am J Otolaryngol. 1993;14(3):155–167. doi: 10.1016/0196-0709(93)90024-2. [DOI] [PubMed] [Google Scholar]
- 52.Denning DW. Invasive aspergillosis. Clin Infect Dis. 1998;26(4) doi: 10.1086/513943. 781–803; quiz 4–5. [DOI] [PubMed] [Google Scholar]
- 53.Kamei K, Watanabe A. Aspergillus mycotoxins and their effect on the host. Med Mycol. 2005;43(suppl 1):S95–S99. doi: 10.1080/13693780500051547. [DOI] [PubMed] [Google Scholar]
- 54.Pennerman KK, Yin G, Glenn AE, Bennett JW. Identifying candidate Aspergillus pathogenicity factors by annotation frequency. BMC Microbiol. 2020;20(1):342. doi: 10.1186/s12866-020-02031-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Rabagliati R, Rodríguez N, Núñez C, Huete A, Bravo S, Garcia P. COVID-19–associated mold infection in critically ill patients. Chile. Emerg Infect Dis. 2021;27(5):1454. doi: 10.3201/eid2705.204412. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Spellberg B, Edwards J, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Microbiol Rev. 2005;18(3):556–569. doi: 10.1128/CMR.18.3.556-569.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Rapidis AD. Orbitomaxillary mucormycosis (zygomycosis) and the surgical approach to treatment: perspectives from a maxillofacial surgeon. Clin Microbiol Infect. 2009;15:98–102. doi: 10.1111/j.1469-0691.2009.02989.x. [DOI] [PubMed] [Google Scholar]
- 58.Safder S, Carpenter JS, Roberts TD, Bailey N. The “black turbinate” sign: an early MR imaging finding of nasal mucormycosis. Am J Neuroradiol. 2010;31(4):771. doi: 10.3174/ajnr.A1808. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Chikley A, Ben-Ami R, Kontoyiannis DP. Mucormycosis of the central nervous system. J Fungi. 2019;5(3) doi: 10.3390/jof5030059. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Sandron J, Hantson P, Duprez T. Intracranial brain parenchymal spread of mucormycosis through olfactory tract: a diffusion-weighted imaging-based concept. Acta Radiologica Open. 2020;9(12) doi: 10.1177/2058460120980999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Galletti B, Gazia F, Galletti C, et al. Rhinocerebral mucormycosis with dissemination to pontine area in a diabetic patient: treatment and management. Clin Case Rep. 2019;7(7):1382–1387. doi: 10.1002/ccr3.2255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Auluck A. Maxillary necrosis by mucormycosis. a case report and literature review. Med Oral Patol Oral Cir Bucal. 2007;12(5):E360–E364. [PubMed] [Google Scholar]
- 63.Walther G, Wagner L, Kurzai O. Updates on the taxonomy of mucorales with an emphasis on clinically important taxa. J Fungi (Basel) 2019;5(4) doi: 10.3390/jof5040106. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.