INTRODUCTION:

Corona virus or covid-19 is a type of acute respiratory syndrome with a viral agent from the family of viruses that has affected the whole world in a short period of time^1,2. Ever since December 2019, there has been a remarkable occurrence of viral pneumonia caused by an initially unidentified viral pathogen linked to a seafood-related wholesale market that emerged in Wuhan, Hubei Province, China.

The causative agent was promptly identified as a novel coronavirus (SARS-CoV-2), hence leading to the designation of coronavirus disease-19 (covid-19). Despite the global containment endeavors, the surge in cases persisted, disseminating to various other countries, and resulting in a widespread pandemic characterized by a significant mortality rate^1,2. To date, not enough attention has been given to the prevalence of fungal infections in patients afflicted with covid-19, particularly those who experience lymphocytopenia, are admitted to the intensive care unit (ICU), are given broad-spectrum antibiotics and corticosteroids, are intubated, experience cytokine storms, or have previous medical histories that significantly compromise their immune systems³. Consequently, these individuals face a notable susceptibility to developing mucosal candidiasis⁴. Oral candidiasis (OC) is an opportunistic infection that affects the oral mucosa. It is caused by a rise in virulence of normally innocuous yeasts from the Candida species under conditions that are both systemic and locally predisposing. The age of the patient, harmful behaviors, syndromic or genetic disorders, iatrogenic factors, and long-term systemic illnesses are the main extraneous conditions that are associated with this condition^5,6. On the other hand, oral candidiasis and an emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have recently been linked, and this finding demands more research. With more than 80% of cases, Candida albicans is thought to be the most common species that causes oropharyngeal candidiasis (OPC)^7,8. Nevertheless, other non-albicans species, such as C. tropicalis, C. glabrata, C. parapsilosis, Pichia kudriavzevii (=C. krusei), and C. dubliniensis, are also recognized for their involvement in this infection⁹. Untreated or ineffectively treated OPC may have a regional spread from the oropharynx to the esophagus or systemic dissemination through the bloodstream or upper gastrointestinal tract, leading to candidemia—a serious condition associated with significant morbidity and mortality—especially when it is caused by fluconazole-resistant Candida species or in individuals with weakened immune systems. Thus, early OPC diagnosis and accurate causal agent identification in covid-19 patients are essential for improving treatment approaches and improving clinical outcomes. As the most prevalent mucocutaneous mycosis affecting the oral cavity in severe instances of COVID-19, the possible development of OPC has not been well studied so far^9,10.

Literature Search and Selection:

A narrative review of the literature on vaccination in the context of oropharyngeal candidiasis (OPC) in the coronavirus disease-19 (covid-19) pandemic was carried out. Inclusion criteria encompassed articles written in English, available in full-text format, comprehensive, and directly relevant to the subject matter under investigation. A thorough search was conducted in PubMed and Scopus databases in October 2023, utilizing keywords associated with OPC/OC, oropharyngeal candidiasis,Candida albicans, Candida infection, covid-19, andsevere acute respiratory syndrome coronavirus 2 or SARS-Cov2. From the initial search, 145 articles were retrieved based on their titles, abstracts, and publication dates. After eliminating duplicate entries, a total of 54 distinct articles remained. The complete texts of these articles were carefully read, and a subset of 4 articles that were pertinent to the research question were selected.

SARS-Cov2 Virus and Immune System:

The multifarious pathogenicity of covid-19 is also associated with the virus's activation of the cytoplasmic NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, which may trigger immunological reactions in infected hosts^11,12. Interleukin (IL)-1β and IL-18 are pro-inflammatory cytokines that are generated when inflammatory cascades are activated by macrophages, epithelial cells, and maybe even endothelial cells. The pathogenic inflammation that contributes to covid-19 symptoms is increased by this mechanism¹³. Moreover, toll-like receptors (TLR) 3, TLR7, TLR8, and TLR9 recognize viral RNA and initiate the NF-κB pathway and several pro-inflammatory cytokines. An important part of the initial stages of virus-induced inflammation is played by this mechanism. There is no information available on the innate immune response, except for increased levels of cytokine storm and acute-phase reactants^14,15. With covid-19, fungus superinfections have been noted, with candidiasis being a significant consequence. Superinfections during covid-19. LPS, HKLM, A. fumigatus, and C. albicans were used in whole blood ex vivo incubation tests to study leukocyte phenotypes and cytokine responses. The commensal polymorphic fungus C. albicans preserves the activation capabilities, co-stimulatory, and antigen-presenting abilities of monocytes; nevertheless, stimulation has little effect on the ratios of monocyte subtypes in covid-19^16,17. On the other hand, in reaction to C. albicans, monocyte surface expression of co-stimulatory CD80 was considerably less elevated than in response to HC, suggesting that this fungus inhibited monocyte activation and decreased the co-stimulatory effects of CD80 on the adaptive immunological responses. Despite findings suggesting a generally reduced TLR response of the peripheral innate immune system from covid-19 patients, the compromised cytokine release profile lends credence to the idea of intact immune function in covid-19^16-18.

Candidiasis:

An opportunistic infection of the mouth cavity is called oral candidiasis. It affects many older people, especially those who wear dentures, and is frequently preventable with proper oral hygiene practices. It is a typical issue in those with impaired immune systems and may indicate a systemic condition such as diabetes mellitus. Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, and Candida krusei are the most significant ones^19,20. Oral candidiasis typically arises as a consequence of immune suppression, which may manifest at a local or systemic level²¹. Risk factors associated with the pathological colonization of Candida encompass a range of variables, including malnourishment, extremes of age (both young children and the elderly), metabolic disorders, conditions that compromise the immune system, concurrent viral or bacterial infections, exposure to radiation therapy, undergoing organ transplantation, prolonged use of steroids, administration of antibiotics, and decreased salivary gland function. The risk of oral candidiasis might be increased by impaired salivary gland function. Saliva secretion dilutes substances and eliminates microorganisms from the mucosa²². The most prevalent fungal infection in humans, particularly in early and later life, is oral candidiasis^23,
24. It has been shown that carriage rates vary from 20% to 75% in the general community without symptoms. 45% of newborns, 45%–65% of healthy children, 30%–45% of healthy adults, 50%–65% of people wearing removable dentures, 65%–88% of patients in acute and long-term care facilities, 90% of patients receiving chemotherapy for acute leukemia, and 13 and 95% of HIV patients have been found to have an isolated Candida albican infection in their mouths^25-27.

Prevalence of Oral Candidiasis in Adult and Pediatric Patients with COVID-19:

Disease severity has been correlated with different host factors. Detecting disease severity advancement and susceptibility to fungal infections at an early stage can aid in tailoring treatment approaches, ultimately resulting in improved outcomes^28,29. Oral transmission is regarded as a significant pathway for the transmission of covid-19. Saliva also serves as a means for detecting covid-19 infection. Cases of covid-19-associated fungal diseases, including oral candidiasis and invasive aspergillosis, have been brought to light by a recent study. The pathophysiology and immunological response to fungal superinfection and candidiasis associated with covid-19 are still poorly understood, which may account for the rising incidence rates that have been reported⁶. Candida albicans is a commensal fungus present in the oral cavity of nearly 40–65% of healthy adults but can cause opportunistic infections, particularly in cases of compromised immune systems^30,31. Several instances of oral candidiasis in individuals positive for SARS-CoV-2 have been documented in the literature. In individuals with covid-19 and oropharyngeal candidiasis, Candida albicans was the most frequently isolated species (70.7%), followed by C. glabrata (10.7%), C. dubliniensis (9.2%), C. parapsilosis (4.6%), C. tropicalis (3%), and C. krusei (1.5%)³².

A recent systematic review assessed the prevalence of oral manifestations in 4925 adults (>18 years) with SARS-CoV-2, revealing oral candidiasis in 10.74% of cases³³. A similar study involving 35 pediatric subjects (<18 years) identified oral candidiasis in 11.63% of cases⁶. An earlier study from Iran reported a lower prevalence of oral candidiasis among 1059 covid-19 patients, estimated at 5%. The treatment of covid-19 may necessitate the use of antibiotics or corticosteroids, which are frequently associated with the development of oral candidiasis³². Babamahmoodi et al. noted that covid-19 patients undergoing corticosteroid or antibiotic therapy exhibited a higher prevalence of candidiasis compared to SARS-CoV-2-positive patients not under pharmacological treatment^33-36. Salehi et al. arrived at analogous findings, pointing towards a correlation where 92.5% of oropharyngeal candidiasis instances in individuals with covid-19 were connected to the application of broad-spectrum antibiotics. Elderly individuals afflicted with chronic medical conditions, including arterial hypertension, diabetes, and cardiovascular ailments, exhibit an elevated susceptibility to the onset of both severe covid-19 and oropharyngeal candidiasis³². Specifically, individuals over the age of 50 who tested positive for SARS-CoV-2 were at a heightened risk of developing oral candidiasis, with lymphocytopenia (71%) being the most commonly linked predisposing factor⁶. Concerning denture wearers affected by covid-19, findings indicate that 60% of them also suffered from denture stomatitis, predominantly caused by strains of C. albicans²³. Individuals diagnosed with covid-19 exhibited decreased levels of zinc, as well as vitamins A, B6, C, D, and E. An underlying factor linked to oral candidiasis is inadequate nutrition, particularly deficiencies in vitamin A, B6, and iron^37,38. Paillaud et al. postulated a theory suggesting that deficiencies in these vitamins could disrupt the integrity of the oral mucosa, consequently facilitating the development of oral fungal colonization³⁹. Additionally, it is proposed that SARS-CoV-2 may trigger a direct cytopathic effect due to its ability to infiltrate oral epithelial cells utilizing angiotensin-converting enzyme 2 (ACE2) receptors present on oral epithelial and salivary gland ductal cells, thus inducing cellular apoptosis. The invasion of salivary glands by SARS-CoV-2 results in xerostomia, which is another predisposing factor for oral candidiasis owing to the diminished levels of histatin, calprotectin, and antifungal proteins like lysozyme or lactoferrin^40,41.

Upon review of the increasing amount of evidence on oral candidiasis in individuals with covid-19 as reported in prior studies, a total of 63 cases were observed. The majority of cases (84.1%) originated from the Middle East³², with smaller proportions from Europe (11.1%), Latin America (3.2%), and Africa (1.6%). Predominantly, female patients (56.7%) exhibited the condition compared to male patients (43.3%), with an average age of 59.5 years old. Treatment of these cases primarily involved hospitalization and administration of various medications, predominantly broad‐spectrum antibiotics like azithromycin, corticosteroids, hydroxychloroquine sulfate, and vitamin D, particularly in pediatric cases. The onset of oral candidiasis varied widely among patients, ranging from 1 to 30 days following the emergence of covid-19 symptoms. The majority of cases exhibited oral pseudomembranous candidiasis, characterized by a white plaque primarily on the tongue dorsum and oral mucosa⁴².

In a publication authored by Samaranayake et al. in 2022, it was observed that 8.7% of patients diagnosed with asymptomatic or mild covid-19 and 91.3% of those with moderate to severe covid-19 exhibited candidosis, aspergillosis, or mucormycosis. None of the individuals exhibited the simultaneous occurrence of two distinct mycoses in the oral cavity. Concerning the initiation of fungal infections, 95.8% (92 out of 96) experienced candidosis alongside their covid-19 symptoms, while 4.2% developed it during the convalescent phase following covid-19. The onset of candidosis ranged from several days to one month after the initial onset of covid-19 symptoms. All patients afflicted with candidosis were receiving treatment involving antibiotics, antivirals, and/or steroids. With regards to the sites of candida manifestations, the tongue was recognized as the most common location of infection, followed by the soft palate, oropharynx, and buccal/labial mucosa. Ultimately, all instances of candida infections were managed using either oral nystatin, miconazole, or systemic fluconazole therapy ⁴³. In 2020, Baraboutis et al. gathered data on 49 people who were infected with covid-19 over four weeks. The participants' ages ranged from 20 to 95 years old, with a median age of 63 years. Days 7–10 saw the onset of symptoms for "unexpected" oral candidiasis in two of the patients (no risk factors, such as recent antibiotic use or known immunosuppression) ⁴⁴ (Table 1).

Table 1: Characteristic of the patient infected with SARS-Cov2 who revealed Oral or Oropharyngeal Candidiasis

Study (country)	Age/sex	Underling Conditions	Fungal test	Treatment	Ref
Salehi et al (2020) (Iran)	Age range: 27 to 90 years Mean age: 63.1 years The Number of Males: 23 The Number of Females: 30	Cardiovascular diseases (52.83%); Diabetes (37.7%); Lymphopenia (71%); Chronic kidney diseases (20.7%); Hematological malignancies (9.4%)	C albicans (70.7%), C glabrata (10.7%), C dubliniensis (9.2%), C parapsilosis sensu stricto (4.6%), C tropicalis (3%) Pichia kudriavzevii (=C krusei, 1.5%).	Antiviral (53/53; 100%), Antibacterial (49/53; 92.5%); Antifungal (52/53; 98.1%); Methylprednisolone (18/53; 33.9%) Hydrocortisone (5/53; 9.4%); Dexamethasone (4/53; 7.5%). Fluconazole (21; 39.6%); Nystatin (13; 24.5%); Caspofungin( 1 ;1.8%);	32
Mahmoud A. et al(2022) (Egypt)	Mean age: 58.36 years The Number of Males: 25 The Number of Females: 14	NA	Candida albicans ; 74.36% Candida tropicalis; 15.38% Candida glabrata ; 10.26%	Macrolides (AZT: azithromycin); 38 (97.44%) Fluoroquinolones (LV: levofloxacin);3 (7.69%) Cephalosporins (CFX: cefotaxime);33 (84.62%) Oxazolidinones;4 (10.26%) AZT+ CFX;30 (76.92%) AZT-CFX-LZ;2 (5.13%) AZT-CFX-LV; 1 (2.56%)	8
Nobuhide Ohashi et al (2021)(Japan)	75-year-old man patient	Atrial fibrillation	Candida albicans	Oral combination of lopinavir/ritonavir (800 mg/200 mg/ day, twice daily) ciclesonide (800 µg/ day, twice daily) for 7 days	1
Federica Di Spirito et al (2022)(Italy)	Age range: 10 - 14 years Mean age: 5.98 The Number of Males: 20 The Number of Females: 15	Glucose-6-phosphate deficiency and MIS-C mimicking Kawasaki disease in a 13-year-old female; Dystonia and epilepsy in a 9-year-old male; Cryptorchidism in 15-day-old male	Oral candidiasis in 11.63%	IVIG in 7 studies; plasma therapy in 1 study; artificial ventilation in 3 studies; vitamin D supplementation in 1 study; antibiotics in 4 studies; antivirals in 3 studies; antiprotozoals in 1 study; antiemetics in 1 study ; monoclonal antibodies in 3 studies; FAS in 5 studies ; inotropic therapy in 2 studies ; anticoagulants in 3 studies ; antiaggregants in 1 study ; phosphodiesterase-III inhibitors in 1 study ;sympathomimetics in 1 study ; stem cell treatment in 1 study ; normal saline bolus in 1 study; parenteral nutrition in 1 study ; VV-ECMO in 1 study; unspecified creams for topical use in 1 study	33
Gianfranco Favia et al, (2021)(Italy)	Mean age: 72 The Number of Males: 70 The Number of Females: 53	NA	Candidiasis was noticed in 28 patients (22.7%)	Hyaluronic acid gel and chlorhexidine 2% mouthwash for 14 days Miconazole Nitrate twice Tranexamic acid for local hemorrhages	57
Mohammadreza Salehi et al (2021) (Iran)	Mean age: 61.2 The Number of Males: 61 The Number of Females: 43	Lung disease (10.5%) Cardiovascular disease (22.9%) Diabetes (44.8%) Liver cirrhosis (1%) Chronic kidney disease (4.8 %) Hematological malignancy (1.9%) Solid tumor (4.8%) Organ transplant (2.9%) Hypertension (45.7%) Hypothyroidism (2.9%)	Pseudomembranous candidiasis (77/105, 73.3%)	Chloroquine (71.4 % ), IVIG (11.4 %), Diuretic (21 %), Corticosteroid pulse therapy (42.9 %), Naproxen (12.4 %) Acetaminophen (13.3 %) Kaletra (25.7 %) Interferon (60 %) Atazanavir (60 %) Antibiotics (41.9 %) Vitamin C (13.3 %) Corticosteroid (47.6 %)	(7)
Abanoub Riad et al (2021)( Czech Republic)	70‐year‐old female 25‐year‐old female 56‐year‐old female patient	Diabetes mellitus type 2 and rheumatoid arthritis, geriatric depression, peripheral neuropathy, urinary incontinence, chronic constipation	Candidiasis	Azithromycin (Zithromax), levofloxacin (Uniloxam), rivaroxaban (Xarelto), and lactoferrin (Pravotin), nystatin (Micostatin), chlorhexidine 0.2%,miconazole (Daktarin Gel) moxifloxacin, pantoprazole (Zurcal), and multivitamins , fluconazole ,azithromycin (Zithromax)	(42)
Corchuelo et al (2020) (Colombi)	40-year-old female patient	NA	Candidiasis	Nystatin Oral Suspension, Chlorhexidine gluconate 0.12%, sodium hypochlorite solution, ibuprofen, vitamin D2, and azithromycin	(58)

covid-19 patients in the ICU are ten times more likely to develop secondary bacterial or fungal infections than secondary viral infections, as per Nambiar et al. Candida was found in nearly 78% of pulmonary samples from these patients⁴⁵. This could be because, as shown by Jerônimo et al., mechanical intubation can lead to aspiration of oral biofilm. In a previous study, 59.37% of intubated patients had both oral biofilm and tracheal aspirate with the same microbes. There was a 70% mortality risk, a 5.2% incidence of aspirated pneumonia, a 42.1% occurrence of ventilator-associated pneumonia (VAP), and candidemia in these cases⁴⁶. Many different types of fungi can create biofilms, and hyphal cells may play a role in this process. Filamentous hyphae and pseudohyphae in fungal biofilms may have similar roles in promoting metabolite exchange between biofilm cells. In addition to the study of fungal infection biology, one prominent factor contributing to recurring infections is the creation of biofilms on implanted medical devices^47,48. It has been proposed that the detoxification of reactive oxygen species (ROS) in biofilm cells requires an environment high in cysteine. Numerous hyphal growth regulators including HSP-90 are known to control the release of biofilm cells and build an extracellular matrix that is resistant to a wide range of antibiotics⁴⁹.

The Function of Medicines for Co-Infections with Candida in COVID-19 Patients:

Among the medications commonly used in the treatment of covid-19 are antiviral drugs, antimicrobial agents, anti-inflammatory medications (including corticosteroids, acetylsalicylic acid, and indomethacin), intravenous immunoglobulins, interferon, monoclonal antibodies, anticoagulants, and vitamins C, D, and zinc ⁵⁰. As expected, most instances of oropharyngeal candidiasis in covid-19 patients are associated with the use of broad-spectrum antibiotics, especially when provided on an empirical basis.There was also a significant correlation found between the use of steroids and the prevalence of Candida colonization. Steroid use has the potential to disturb the oral microbiome like that of chronic and broad-spectrum antibiotic use. Other oral microbiota microbes limit the growth of Candida under normal health conditions, but prolonged use of antibiotics or corticosteroids can promote oral candidiasis, which presents as thrush or, more frequently, acute erythematous candidiasis⁶. Additionally, saliva from those receiving antibiotic treatment showed elevated glucose levels; mean values were 7.41mg/100 mL, compared to 0.05 mg/100 mL in the control cohort⁵¹. Dexamethasone may also be internalized by Candida cells, which they then use to engage directly with surface receptors to improve adherence to oral mucosal cells. While Dogan et al. observed that 37.6% of children receiving inhaled corticosteroids for asthma therapy also acquired oral candidiasis⁵², Kuna et al. showed that oral candidiasis appeared in 10–30% of patients taking inhaled corticosteroids for prolonged periods. Reports of oral candidiasis in SARS-CoV-2-positive patients have been linked to ciclesonide therapy⁵³.

The excessive utilization of broad-spectrum antibiotics poses a significant risk for fungal superinfection, as it depletes the normal flora, creating a conducive environment for fungal growth. Initially, management strategies during the early phases of the pandemic involved the use of azithromycin due to its potential antiviral, anti-inflammatory, and IL-6-modulating properties⁵⁴. Additionally, other antibiotics like respiratory fluoroquinolones (moxifloxacin and levofloxacin), cephalosporins, and linezolid is occasionally prescribed. A previous study by Akhtar et al. argued against the routine use of azithromycin to hasten recovery time or reduce the risk of hospitalization^55,56. In the study in Egypt, oral swabs from oropharyngeal candidiasis patients revealed the presence of C. albicans (74.36%), C. tropicalis (15.38%), and C. glabrata (10.26%). Candida albicans was identified as the most prevalent strain among oropharyngeal candidiasis patients, consistent with previous findings. In this investigation, individual species exhibited elevated levels of susceptibility towards amphotericin and nystatin. Nevertheless, fluconazole demonstrated diminished efficacy against various strains of candida, and candida isolates revealed the presence of resistant strains³⁹.

FUTURE DIRECTIONS AND CONCLUSIONS:

Conducting thorough oral examinations can play a pivotal role in averting morbidity and improving long-term health outcomes through early detection and management of secondary oral fungal infections in covid-19 patients. Studies indicate an escalated likelihood of oral candidiasis in individuals during and after covid-19 infection, particularly in ICU patients requiring mechanical ventilation, with reduced saliva production, administration of broad-spectrum antibiotics, and intubation, all of which pose challenges to maintaining optimal oral hygiene. The occurrence of oral candidiasis in covid-19 patients is associated with both direct and indirect impacts of SARS-CoV-2, such as immune dysregulation, the viral influence on salivary gland cells expressing ACE2 receptors, and alterations in oral microbiota and immune suppression induced by covid-19 treatment. Furthermore, changes in dietary habits and oral hygiene practices during lockdown measures, coupled with heightened salivary glucose levels from corticosteroid usage, foster an oral environment conducive to opportunistic infections by promoting Candida growth, reducing salivary antimicrobial proteins, and facilitating dental biofilm formation. The covid-19 epidemic caused by SARS-CoV-2 has been linked to numerous bacterial and fungal coinfections. Among the common secondary oral fungal coinfections associated with covid-19 are aspergillosis, mucormycosis, and candidosis. While approximately half of the general population harbors oral Candida commensals, in specific circumstances—such as SARS-CoV-2 infection—these organisms can transition into opportunistic pathogens, precipitating localized and systemic diseases. Not solely attributable to lymphopenia in covid-19 patients, the increased susceptibility to oral candidiasis stems from various underlying mechanisms following reinfection with SARS-CoV-2.

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Received on 20.05.2024 Modified on 30.07.2024

Research J. Pharm. and Tech 2024; 17(11):5646-5652.

DOI: 10.52711/0974-360X.2024.00860