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REVIEW ARTICLE
Year : 2022  |  Volume : 49  |  Issue : 2  |  Page : 106-113

Predisposing factors of mycotic infections in COVID-19 patients


1 Department of Medicine, Datta Meghe Institute of Medical Sciences (Deemed to be University), Jawaharlal Nehru Medical College, Wardha, Maharashtra, India
2 Department of Pathology, Datta Meghe Institute of Medical Sciences (Deemed to be University), Jawaharlal Nehru Medical College, Wardha, Maharashtra, India
3 Department of Community Medicine, Datta Meghe Institute of Medical Sciences (Deemed to be University), Jawaharlal Nehru Medical College, Wardha, Maharashtra, India

Date of Submission14-Feb-2022
Date of Acceptance19-Apr-2022
Date of Web Publication23-Aug-2022

Correspondence Address:
Satyam Singh
Datta Meghe Institute of Medical Sciences (Deemed to be University), Jawaharlal Nehru Medical College, Sawangi, Meghe, Wardha - 442 004, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jss.jss_31_22

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  Abstract 


The coronavirus disease 2019 pandemic (COVID-19) has led to considerable hike in hospitalizations for pneumonia with multiorgan disease requiring immediate hospital care, maintenance of oxygen saturation level, and severe cases requiring mechanical ventilation. This opens the window of opportunity to microscopic organisms such as different species of fungus including Candida, Aspergillus, Rhizopus, and Cryptococcus adding other fungi causing opportunistic invasive fungal infections (OIFIs), and other bacteria to cause concurrent infections in COVID-19-diseased patients which on occasion not promptly diagnosed and are mostly diagnosed after death, which get chance due to invasive procedures such as intubation and immunosuppressant drugs which mostly consists of corticosteroids, patient with diabetes mellitus or any other chronic disease causing immunosuppression, patient having a history of chronic obstructive airway disease, development of antibiotic resistance, and vulnerability of pulmonary tissues regarding developing colony for mycotic infections. In this review, we talk over the character of mycotic concurrent infections in aggravation of COVID-19 disease severity and focus on arising trends associated with fungal infections in coronavirus-diseased (COVID-19 diseased) cases. In addition, this review impart the view on the risky component for concurrent mycotic infections in COVID-19 diseased patients who are hospitalized and focuses the possible task of extended immunemodulatory treatments in managing concurrent mycotic infections, comprising COVID-19-associated pulmonary aspergillosis, COVID-19-associated Candidiasis, and mucormycosis. This article restates the demand for prompt detection regarding presumed COVID-19-related systematic mycosis in the health-care settings which could empower fast OIFI diagnosis, treatment, and lowers the mortality rate.

Keywords: Aspergillosis, candidiasis, COVID-19, mucormycosis


How to cite this article:
Singh S, Acharya S, Shukla S, Muneshwar K. Predisposing factors of mycotic infections in COVID-19 patients. J Sci Soc 2022;49:106-13

How to cite this URL:
Singh S, Acharya S, Shukla S, Muneshwar K. Predisposing factors of mycotic infections in COVID-19 patients. J Sci Soc [serial online] 2022 [cited 2022 Oct 6];49:106-13. Available from: https://www.jscisociety.com/text.asp?2022/49/2/106/354268




  Introduction Top


A pattern of acute atypical pulmonary infection struck the Wuhan in China in the latter month of 2019. This quickly spread to the other parts of the country. The culprit behind such unusual infections was found a novel coronavirus affiliated with the Coronaviridae family, which was dubbed SARS coronavirus-2 (SARS-CoV-2).[1],[2] Pulmonary infection caused due to this virus is designated as coronavirus disease 2019 or straightforwardly COVID-19 by the World Health Organization. Subsequently, transfer from person to person was discovered to be the cause of this disease's advancement in the community, with cases identified across >200 nations on the globe.

Coronavirus disease (COVID-19) was eventually declared as the pandemic on March 11, 2020.[3],[4],[5],[6]

In this review, we emphasize growing trends in fungal disease burden and antibiotic resistance in the coronavirus-diseased (COVID-19) patients, as well as significance related to mycotic co-infections in worsening coronavirus disease (COVID-19 illness) severity. We investigate whether immunomodulatory and/or immunosuppressive medications are to blame for the increased incidences of concurrent mycotic infections seen in coronavirus-diseased (COVID-19) patients.


  Symptoms of Coronavirus Disease Top


The coronavirus causes extended the array of clinical manifestations, the most noticeable are respiratory difficulties among severe instances.[7]

Such severe instances necessitate immediate hospital assistance, which includes oxygenation and mechanical ventilation. Other issues, such as nosocomial infection with opportunist microorganisms counting yeast and molds infection may arise among these patients.[8],[9],[10],[11],[12] However, limited gaps in combating the virus and its associated disorders have resulted in a massive increase in fatalities from less important microbes, i.e., fungus/bacterial infection. Aspergillus causes aspergillosis, candidiasis caused by Candida auris, cryptococcosis caused by Cryptococcus, histoplasma causes histoplasmosis, and blastomycosis are among of the most frequent fungal diseases linked to the COVID-19.

Acinetobacter baumannii and Staphylococcus aureus bacteria which are resistant to extended-spectrum antibiotic are found in COVID-19-infected patients.

Minimum 20 distinct fungus species have been identified among COVID-19 patients who are admitted in health-care settings.

Cunninghamella bertholletiae; Rhizomucor; Apophysomyce; Saksenaea; Syncephalast-rum species; Rhizopus arrhizus; Lichtheimia; Rhizopus oryza;

Candida albicans, C. auris, Candida glabrata, Candida parapsilosis, Candida tropicalis, C. glabrata, Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, and Aspergillus niger.


  COVID-19 Disease, Mucormycosis, and Concurrent Mycological Infections: Severity of Disease, the Development of Multidrug Resistance Top


Endowment to COVID-19 disease severity and mortality

Patients infected with coronavirus disease (COVID-19 disease) and hospitalized in intensive care units (ICUs) in the hospital are sensitive to invasive microbial co-infections during hospitalization, according to prospective and retrospective studies, and these infections may result in more severe outcomes.[8],[12],[13],[14]

According to a cohort study conducted prospectively among 135 individuals done across several locations in Wales, mortality rate was remarkably elevated (up to 25%) among coronavirus-infected (COVID-19 infected) patient with mycotic infection than COVID-19 patient not infected with fungus.[12]

According to a research conducted across more than one medical or research institution involving 108 COVID-19 patient hospitalized in ICUs in Italy, individuals with likely COVID-19-associated pulmonary aspergillosis (CAPA) or putative invasive pulmonary aspergillosis had a considerably elevated 30-day mortality rate than patient without doubting aspergillosis.[11]

In the same way, Meijer et al.[15] studied that in Brazil, 40%–50% of mortality rate was recorded during the first wave of coronavirus disease (COVID-19) (March–April 20) among patients infected with CAPA and 2nd wave (mid-September–mid-December 20) of COVID-19 pandemic.

Although in comparison to CAPA, the incidence rates of COVID-19-associated candidiasis (CAC) may be marginally less, while the COVID-19 patient infected with candidemia, mortality rate does not seem to be vary significantly.

According to the reports obtained from Italy, COVID-19-infected patients with Candida infection in blood, i.e., candidemia and C. auris candidemia[16] experienced mortality rate up to 57.1% and 50%,[17] respectively.

Somewhere else in Iran, COVID-19 patients with candidemia died at a greater rate than COVID-19 patients died in the absence of candidemia (100% vs. 22.7%).[14]

Overall, our data underscore and re-emphasizes the risk of concurrent fungal infection worsening severity of illness and as a result, increasing the mortality of patient with critical illness hospitalized in ICU.

Fungus adventing multidrug resistance

Multidrug-resistant microorganisms are becoming more common, which is a concerning trend.

A. fumigatus[18] and C. auris,[16],[19],[20] additionally pan-echinocandin-resistant C. glabrata among coronavirus-diseased (COVID-19) patients.[21]

C. auris is a fungus with resistance to multidrug causing fatal systemic infection with 35% fatality rate after 30 days[22],[23],[24] and 60% of COVID-19 patient infected with C. auris which is multidrug-resistant died due to candidemia, according to an Indian report.[19]

Controlling candidemia outbreaks generated by C. auris is difficult because of its resistant nature to numerous treatments and persistent inside the body of human and environment.[25],[26]

Suarez-de-la-Rica et al.[27] COVID-19 prognosis has been discovered to be influenced by co-infections with antimicrobial-resistant organisms.

In their investigation, antimicrobial resistance bacteria increased the risk ratio regarding mortality in COVID-19 patients who are severely sick within 90 days.

As a result, report regarding the emergence of multidrug-resistant antifungals, particularly pan-echinocandin, is alarming, because antifungal resistance thwarts treatment attempts and raises treatment costs.

In addition, these investigations focus on the necessity of determining the worldwide prevalence of concurrent mycotic infections in the on-going pandemic of COVID-19, as well as the detection and treatment of fungal pathogen in COVID-19 patient who are hospitalized.

Incidence of mucormycosis

According to the new statistics from India, mucormycosis is common among the survivors of COVID-19-infected patient (in spite of the fact that it has also been studied in currently admitted COVID-19 patients).[28],[29],[30],[31]

Mucormycosis is infrequent mycotic infections which have causative agent filament-fungus (molds) belong to the order Mucorales. This might be lethal if the fungal infects reaches to the central nervous system.[32],[33]

The chief causative envoy of COVID-19-associated mucormycosis (CAM) in India is R. arrhizus, according to one study, with other species of Rhizopus, i.e., Rhizopus microsporus, Rhizopus homothallicus; other fungus also involved in some cases in India and elsewhere are Mucor irregularis, Saksenaea erythrospora, and Apophysomyces variabilis.[34],[35],[36]

Diabetic patients, immunocompromised individuals, and those using immunosuppressive drugs are reported to be more prone for Mucormycosis infection.[33],[37]

According to a recent systematic investigation, regarding India and globally, corticosteroids were utilized in 76.3% of patients with mucormycosis and fatality percentage of mucormycosis is 30.70% that were fatal.[38]

This fact is unknown that either the prevalence of CAM is global at this time and further research is needed in this area.

Overall, the findings of this study and others suggest that in India, increased prevalence of mucormycosis is linked to a number of risk-factor, counting poorly controlled diabetic patients, and long-term COVID-19 therapy with high-dose steroids.


  Outline of Risk Factors regarding Opportunistic Mycotic Infection in COVID-19 Patients Who Are Severely Ill Top


Altogether, intrusive procedures (e.g., intubation),[39],[40],[41] history of chronic respiratory disease,[12] long-term corticosteroid treatment,[12],[42] immunological constitution of patient, and antimicrobial treatment[21],[26] predispose lung tissues to fungal colonization and growth, which are associated with a high frequency regarding Aspergillus infection and Candidemia in coronavirus-diseased (COVID-19-infected) patient.

A contrasting study regarding concurrent infection in severely diseased patient with and with-out coronavirus diseased (COVID-19 infections), the demand for intrusive assisted breathing was revealed to be the highly important risk for concurrent infection along with anti-mycotic-resistant bacteria in patient with severe coronavirus disease (COVID-19 infection).[39]

The following sub-divisions given below, the risk factors connected to CAPA and CAC are the two frequently reported concurrent mycotic infection in COVID-19 admitted patient are described.

Perilous agent for COVID-19-associated pulmonary aspergillosis

Case criteria for CAPA were devised to provide uniformity for reporting across medical practices, given the high frequency of CAPA and clinical distinctions across CAPA and Invasive pulmonary aspergillosis (IPA). For such purpose, a number of case definition/criteria for describing plausible, putative, likely, and proved CAPA cases have also been presented.[12],[43],[44]

In coronavirus diseased (COVID–19) patient, species of Aspergillus causing infections into lungs or tracheobronchial tubes are known as CAPA. Koehler et al. put forward case definition by,[43] direct microscopy and/or histological proof of Aspergillus spp-like fungus characters can be used to prove a disease of CAPA. Invasive growth of Aspergillus spp. into the tissues along with damage of tissues, Aspergillus spp. growth on culture media, microscopic identification of the Aspergillus species on histopathological slide examination or by polymerase chain reaction (PCR) from the material collected during aseptic aspiration/biopsy from respiratory system site signifying an infectious disease are all example of such evidences. COVID-19 (coronavirus disease)-diseased patient in hospitals have high chances to progress CAPA for the variety of reasons. SARS-CoV-2 assaults into the lungs triggers the production of Dangers-Associated Molecular Pattern in severe infection of COVID-19 danger-associated molecular patterns (DAMPs).[40]

DAMPs are the substances produced by the host that affects the response of organ to the injury and regulates the initiation of pathogen recognition receptors.[45]

The production of DAMPs, which are important risk factor for invasive pulmonary aspergillosis, is companied by inflammation and severe damage to epithelial tissues of lung.[40]

A dysfunctional inadequate mucociliary activity and an impaired local immune response have also been identified as pathophysiological determinants for invasive pulmonary aspergillosis (IPA) and maybe CAPA.[46],[47]

Acute respiratory distress syndrome (ARDS) is caused because of substantial inflammation and harm to the lungs in severely diseased patient of COVID-19 (ARDS). ARDS is marked by difficulties breathing, necessitating the use of assisted ventilation in these patients. Into the ICU, mechanical-assisted ventilation and the duration of time spent on it is an proven risk factor for invasive aspergillosis and CAPA.[47],[48],[49]

The use of corticosteroids (described below) and antibiotics, as well as pharmaceutical cancer treatments, may all be perilous agent for CAPA.[12],[50]

A multicenter study performed across Wales, for example,[12] patients diagnosed or being managed with the solid neoplasm were found to have a significant connection to COVID-19 people with IPA (invasive pulmonary aspergillosis). Furthermore, a cohort study conducted in France retrospectively, Dellière et al. in COVID-19 patient, azithromycin therapy for up to 3 days was found to be substantially associated to the occurrence of probable invasive pulmonary aspergillosis. This was ascribed to azithromycin's immunomodulatory characteristics, which may decrease the host's immunological response and so increase vulnerability to Aspergillus infection.[50],[51]

Perilous agent for COVID-19-associated candidiasis

CAC usually defined by the presence of one/higher than one species of Candida into the circulation or bodily tissues of COVID-19 patient's body (CAC). As revealed earlier, in hospitalized COVID-19 patients, Candida species and other Candidal species (nonalbicans) have been found.[17],[41],[52],[53]

CAC is caused by protracted hospital stay, mechanical (assisted) ventilation, central venous catheters, surgeries, and uses of broad-range anti-microbial drugs.[52],[53]

For example, Nucci et al.[52] reported that coronavirus disease (COVID-19)-infected patients with assisted (mechanical) ventilation have high chances for Candida infection in blood (candidemia) than non-COVID-19-infected patients.

In the same manner, Mastrangelo et al.[17] reported that COVID-19-infected patients along with Candida infection in blood (candidemia) were mostly in the ICU and receiving immunosuppressive medications than non-COVID-19-infected patients for other reasons to be in the ICUs.

The appearance of pan-echinocandin-resistant C. glabarata concurrent infection in a hospitalized 53-year-old COVID-19 patient manifesting anti-mycotic management unsuccessful and possibly hastened disease advancement, according to another study.[21]

According to different authors, their cases study revealed that demand of effective anti-fungal resistance supervising in series to recommend dynamic anti-fungal medication administration during the management of patient in the critical care unit (CCU).


  Immunosuppressants as Perilous Agent for Developing Mycotic Infection in Severely Diseased COVID-19 Patients Top


Immunomodulators make up majority of the recent ongoing treatment choices for COVID-19-infected patient.[54]

During SARS–CoV-2 infection, anti-inflammatories property of all such immunomodulator are crucial in countering the lungs' increased and uncontrolled liberation of pro-inflammatory cytokine markers (referred as “Cytokine Storm”).[55],[56]

Immunosuppressants' drugs including methylprednisolone, prednisone, dexamethasone, hydrocortisone, and tocilizumab are the utmost popular therapies in case of severe case of coronavirus disease (COVID-19) admitted in ICUs.[54]

Immunostimulants are necessary during the starting stage for the treatment of COVID-19 disease, whereas immunosuppressants may be more useful during the late stage of this illness for lowering cytokine storm production.[57]

For example, in coronavirus disease (COVID-19)-infected patient with pulmonary support invasion/receiving only oxygen solely, treatment with dexamethasone helps to reduce mortality by 28 days, while in coronavirus disease (COVID-19)-infected patient along with low severity diseases, implying that progressive stage of the illness is mediated by hyperinflammation and thus could be reduced with immunosuppressants.[57],[58]

Sadly, innate and adaptive immune responses are disrupted by immunosuppressants, causing complicated quantitative and qualitative immunological dysregulation,[50],[59],[60],[61],[62] resulting in high susceptibility for patients regarding invasive mycotic diseases.

Steroid immunosuppressant, like corticosteroid, affecting the activity of a number of effecter immunological cells, such as monocyte, polymorphonuclear leukocyte, T-lymphocyte, and macrophage, largely influencing the protective immunity process qualitatively[60] and it is also a major acquired immune risk factors for respiratory Aspergillus infection.[63],[64]

As a result, corticosteroids such as dexamethasone and methylprednisolone, which are used to treat COVID-19 individuals who are critically ill, have side effects, such as increasing secondary microbes infection in patient.[63],[65]

In this current COVID-19 pandemic, researchers are looking into possibility of a link between immunosuppressant or corticosteroids uses and the occurrence of mycotic infection in COVID-19 patient who are critically ill.

According to a study conducted in Wales prospectively across several COVID-19 CCUs, systemic corticosteroids given in higher doses, remarkably escalate the risk of COVID-19 patient contracting aspergillosis.[12]

In the same way, in Brazil, Riche et al.[42] a group of severely diseased COVID-19 patient given large dose of corticosteroid such as methylprednisolone, prednisone, hydrocortisone, and dexamethasone developed candidemia tenfold.

In Chicago, a retrospective analysis of 111 COVID-19 patient taking drug Tocilizumab (a mono-clonal antibody which blocks binding of interleukin (IL-6) to membrane and to soluble receptor) discovered a relationship between the likelihood of getting fungal pneumonia and sinusitis[66] and tocilizumab is a drug that is used to treat cancer (a mono-clonal antibody which blocks binding of IL-6 to membrane and to soluble receptor).[67]

In a study conducted in New York, retrospectively which involves 4313 COVID-19 patient, corticosteroids were not connected to increased blood infections of bacterial or fungal with comparison to COVID-19 patient not receiving corticosteroid treatment during the initial 7 days of hospital admission.[68] The use of low-dose corticosteroids early in the treatment is recommended in this study.

It should be emphasized, however, that high dosages of corticosteroids, often given for long periods of time,[69] are mentioned in many of the other studies, which could describe the increased frequency of systemic mycotic infection and in turn, neglect the life-saving advantages of such treatments.

Other coexisting risk factors for mycotic infection, such as the history regarding patient's respiratory disease, comorbidities, and assisted (mechanical) ventilation, could obscure the link between corticosteroids uses and the prevalence of mycotic infection in COVID-19 patient who were hospitalized.[12],[70]

For example, in a study conducted by White et al. at different institution,[12] in addition to the uses of corticosteroids, a history of long-standing (chronic) pulmonary illness remarkably escalated the risk for Aspergillus infection. Evidently, along with the exclusion of a study by Ho et al.,[69] the majority of the current research into probable link between immunosuppressive drugs and fungal infections is based on a less number of patient. A study with such a less sample size should be short of statistical power, which could lead to erroneous findings. To completely understand the contribution of immunesuppressants in influencing COVID-19-infected patient to mycological concurrent infection, more retrospective and randomized control studies are required.


  Detection Techniques Related to Opportunistic Invasive Fungal Infections in Patients of Coronavirus Disease (COVID-19) Top


COVID-19 mortality rate is affected by secondary infection/concurrent infection caused by bacteria, virus, and fungus. The importance of a quick and correct diagnosis in the therapy process cannot be overstated.[41]

Invasive fungal illnesses can affect any organ or tissue, although the lungs are the most frequently affected. Due to unique clinical symptoms and unclear laboratory test results, diagnosis remains a major challenge. These variables have a direct impact on therapy and prognosis. However, radiological changes in extremely unwell people are generally nonspecific, opportunistic invasive fungal infections are difficult to diagnose.[63]

Three methods are used to make a diagnosis. First, clinical examination can help with the diagnosis by assessing clinical symptoms such as febrile illness, coughing, breathlessness, discomfort in the chest, and hemoptysis; yet, such symptoms are observed only in a small percentage of patients. Second, radiologic imaging findings such as density, cavitation, air crescent indications, and halo signs can be used to make a diagnosis; only a few patients, however, experience normal symptoms and some even have bad outcomes. Third, mycological procedures can be used to make a definitive diagnosis of the causal agent.[71]

Infections caused by Aspergillus and Candida must be detected early in COVID-19 patients utilizing a complete diagnostic examination.[9]

Additionally to fungal approaches such as direct microscopic evaluation and sample culture, invasive fungal infections can also be diagnosed using the serological and genetic methods.

Diagnostic technology and patient management must be improved to enable the prompt detection and treatment of fungal infections.[72]

CAPA needed to be screened in the patient of COVID-19 and increasing symptoms. CAPA is diagnosed by chest radiograph, Aspergillus antigen testing on sample fluid obtained through bronchoalveolar lavage, blood galactomannan tests, enzyme-linked immunosorbent assay, lateral-flow assays, and Aspergillus PCR.[63]

For confirmation of Candida infection as follows:

  • C. albicans germ-tube antibody test
  • 1,3-D-glucan assay
  • PCR-based assays targeting the recombinant-DNA (r-DNA) internal transcribed spacer (ITS).


Furthermore, other newer methods such as

  • T2 magnetic resonance
  • Matrix-assisted laser desorption/ionization mass spectrometry is all advised diagnostics tests.


For confirmation of Cryptococcus infection:

  • Cryptococcus-antigen tests
  • Latex agglutination tests
  • Enzyme-linked immunoassay
  • Lateral-flow immunoassay
  • Pan-fungal PCR
  • DNA sequencing
  • Multiplex PCR
  • Isothermal amplification
  • Probe-based microarrays
  • High-resolution melting analysis.


The above diagnostic tests are advised

Genes which are targeted consisting of IGS1-CAP5-ITS also 18S, ITS, 28S, and r-DNA.[9]

Patients admitted in ICU with severe pulmonary disease or pulmonary functions worsening should be screened using advanced mycological tests 1 week after being diagnosed with COVID-19.[73]


  Conclusions Top


According to our literature review, concurrent mycological infections have been identified in very unwell coronavirus disease (COVID-19) patient hospitalized in ICU, along with aspergillosis the most common, followed by candidemia. In the ICU, host variables, medical procedures, and drugs such as corticosteroids, which are meant to help with COVID-19 disease constitutes possible risk factor developing mycotic concurrent infections.

As a result, the relationship between mycotic infection and high death rate in COVID-19 patient, as well as the relationship between treatment option and mycotic infections offers an enigma that calls for new approaches to reducing secondary nosocomial fungal infections in hospitals. Meanwhile, early diagnosis of concurrent mycological infections and anti-mycotic treatment may aid COVID-19 patients who are hospitalized have a better outcome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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