COVID-19-associated mucormycosis: A review of an emergent epidemic fungal infection in the era of COVID-19 pandemic
Vinay Chamola1, Rasoul Mohammadi2, Harish Nair3, Adit Goyal4, Aarya Patel5, Vikas Hassija4, Matteo Bassetti6, Pratik Narang7, Roger Paredes8, Jose R Santos9, Seyed Jamal Hashemi10, Mahnaz Pejman Sani11, Kiana Shirani12, Neda Alijani13, Bahareh Abtahi Naeini14, Mohsen Pourazizi15, Seyed Hamidreza Abtahi16, Farzin Khorvash17, Mahdi Khanjari18, Kazem Ahmadikia10
1 Medsupervision Pvt. Ltd., Faridabad, Haryana; Department of Electrical and Electronics Engineering, Internet of Things Research Group, Birla Institute of Technology and Sciences, Pilani Campus, Pilani, Rajasthan, India
2 Department of Medical Parasitology and Mycology, School of Medicine, Infectious Diseases and Tropical Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
3 Usher Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, Scotland EH8 9 AG, Noida, Uttar Pradesh, India
4 Department of Computer Science and IT, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
5 Vitrana, a Lifesciences and Pharmacovigilance Company, Noida, Uttar Pradesh, India
6 Department of Health Sciences, University of Genoa and Policlinico San Martino IRCCS Hospital, Genoa, Italy
7 Department of Computer Science and Information Systems, Birla Institute of Technology and Sciences, Pilani Campus, Pilani, Rajasthan, India
8 Department of Infectious Diseases, irsiCaixa AIDS Research Institute, Germans Trias i Pujol University Hospital, Badalona, Spain
9 Department of Infectious Diseases, AIDS Fight Foundation, Germans Trias i Pujol University Hospital, Badalona, Spain
10 Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
11 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
12 Nosocomial Infection Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
13 Department of Infectious Disease, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
14 Division of Pediatric Dermatology, Department of Pediatrics, Imam Hossein Children's Hospital; Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
15 Isfahan Eye Research Center, Department of Ophthalmology, Isfahan University of Medical Sciences, Isfahan, Iran
16 Department of Otolaryngology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
17 Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
18 Department of Burn and Regenerative Medicine Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
|Date of Submission||16-Dec-2021|
|Date of Decision||08-Mar-2022|
|Date of Acceptance||14-Mar-2022|
|Date of Web Publication||29-Jul-2022|
Dr. Kazem Ahmadikia
Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran
Dr. Rasoul Mohammadi
Department of Medical Parasitology and Mycology, School of Medicine, Infectious Diseases and Tropical Medicine Research Center, Isfahan University of Medical Sciences, Isfahan
Source of Support: None, Conflict of Interest: None
At a time when the COVID-19's second wave is still picking up in countries like India, a number of reports describe the potential association with a rise in the number of cases of mucormycosis, commonly known as the black fungus. This fungal infection has been around for centuries and affects those people whose immunity has been compromised due to severe health conditions. In this article, we provide a detailed overview of mucormycosis and discuss how COVID-19 could have caused a sudden spike in an otherwise rare disease in countries like India. The article discusses the various symptoms of the disease, class of people most vulnerable to this infection, preventive measures to avoid the disease, and various treatments that exist in clinical practice and research to manage the disease.
Keywords: Black fungus, coronavirus, COVID-19, fungal infection, mucormycosis, pandemic
|How to cite this article:|
Chamola V, Mohammadi R, Nair H, Goyal A, Patel A, Hassija V, Bassetti M, Narang P, Paredes R, Santos JR, Hashemi SJ, Sani MP, Shirani K, Alijani N, Naeini BA, Pourazizi M, Abtahi SH, Khorvash F, Khanjari M, Ahmadikia K. COVID-19-associated mucormycosis: A review of an emergent epidemic fungal infection in the era of COVID-19 pandemic. J Res Med Sci 2022;27:57
|How to cite this URL:|
Chamola V, Mohammadi R, Nair H, Goyal A, Patel A, Hassija V, Bassetti M, Narang P, Paredes R, Santos JR, Hashemi SJ, Sani MP, Shirani K, Alijani N, Naeini BA, Pourazizi M, Abtahi SH, Khorvash F, Khanjari M, Ahmadikia K. COVID-19-associated mucormycosis: A review of an emergent epidemic fungal infection in the era of COVID-19 pandemic. J Res Med Sci [serial online] 2022 [cited 2022 Nov 30];27:57. Available from: https://www.jmsjournal.net/text.asp?2022/27/1/57/352939
| Introduction|| |
Mucormycosis is a fungal infection associated with high morbidity and mortality. The mortality rate ranges from 40% to 80% and depends on the site of infection and the underlying conditions. Although the infection is caused by a group of ubiquitously distributed hyaline genera under Mucorales order, due to angioinvasion and subsequent tissue necrosis, which make a black appearance in the tissue, the infection is popularly known as black fungus. The recent rise in the number of patients with mucormycosis is alarming, and it has been attributed to the fact that COVID-19 has forced many of its victims to be administrated by corticosteroids in high doses. These medicines taken over a long period are necessary to cure the COVID-19 infection in some severe cases. However, these immunosuppressive agents have been found to cause a negative impact of leading to mucormycosis for a few patients, especially those having health conditions like diabetes. As of June 2021, India has reported over 28,000 cases of COVID-19-associated mucormycosis (CAM). Moreover, cases of mucormycosis have been reported in countries such as Iran, Pakistan, and Russia.,
Mucormycosis (previously referred to as zygomycosis) is caused by a group of molds called mucormycete. It grows in damp and moist environments and is common in our surroundings. The infection transmits easily because the spores are easily aerosolized, dispersed, and inhaled.,, Mucormycosis starts in the lungs or sinus when the spores are inhaled along with oxygen., Due to the fact that they are present ubiquitously, the chances of inhaling these spores in daily life are quite high. It is noteworthy that the healthy immune system does not allow the infection to grow, and hence it rarely causes disease in an immunocompetent host.
| Previous Works and Contributions|| |
Sahoo et al. provided a short case study of mucormycosis in India accompanying the COVID-19 wave. Garg et al. gave a detailed case report of 8 patients who suffered from CAM. In 2 recently published studies from Iran, 27 CAM cases were reported., The number of studies reporting single or case series of CAM is still on an upsurge trend globally. Hoenigl et al. presented a detailed analysis on 80 COVID-19 affected patients suffering from mucormycosis worldwide.
To the best of our knowledge, articles presenting a comprehensive overview of mucormycosis from the perspective of COVID-19 patients are scarce. In this article, we give a background on mucormycosis, explaining its epidemiology and giving some brief history and also discuss the main clinical characteristics, risk factors, diagnosis, and management of CAM.
| Background|| |
In general, the disease was rarely reported, and there have not been many outbreaks as such are currently happening in COVID-19 settings. A set of 13 cases of cutaneous mucormycosis in Joplin, Missouri (USA), after a tornado in 2011, were investigated by Neblett Fanfair et al. An outbreak of rhinocerebral mucormycosis occurred in 2006 at the pediatric oncology department of a hospital in the UK after some water damage. A small outbreak of cutaneous Rhizopus infection due to ostomy bags in 2005 has been reported in Ohio (USA). A community onset of the outbreak was seen in Argentina during 2010 − 2011, which could be associated with the trauma caused by some natural disasters.
In developing countries, diabetes mellitus (DM) is the most predominant risk factor of mucormycosis, whereas, in developed countries with a high-income level, transplantation and hematological malignancy are the leading factors predisposing individuals to mucormycosis. Nonetheless, with advancements and changes in the therapeutic approaches of diseases like cancer, the epidemiology of mucormycosis is also evolving due to the new immunomodulating agents. [Figure 1] presents some of the common myths and the respective counter-facts regarding the growth, prevention, and treatment of mucormycosis.
|Figure 1: Debunking myths surrounding COVID-19-associated mucormycosis. Note: The figures are original figures which were drawn by ourselves and were not directly adopted from anywhere. Nonetheless, the sources and articles for the reports from which data has been taken to create Figures 2 and 3 have been provided|
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| Types of Mucormycosis|| |
Generally, the infection is anatomically classified into 5 different clinical forms including, rhinocerebral (30%–50%), cutaneous, pulmonary, gastrointestinal, and disseminated mucormycosis.,
Depending on the underlying conditions and the risk factors, mucormycosis shows a specific predilection to particular anatomic sites. For example, rhino-orbito-cerebral mucormycosis (ROCM) is a typical presentation in diabetic and patients diabetes ketoacidosis (DKA) (70%). This clinical form starts in the sinus and might involve the orbit and the brain eventually. Interestingly, in both COVID-19 and non-COVID-19 individuals, the infection is most predominantly presented as ROCM, while other forms of mucormycosis constitute the low percentages of the clinical form in COVID-19 patients (<10%). Cutaneous and soft-tissue mucormycosis is the most common type of infection in people who are not immunocompromised and have with traumatic injury. Patients with profound neutropenia and graft-versus-host disease, those suffering from hematological malignancy, solid organ transplant, and bone marrow recipients develop usually pulmonary mucormycosis; gastrointestinal mucormycosis is usually caused in neonates (premature infants with very less body weight) with very low immunity due to medications, malnutrition, antibiotics, or surgery. Disseminated form of mucormycosis is caused when the infection travels through the bloodstream and affects other parts of the body, like the brain, spleen, skin, or heart which presented more frequently in patients receiving deferoxamine therapy.
| The Etiological Agents of Mucormycosis and COVID-19-Associated Mucormycosis|| |
Rhizopus, Mucor, Lichtheimia, Apophysomyces, Saksenaea, Cunninghamella, Rhizomucor, and Syncephalastrum are some types of Mucorales fungi causing mucormycosis. Rhizopus species and the Mucor species are the most etiologic agents. Results of the literature review regarding CAM cases indicate that in only 51% and 22.5% of cases, identification to genus and species level was described, respectively. However, Rhizopus species were the most prevailing species identified. Rhizopus arrhizus was more frequently in ROCM cases while Rhizopus microsporus was mostly in cases with lung involvement.
| Spread of Mucormycosis in COVID-19-Affected Patients|| |
COVID-19 exacerbates the tendency of mucormycosis in the patients because, regardless of the management recommended for treatment of COVID-19, e.g., corticosteroids therapy and remdesivir, which exacerbate glucose homeostasis in both diabetic and nondiabetic patients, the infection on its own causes a diabetogenic state (as there is evidence suggesting that the virus induces damage of pancreatic islets which resulting in acute diabetes and DKA) and hyper-ferritinemic syndrome increasing both intracellular and free iron levels in patients with COVID-19 pneumonia that results in elevated iron uptake by Mucorales species and consequently stimulates rapid fungal growth.,,, This problem is further augmented in patients with severe COVID-19 and ketoacidosis, since the increased free iron is released from the binding proteins in the background of acidosis. Excess free iron levels are also observed in patients with renal failure due to deferoxamine chelation which make them predisposed to develop mucormycosis. The impairment of neutrophil migration to the infected tissue, ingestion and phagolysosome fusion caused as a result of corticosteroids taken during the treatment of COVID-19 also increases the chances of getting mucormycosis. Moreover, a permissive environment for the growth of Mucorales is provided by the dysbiosis caused by excessive use of antibiotics along with damage of the epithelium. Other factors that are supposed to be associated with the development of CAM in COVID-19 patients include cytokine storm, subsequent immune dysregulation, and endothelialitis. Widespread endothelial injury, as observed in COVID-19 patients with severe form of disease might increase adhesion and penetration of Mucorales to the endothelium. Adhesion and penetration to the endothelium are critical initial steps in the pathogenesis of mucormycosis.
By April 2021, while India was facing the second wave of the COVID-19 pandemic, a sudden rise in the number of mucormycosis cases, an otherwise rare disease, in the patients suffering or just recovered from the COVID attracted great attention and made a public menace. As discussed earlier, considering the COVID-19-associated medication and pathogenesis leading to suppressing immune system and factors aggravating the blood glucose control, CAM is most predominantly observed in cases with diabetes background, particularly those having a history of intravenously administered glucocorticoid agents.,, Mucormycosis has been proven fatal if not promptly diagnosed or left unattended, as it may even invade the brain.,, The Ministry of Health and Family Welfare and the Indian Council of Medical Research (ICMR) issued specific guidelines for the general public to handle the situation in an optimal and informed way. On account of the spread of CAM, various states of India have declared the disease as a notifiable disease/epidemic.
The number of cases of mucormycosis has risen from around 100 cases annually across India (worst-case scenario) to around 100 cases in 20 days from a single hospital in New Delhi. [Figure 2] is a graphical representation of the distribution of the number of mucormycosis cases across India till June 10. On May 20, 2021, the Health Ministry of India asked all the states and union territories of the country to declare mucormycosis as an epidemic under the Epidemic Diseases Act of 1987.
|Figure 2: Distribution of number of COVID-19-associated mucormycosis cases reported from different states in India as of June 10, 2021|
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This letter was issued after the spike in the number of CAM cases was evidenced throughout the country. Before this, the state of Rajasthan had already declared this an epidemic, and the state government of Haryana formed The Haryana Epidemic Diseases (Mucormycosis) Regulations, 2021 to control the outbreak of this fungal infection. CAM reports were also elicited from other developing countries. A previous meta-analysis described the characteristics of 80 CAM cases dominantly presented as ROCM across 18 countries globally. [Figure 3] shows the countries that have reported mucormycosis cases in COVID-19 affected patients. Obviously, the number of countries reporting CAM cases is daily increasing.
|Figure 3: The countries having reported cases of mucormycosis in COVID-19 affected patients|
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| Who All are at Risk?|| |
The classical risk factors predisposing patients to mucormycosis are uncontrolled DM, neutropenia, hematological malignancies, organ transplantation, trauma and burn, and use of immunosuppressants such as corticosteroids.,
The people who recently recovered or are still infected with COVID-19 is the current vulnerable population most recently added to the risk list of acquiring mucormycosis, especially when the following conditions are present [Figure 4]: Hyperglycemia occurs in undiagnosed or uncontrolled diabetics but may also be induced by corticosteroids. Previous investigations concerning CAM, particularly those reported from India and Iran, are clearly shown that CAM cases are predominantly seen in patients with DM (94%), especially in those with poorly controlled DM (67%) and severe or critical COVID-19 (95%)., More so, in 75%–88% of CAM cases, history of systemic corticosteroids therapy was documented as the second common factor after diabetes outlining the high vulnerability of these groups of COVID-19 patients to CAM development.,,,, Treatment with corticosteroids (e.g., IV dexamethasone), although recommended to be administrated in COVID-19 patients, appears to be a double-edged sword potentially increasing the risk of developing invasive mold infections, particularly in patients with known DM., Patients with diabetes and hyperglycemia often display an inflammatory state that elicits constant recruitment and local activation of immune cells, including macrophages and neutrophils that secrete further proinflammatory cytokines and generate persistent inflammation. In patients with SARS-CoV-2, the activation of antiviral immunity may paradoxically potentiate this inflammatory phenotype and thus may favor secondary infections.
Furthermore, many COVID-19 subjects may have comorbidities (some disease along with COVID-19) and have been taking immunosuppressants/steroids/antibiotics and even antifungals as medication for a long time, favoring mucormycosis and other fungal infections.,,
Given the usage of immunosuppressive agents, e.g., anti-interleukin 6 receptor antibody, the COVID-19 patients may become immunocompromised. Further, small fraction of the COVID-19 patients may simultaneously suffer from diseases impairing immune system like HIV, cancer, or because of organ transplant which put them at manifold risk for fungal infections.,
However, fortunately, mucormycosis is not contagious, and neither does it spread from person to person nor animal to person.,
| Precautions|| |
The spores of Mucorales species enter the body through the nose while breathing, and in individuals with suppressed or deficient immune system grow and invade., Considering the fact that the fungi often get eradicated by the polymorphonuclear phagocytes in healthy people, COVID-19 patients with healthy immune system, e.g., those who did not have diabetes, did not take high doses of corticosteroids, or those experienced the mild form of the disease, are less needed to be concerned about CAM occurrence. However, public knowledge about the warning symptoms and preventive measures of CAM is issue of great importance because the infection has been shown to be near to be happened in those with higher risks.
It is noteworthy that the availability of spores is most likely in humid places with some decaying organic substances. To avoid mucormycosis, the precaution measures summarized in [Table 1] are suggested to be taken, especially by the COVID-19 patients who have diabetes, history of systemic corticosteroid therapy or those who have both last conditions.,
|Table 1: Preventive measures minimizing exposure of COVID.19 patients to potential sources of mucormycosis|
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The aforementioned approaches can effectively minimize the patient exposure to potential sources of infection.
| Symptoms|| |
As per the guidelines issued by the ICMR, the symptoms leading to rule in the diagnosis of different clinical forms of CAM in COVID-19 patients with diabetes or in those with suppressed immunity are summarized in [Table 2].
|Table 2: The symptoms prompting high index of suspicion for mucormycosis in high-risk individuals|
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The CAM-associated symptoms generally start in high-risk patients 8 − 10 days after testing positive for COVID-19, but might even occur after 2 months in some cases., The patients should be the most vigilant for any signs and symptoms during the 2–6-week period after testing positive.,,
| Diagnosis and its Associated Challenges|| |
Given the acuteness, aggressiveness, high mortality and morbidity rate of CAM, an early diagnosis approach and timely initiation of antifungal therapy along with urgent surgical intervention is required upon suspicion of CAM., Early diagnosis and management of CAM can prevent from eye exenteration, cerebral involvement and minimize the rate of mortality., A complex of the patient's medical history, related risk factors, assessment of clinical presentations, and pulmonary or cranial CT scan or MRI (based on anatomical involvement), should be sequentially evaluated in cases with high suspicion., If mucormycosis or aspergillosis is a potential diagnosis, biopsy or fluid specimens collection from affected area is strongly recommended and pathological and mycological observations to confirm the presence of the septate (suggestive of aspergillosis) or aseptate hyphae (suggestive of mucormycosis) or even both simultaneously in cases with co-infection is required., More so, differential diagnosis of mucormycosis from other deep mycoses and pathologies with similar clinical manifestations should be precisely considered. Based on anatomical involvement, the tests might involve analyzing a sample of fluid taken from the respiratory system, a tissue biopsy, and a CT scan of the parts of the body suspected to be infected.,, The clinical specimens should be sent in parallel for pathological and mycological investigation to be screened for the presence of wide nonseptate or pauciseptate hyphae (at least 6-16 μm) in tissue usually appearing as ribbon-like with an irregular pattern of branching. Direct mycological examination of tissue biopsy using 10%–15% potassium hydroxide or stained with fluorescent brighteners calcofluor white has lower turnaround time to establish the diagnosis than those tissue sections stained with hematoxylin and eosin, periodic acid Schiff stain, or Grocott Gomori's methenamine silver stain used for histopathological examination. However, to verify an infection, tissue and vascular invasion of non-pigmented aseptate hyphae must be shown in pathological examination. The pathological and mycological investigations for evaluation of Mucorales hyphae and differentiate from those observed in other mold infections like aspergillosis is challenging and needs personal expertise. Aspergillus hyphae are 3–5 μm wide, regularly septated, and dichotomously branched (45° branching angle)., Despite capability of culture-based methods in discrimination between Aspergillus and Mucorales species and initial identification of causal agent, however, the positivity rate of the method in diagnosis of mucormycosis is scarcely exceeds 50%.
The reverse halo sign predominantly presented in peripheral locations of the lung may be suggestive of pulmonary mucormycosis in immunodeficient patients and is useful for the initiation of preemptive antifungal therapy; however, in COVID-19 patients, the pattern is less specific as it has also been described as one of the potential radiological features of COVID-19. Furthermore, due to the fear of risk pertaining to airborne transmission of SARS-CoV-2 during aerosol-generating procedures, collecting bronchoalveolar lavage specimens for potential diagnosis of pulmonary mucormycosis has been scaled down which exacerbated the condition required for timely diagnosis of mucormycosis and probably pulmonary mucormycosis is under-diagnosed or under-reported.,
Unlike aspergillosis, no standardized serologic test for mucormycosis has been developed yet; however, PCR-based techniques using Mucorales specific primers on either fresh or formalin-fixed paraffin-embedded tissue have been shown to be highly sensitive and specific.,
Considering the difference in antifungal susceptibility patterns of species under Mucorales order, precise identification of the etiology to the species level through molecular based methods is recommended for species-specific antifungal treatment. As in infections caused by Cunninghamella bertholletiae, the highest rate of clinical failures was observed which is in line with the high amphotericin B MICs reported for this Zygomycete.
The fact that is less considered is the dependence of all aforementioned diagnostic methods on biological specimens, e.g., bronchoalveolar lavage and biopsy collected by invasive procedures from clinically affected tissues, which make their application for detection of mucormycosis to be limited wherever the condition cannot be provided particularly in hematological setting with great number of patients with thrombocytopenia and which may result in delayed diagnosis and unintended consequences., Nonetheless, the capacity of molecular methods for detection of Mucorales DNA from noninvasive specimens like serum specimen has appeared a bright horizon for prompt detection of mucormycosis and should be assessed as a new pivotal strategy for CAM diagnosis.
| Treatment|| |
The treatment of CAM should not be delayed under any condition as the sequela may be irreparable. Reduction of immunosuppressive therapy is desirable and surgical debridement of involved tissue is a priority whenever is possible. The initial course of treatment is giving antifungal medicines either orally or intravenously, depending on how invasive the fungal attack is. Amphotericin B and isavuconazole are the two main antifungal agents currently recommended for the initial therapy of mucormycosis., Posaconazole is an appropriate drug for salvage therapy in patients who are unable to tolerate amphotericin B. Liposomal amphotericin-B is the most effective medicine for mucormycosis. The aim of this medication is to reduce the pace of fungal growth and to stop its activity. The standard recommended doses of liposomal amphotericin-B are 5 − 10 mg/kg intravenously per day. If a patient is not tolerant to amphotericin-B, a reduced dosage can be administered; however, it should be at least 5 mg/kg/day. In patients with kidney failure, posaconazole or isavuconazole can be given. These medicines can also be given along with liposomal amphotericin-B if the infection is causing serious damage or if it is progressing rapidly throughout the body. In the case of posaconazole, a step-down therapy can be considered once disease is controlled and the susceptibility confirmed. Susceptibility testing to guide therapy may be important because of in vitro resistance demonstrated for some species (Rhizomucor sp. and Rhizopus sp.)., As said before, surgical debridement can also be performed to remove the necrotic tissues and should be considered along with the antifungal medicines as early as possible.
Generally, the therapy should be continued until resolution of clinical signs and symptoms, resolution or stabilization of radiographic findings, and resolution of underlying immunosuppression. However, this treatment is usually needed for 6 weeks but can go up to 6 months with monitoring kidney function.
| Conclusion|| |
Mucormycosis is an extremely dangerous disease due to its high morbidity and mortality rate. Till now, it was a rare disease. There is not even a standardized test to detect the presence of this infection, and an experienced pathologist is required to differentiate this from other filamentous fungi present in the tissue. Surgical debridement and intravenously treatment with liposomal amphotericin-B are crucial for patient survival. Improvements in sanitary conditions are important and in the current times of COVID-19 pandemic, the optimization of metabolic complications of an uncontrolled DM or hyperglycemia associated with corticosteroids is mandatory. In this paper, we have provided comprehensive information available on mucormycosis that would be relevant to COVID-19 patients. However, other fungal infections, e.g., COVID-19-associated aspergillosis and candidiasis, have been reported in COVID-19 patients. Everyone must be aware of the symptoms to look out for and contact a doctor immediately for the differential diagnosis and timely management of the infection. It can get worse if proper care is not taken and prove to be fatal.
Ethics approval statement
Neither human nor animal participants were involved in this review study. Therefore, taking an ethics approval was not required.
Data availability statement
All data relevant to the study are included in the article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]