|Year : 2022 | Volume
| Issue : 3 | Page : 256-261
Mucormycosis, COVID-19 Pandemic and the Lessons Learnt: A Review
Anila Varghese1, Anita Upadhyay2, Roy A Daniel3, Twinkle Sharma4, M Shyam Mohan4, Balaji Susindran4, Priyanka Singh5, Chandrakant Lahariya6
1 1Department of Community Medicine, LLR Medical College, Meerut, Uttar Pradesh, India
2 Director-Projects, Human Capital Lighthouse Consulting Private Limited, New Delhi, India
3 Centre for Community Medicine, All India Institute of Medical Sciences, New Delhi, India
4 Integrated Department of Community Medicine and Pediatrics, Foundation for People-Centric Health Systems, New Delhi, India
5 Health Division, United Nations Children's Fund (UNICEF) India Country Office, New Delhi, India
6 Integrated Department of Community Medicine and Pediatrics, Foundation for People-Centric Health Systems, New Delhi; Adjunct Professor, SD Gupta School of Public Health, IIHMR University, Jaipur, India
|Date of Submission||18-Sep-2022|
|Date of Decision||01-Nov-2022|
|Date of Acceptance||09-Nov-2022|
|Date of Web Publication||28-Dec-2022|
Dr. Chandrakant Lahariya
Foundation for People-Centric Health Systems, B-2/105, Safdarjung Enclave, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
Mucormycosis emerged as a major public health challenge during the second wave of the COVID-19 pandemic in India in mid-2021. The disease, colloquially known as the Black fungus, was declared epidemic by the government. This review describes the epidemiological pattern and the determinants of mucormycosis. The review also proposes evidence based public health strategies for the prevention and control of mucormycosis. The rationale use of steroids in clinical management, formulation of evidence-based standard treatment guidelines and adherence to those guidelines by physicians, the strengthening of primary healthcare services to facilitate early care; compliance with infection prevention and control measures at all the health facilities; and early diagnosis and case management are the key strategies to prevent future emergence of mucormycosis. The article concludes that it is not enough that we tackle a health challenge at hand, in crisis mode. It is equally important that we derive learnings and take measures prevent any future. Effective control of mucormycosis and prevention of future outbreaks of disease is possible through coordinated actions of health policy makers, public health experts and clinicians. The entire episode is also a reminder for strengthening India's health systems at all levels – primary, secondary and tertiary – as well as in both public and private sector.
Keywords: COVID, India, mucormycosis, public health
|How to cite this article:|
Varghese A, Upadhyay A, Daniel RA, Sharma T, Mohan M S, Susindran B, Singh P, Lahariya C. Mucormycosis, COVID-19 Pandemic and the Lessons Learnt: A Review. J Med Evid 2022;3:256-61
|How to cite this URL:|
Varghese A, Upadhyay A, Daniel RA, Sharma T, Mohan M S, Susindran B, Singh P, Lahariya C. Mucormycosis, COVID-19 Pandemic and the Lessons Learnt: A Review. J Med Evid [serial online] 2022 [cited 2023 Feb 1];3:256-61. Available from: http://www.journaljme.org/text.asp?2022/3/3/256/365848
| Introduction|| |
Mucormycosis (colloquially referred to as “Black Fungus”) emerged as a major public health challenge and crisis during the second wave of the COVID-19 pandemic in India in May 2021. The rare but highly fatal disease is caused by a group of fungi in the order of Mucorales., The Union Ministry of Health and Family Welfare, Government of India, declared mucormycosis as an epidemic in the 3rd Week of May 2021, and it was made a notifiable disease. The extensive media coverage made everyone familiar and scared of 'black fungus'. Although the cases of mucormycosis in COVID-19 patients had been reported from many countries as well, India had reported disproportionately high number of mucormycosis cases.,, Even before the COVID-19 pandemic, India had regularly reported the biggest burden and share of mucormycosis cases in the world., This narrative review has been conducted with the objectives to identify the epidemiology of mucormycosis and the COVID-19 infection; to assess the risk factors associated with COVID-19 associated mucormycosis infection and to suggest evidence-based public health measures for accelerating preventive measures.
| Materials and Methods|| |
A desk review of the literature was followed by data analysis and interpretation. The search was conducted on Medline via PubMed, Scopus and Google Scholar amongst others, for the papers published in peer-reviewed scientific journals published in the English language. We included COVID-19 and mucormycosis-related papers, irrespective of study design, published between January 2021 and August 2022, detailing the epidemiology of COVID-19 and mucormycosis, pathogenesis, evidence-based preventive measures related to COVID-19 and mucormycosis infection. The key search terms employed in this unstructured literature review were as follows: 'COVID-19', 'COVID', 'SARS CoV-2', 'Novel corona virus', 'Mucormycosis', 'black fungus', 'diabetes', 'prevention', 'steroids', 'public health' and 'epidemiology'. Cross references were also retrieved from the eligible articles for additional information. Government guidelines related to COVID-19 and mucormycosis were also searched from the Union Ministry of health and family welfare, Government of India and the Indian Council of Medical Research websites.
Mucormycosis: A very brief history
Mucromycosis is known for more than a century. Fürbinger described the first mucormycosis case in Germany in 1876 in a patient with haemorrhagic infarct in the lung, and Arnold Paltauf first published about disseminated mucormycosis in 1885. Globally, mucormycosis prevalence varies from 0.005 to 1.7 cases per million population, while its prevalence in India has been reported many fold higher at 140 cases per million people (an estimated 187,460 patients).
A review in 2005 showed that globally there is an increasing trend in mucormycosis cases over six decades (1940–1999). This trend has partially been attributed to increasingly common as the incidence of immunosuppression in the general population has grown, as well as due to the availability and use of immunosuppressive drugs for a range of illnesses. The other reason for higher cases is improved case detection and better reporting due to the accessibility and availability of testing services.
India has also reported an increasing trend with the incidence of mucormycosis at 12.9 cases/year over the period of 1990–1999, 35.6 cases/year over a 5-year period (2000–2004), and then 50 cases/year (2016–2017). In another prospective multicentric study conducted at four major tertiary care centres of India (two in north and two in south India) during 2013–2015, a total of 388 proven/probable mucormycosis cases were reported, with overall mortality at 46.7%. A review article, with the use of computational-based approach, for a period of 1960–2012 from multiple databases had estimated the prevalence of mucormycosis at 140 cases per million people in India, with a mean of 171,504 (95% confidence interval: 147,688–195,777) cases and a mean of 65,500 (38.2%) attributable deaths per year. Thus, the epidemic of mucormycosis during the second wave of the COVID-19 pandemic was not merely a chance occurrence but an incipient epidemic.
Epidemiology of mucormycosis in India
The epidemiology of any disease can be best understood by the epidemiological triad [Figure 1], which examines the interlinkage and interaction of agent, host and environmental factors.
Mucormycosis is caused by fungi of the class Zygomycetes, order Mucorales, family Mucoraceae and genera Rhizopus, Absidia (now reclassified as Lichtheimia), Rhizomucor and Mucor are most commonly isolated from clinical specimens and less common are the genera Cunninghamella, Mortierella, Saksenaea and Apophysomyces., Mucormycosis is characterised by infarction and necrosis of the host tissues that result from an invasion of the vasculature by hyphae. Nearly 60% of mucormycosis cases in humans are caused due to Rhizopus Oryzae, which also accounts for 90 % of the rhino orbital cerebral form. It contains Ketone reductase, an enzymne which allows it to thrive in high glucose acidic conditions.,
Risk factors in the host include diabetes mellitus (DM), neutropenia, sustained immunosuppressive therapy, haematological malignancy, solid organ transplants, corticosteroid therapy, iron chelation therapy, broad-spectrum antibiotic use and severe malnutrition. Nosocomial and isolated renal mucormycosis have also been reported., A considerable number of cases have also been observed in immunocompetent hosts without any known underlying illness, who often present with cutaneous mucormycosis after trauma, burns, surgery and use of contaminated dressings and injections., The host factor may vary in different settings. DM is the most common risk factor in the Asian continent, whereas haematological malignancies and transplantation are the major risk factors in European countries and the United States.,
These are linked to external factors which facilitate the increased probability of infection in the host. Airborne fungal spores are almost omnipresent in nature, and humans acquire the infection predominantly by inhalation of sporangiospores, occasionally by ingestion of contaminated food or traumatic inoculation., Mucorales are ubiquitous environmental fungi found in decaying organic substrates; mucormycoses with uncommon species have been associated with major health issues, especially in immunocompetent adults. The mucorales are more common in soil than in air, and in summer and fall than in winter or spring. The number of airborne mucor sporangiospores appears to depend on the presence of climatic conditions that favour growth and dispersal. The optimum environmental conditions for the growth and sporulation of zygomycetes on these substrates are 27°C and high humidity. Evidence indicates that mucormycosis cases surge in summer among Indian states such as Gujarat, Rajasthan and Maharashtra, because of the high temperatures during this time and the low relative humidity and precipitation., Seasonal variations and the influence of climatic conditions on the incidence of cases in COVID-19 patients is yet to be fully evaluated. Often, the fungi which cause the black colouration on the walls in our houses could be the mucorale. The other environmental factor is the treatment practices of the physicians and the use of excessive and high dose corticosteroids may result in a weakened immune response of an individual and makes him/her prone to mucormycosis.
The mucormycosis epidemic in India, 2021
The reason for mucormycosis cases in epidemic form in the patients with the COVID-19 pandemic has been attributed to the combination of poor oxygen saturation (hypoxia), high glucose (diabetes, new-onset hyperglycaemia, steroid-induced hyperglycaemia), acidic medium (metabolic acidosis, diabetic ketoacidosis (DKA)), high iron levels (increased ferritin) and decreased phagocytic activity of white blood cells due to immunosuppression (SARS-CoV-2 mediated, steroid-mediated or background comorbidities) coupled with several other shared risk factors including prolonged hospitalisation with or without mechanical ventilation. The novel SARS-CoV-2 infection remains associated with impaired functioning of not only cellular but also humoral immunity, which triggers a higher risk of fungal infection.
Diabetes mellitus: The overlooked pandemic as a risk factor
The COVID-19 pandemic and the mucormycosis epidemic have drawn a lot of attention to DM, one of the top ten causes of death globally. An estimated 77 million people in India are living with DM., Due to its impact of raised blood sugar levels on the human immune system, poorly treated diabetic patients are at risk of infections and of hospitalisation. Patients with severe COVID-19 infection are said to be more likely to develop mucormycosis, and both conditions are made more likely by DM. Many theories have been suggested for this association. Increased angiotensin-converting enzyme 2 receptor expression, hyperglycaemia, overexpression of glucose-regulated protein 78, increased availability of micronutrients and increased availability of iron to the pathogen, makes diabetes the most common risk factor for mucormycosis.
A systematic review on mucormycosis in COVID-19 reported that pre-existing DM was present in 80% of cases, while concomitant DKA was present in 14.9%. The most common type of mucormycosis typically seen in cases with diabetes is the rhino-orbital type., Even in pre-COVID-19 times, many case series have reported diabetes as a risk factor in over 50% of cases with mucormycosis in India and the latter is the diabetes-defining illness in 23% to 43% of patients.,,, Diabetes poses a risk of a very severe course of the disease and is associated with higher in-hospital mortality. High insulin resistance due to cytokine storm, damage to pancreatic islets by SARS/CoV-2 and persistent hyperglycaemia are stated to be the mechanism for this increased risk.
The steroid dilemma: To give or not to give
Steroids play an important role in the management of moderate and severe cases of COVID-19 (and many other health issues), but their use must be carefully coordinated). Long-term (and often high dose) use of corticosteroids and other immunosuppressive agents has often been associated with several opportunistic fungal infections, including aspergillosis and mucormycosis and even a short course of corticosteroids has recently been reported to link with mucormycosis, especially in people with diabetes. Corticosteroids impair the migration, ingestion and phagolysosome fusion in macrophages. In addition, they may lead to drug-induced diabetes. The mucormycosis in COVID-19 patients in the absence of traditional risk factors, such as DM, transplantation or haematological malignancies, has also been reported. This highlights the importance of the judicious use of corticosteroids in patients with COVID-19.
| Discussion|| |
Considering mucormycosis has a ubiquitous presence in the environment, Public health measures for prevention and control are the only way to effectively tackle mucormycosis. The control of risk factors such as improving the management of COVID-19, tackling DM, preventing steroid abuse and improving infection prevention and control measures in hospitals and homes.
The specific focus group for the prevention of mucormycosis should be those infected with COVID-19. It should be ensured that doctors are updated on these guidelines and utilise them for better management of patients. In COVID-19 cases, the prudent administration of corticosteroids (both dosage and duration) is required for the prevention of mucormycosis. Screening for comorbidities, especially diabetes, should be done diligently in all hospitalised patients with COVID-19. The hospital stay can be utilised as an opportunity for counselling regarding lifestyle modification. The standard treatment guidelines during COVID-19 were not being fully adhered to and that was one of the reasons for the emergence of the mucormycosis crisis. The situation has highlighted the need and importance for better adherence to STGs in India.
Infection prevention and control committees should be activated at all healthcare facilities. Protocols should be standardised and should be followed rigorously since the fungus can enter the body through a cut, scrape, burn or other types of skin trauma when the skin comes in contact with fungal spores in the environment. Use of industrial oxygen, impure water in humidifiers and prolonged use of face masks are all hypothesised to have increased mucormycosis cases. Although only further studies can confirm this, the use of distilled or boiled water in humidifiers, improving ventilation in rooms where patients are admitted, washing of re-usable face masks daily, avoiding re-use of surgical masks and ensuring the quality of oxygen cylinders (though practically difficult) may be helpful measures.
Although acute illness deserves immediate attention, non-communicable diseases should also be taken seriously. Under the National Programme for Prevention and control of Cancer, Diabetes, Cardiovascular diseases and Stroke (NPCDCS), improved screening facilities are made accessible even at the subcentre level., Other concerns are lack of accessibility to treatment even after diagnosis, poor quality care, reduced compliance to treatment, poor facility for follow-up care and lack of awareness about the importance of lifestyle modifications. These problems were further aggravated during the COVID-19 pandemic due to reduced access to non-COVID-19 care because of lockdowns and channelling of facilities for COVID-19 care, economic instability and fear of transmission. Globally, NCD diagnosis and treatment services were among the five-most frequently interrupted services.
The current situation points towards the importance of strengthening primary health care. Strengthening primary health care, includes both the required drugs and diagnostics as well adequately trained primary care physicians, which helps in controlling and managing the comorbidities. Early case management by primary care physicians at peripheral facilities can prevent from complications and nosocomial infections. This will eventually reduce the risk factors that favor the development of mucormycosis in COVID-19 patients. India is strengthening primary healthcare services as part of Health and Wellness Centres under the Ayushman Bharat Programme and that is a great opportunity to prevent such epidemics as well.,
Steroids are often administered without the prescription of doctors due to easy over-the-counter availability. Even more dangerously, these drugs are misused by untrained medical practitioners or quacks. A survey in Panipat, Haryana, in 2016 showed that Decadron was used by 87.5% of untrained medical providers. However, these providers are easily accessible to the lower sections of society, especially in rural areas. Gaps in accessibility and affordability of health care that still exist must be addressed. Many of the challenges of existing healthcare systems can be resolved by empowering primary healthcare physicians and mid level care providers, by strengthening Primary Health Care (PHC) system and engaging communities.,
Secondary and tertiary prevention
A concerted effort between general physicians and specialists in ENT, ophthalmic and neurosurgeons can prvent complications in COVID-19 moderate-to-severe cases. Regular trainings and retraining of healthcare providers should be done to tackle even the existing burden of mucormycosis to enable early diagnosis and initiation of treatment. The referral to higher centres should be facilitated without delays. Availability of anti-fungal agents– a major challenge at the time of the mucormycosis crisis in May 2021 – should be ensured. Notification of cases and monitoring should be continued. Aero-mycological study to assess the presence and to quantify Fungal spore count should be done periodically in all intensive care units.
The mucormycosis – a high-fatality disease – cannot be tackled by merely focusing on treatment and prevention is the most cost-effective intervention. Public health measures such as strengthening primary health care, strict implementation of infection prevention and control measures at all health facilities, effective management of risk factors such as DM; reducing the misuse of steroids in COVID-19 patients, early diagnosis and management are the most important strategies in the current situation. It is also important that in a setting where mucormycosis has been reported, the disease condition is included as part of case management for post and long COVID-19 as well.
| Conclusion|| |
The COVID-19 pandemic and mucormycosis epidemic have highlighted the importance of standard treatment guidelines in health services. It has also underscored the importance of the fact that the focus should not be on treating the disease for which patients come to a health facility but also on taking care of comorbidities, which may be known and unknown to the patients. The medical issue of mucormycosis has highlighted the public health challenges of nonadherence to Standard treatment guidelines and the misuse and overuse of corticosteroids. It is not enough that we tackle a health challenge at hand in crisis mode. It is equally important that we derive learnings and take measures to prevent any future. Effective control of mucormycosis and prevention of future outbreaks of disease is possible through coordinated actions of health policymakers, public health experts and clinicians. The entire episode is also a reminder for strengthening India's health systems at all levels – primary, secondary and tertiary – as well as in both public and private sectors.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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