How does the COVID-19 surge relate to a ‘black fungus’ outbreak in India?

Thousands of Indian COVID-19 survivors have developed deadly ‘black fungus’ infection leading to blindness.

Author: Sara Maria Majernikova
Editor: Gracie Enticknap
Artist: Lucie Gourmet

According to the World Health Organisation (WHO), India has been facing high rates of COVID-19, with more than 31 million confirmed cases, 400,000 deaths and 441 million vaccine doses administered since January 2021. Therefore, the B.1.617 mutation (known as delta) has been elevated from a ‘variant of interest’ to a ‘variant of concern’, as WHO informs. The BBC has reported that preliminary studies inform about this version of SARS-CoV-2 showing evidence of easy transmission, more severe illness, reduced neutralisation by antibodies and reduced effectiveness of treatment and vaccines. The mutation has already spread to more than 30 countries and is being studied to establish whether it is responsible for a deadly surge in India, which currently overwhelms hospitals and crematoriums.

Mathew et al. present a comprehensive atlas of changes in the body’s immune system, caused by agents activating or suppressing its function (immune modulation) associated with COVID-19 infection. They performed high-dimensional flow cytometry to characterize cell types and states by measuring expression levels of pre-defined sets of surface and intracellular proteins in individual cells of hospitalized COVID-19 patients and found three prominent and distinct immune types that are related to disease severity and clinical parameters. Arunachalam et al. report a systems biology approach to assess the immune system of COVID-19 patients with mild-to-severe disease. Their results suggest that the enhanced cytokine release may in part be caused by increased bacterial products in the lung or in other tissues. Both studies suggest that severity of COVID-19 could potentially weaken the body’s immune response. This could lead to increased vulnerability to other infections, especially for people who are immunocompromised. Mahalaxmi et al. in their study reports that COVID-19 infection, the consequential immunosuppression, former co-morbidities, and its medications have made the patients susceptible to secondary fungal infections such as Mucormycosis, commonly referred to as black fungus.

Minseo Jeong writes for Medical News Today that Mucormycosis is a rare type of fungal infection that occurs through exposure to fungi called mucormycetes. These fungi commonly occur in the environment, particularly in leaves, soil, compost, and animal dung. Centers for Disease Control and Prevention (CDC) informs that mucormycosis is not contagious, and most people who meet the fungi do not develop an infection. However, hot and humid conditions, oxygen, humidifiers, and oxygen delivery masks may contribute to the spread of infection. Mucormycetes can enter the body through breathing, inhaling, and exposed wounds in the skin. CDC further reports that there are different types of mucormycosis, including rhinocerebral (sinus and brain), pulmonary (lung), gastrointestinal, and cutaneous (skin). An inhalation of Mucor spores by patients with a compromised immune system will lead to colonization of the fungus, invasion of the host and development of mucormycosis. Some respiratory-related symptoms include cough, fever, headache, chest pain, shortness of breath, nasal or sinus congestion and pain. Skin-related symptoms, which can occur in and spread to any part of the body, include blackened skin tissue, redness, swelling, tenderness, blisters and/or ulcers. India Today reports that the symptoms of mucormycosis appear two-three days after a person has recovered from the Covid-19 infection. This fungal infection first occurs in the sinus after the patient is cured of COVID-19 and in about two-four days, it invades the eyes, as otorhinolaryngologist (ENT specialist) Dr Sanket Shah of Kiran Hospital in Surat explained. Within the next 24 hours, the black fungus can travel up to the brain. People with severely weakened immune systems are at increased risk of mucormycosis. This includes cancer, HIV, taking immunosuppressants, heart and/or kidney failure, diabetes mellitus and those who have surgery and skin injury. 

Mahalaxmi et al. found individuals with diabetes are at a higher risk of mucormycosis because the high blood sugar levels make it easier for the fungi to grow and survive. Their weaker immune systems offer less protection against the infection. As a result, diabetic individuals recovering from COVID-19 could be at higher risk for mucormycosis. In addition, the rhino-orbito-cerebral form of this infection is predominantly associated with uncontrolled diabetes. Christopher Coleman, assistant professor of infection immunology at the University of Nottingham in the United Kingdom, told Medical News Today: “the virus, as part of its replication cycle, suppresses the immune system, so the immune system cannot clear other bacteria or fungi. The most famous example of this is HIV, of course, which causes long-term immunosuppression. But other viruses do this on a much shorter timescale i.e., the immune system is only slightly suppressed for a few days or weeks while the virus is there.” As mucormycosis is angioinvasive, once inhaled, its spores begin to grow, and the fungal hyphae invade the blood vessels, further contributing to tissue infarction, necrosis, and thrombosis. This fungal infection is life-threatening as it occurs among those who have immunosuppression accompanied with diabetic ketoacidosis, neutropenia, increased serum levels of iron, excess release of sugar due to overtake of steroids which finally results in a decrease in levels of white blood cells, T-cells and other immunomodulatory cells and triggers the cytokine storm that damages the cellular organs. Therefore, researchers and healthcare professionals should promptly control this mucormycosis infection by understanding its influence and range of severity, especially on COVID-19 patients.

Ahmad Adil showed that in July, India has reported a total of 45,374 cases of mucormycosis and 4,332 related deaths, said the country’s Health Ministry. The Telegraph additionally informs that there are currently 850 people hospitalised with mucormycosis in Maharashtra, home to India’s financial capital of Mumbai, and authorities have warned they will have to treat 5,000 patients over the next few months. BBC states that India’s health authorities declare a mucormycosis as being epidemic. The Hindu reports that on May 19, the state of Rajasthan declared a mucormycosis epidemic, meaning that it will be mandatory for the health facilities to report every case of the disease. Nowadays, India experiences more than 100 black fungus patients, for whom a special ward has been established at the Sawai Man Singh Government Hospital and more of these cases are reported from Jaipur, Jodhpur, Sirohi and Kota districts. India Today further informs that in the city of Surat, 8 out of 40 COVID-19 survivors who developed mucormycosis in the eye lost their eyesight. Another India Today article reports that apart from Surat, doctors at a private facility in Delhi have also reported a rise in the number of Covid-triggered mucormycosis cases. Dr Manish Munjal, senior ENT surgeon at the Sir Ganga Ram Hospital said, “We are seeing a rise again in this dangerous fungal infection triggered by COVID-19. In the last two days, we have admitted six cases of mucormycosis.” Last year, this deadly infection caused high mortality with many patients suffering from the loss of eyesight and the removal of the nose and the jawbone.” Deepali Sharma informs in the article that the state of Maharashtra reported over 2,000 recent cases of mucormycosis, with 8 resulting in death. The state’s health minister, Rajesh Tope, announced that they will be creating special wards and launching an awareness campaign to spread awareness about the disease.

Mahalaxmi et al.  discovered if black fungus is untreated, mucormycosis can be fatal, with a mortality rate of 50%. Physicians can treat the infection by administering antifungal medication or performing surgery to remove the affected area. Chakrabarti and Singh observed black fungus remaining a devastating invasive fungal infection, with high mortality rates even after active management. Therefore, delay in diagnosis and treatment can make the impact of this fungal infection deadlier. Additionally, an increasing number of COVID-19 patients have been developing this infection while still at the hospital or after discharge. Patients hospitalized for COVID-19, particularly those requiring oxygen therapy during COVID-19, are at a much higher risk of mucormycosis. Mucormycosis appears as a side effect among COVID-19 patients, who are put on oxygen support through liquid medical oxygen cylinders or oxygen concentrators. The Indian Government has also given instructions for procurement of oxygen concentrators of good quality and ensure strict compliance with safety measures while using them. Besides, oxygen support, for people with severe COVID-19, can cause drying of the nasal cavity and further increase the risk of infection. Akhil Arora, a Principal Health Secretary, said that the declaration of mucormycosis as an epidemic would ensure the ‘integrated and coordinated’ treatment along with the treatment for COVID-19. The notification was issued under the Rajasthan Epidemic Act in 2020. Additionally, authorities in the northern state of Rajasthan, which has at least 100 active cases, have declared a mucormycosis “epidemic”, while Indian states are now scrambling to procure doses of amphotericin B, an injection that is in short supply but is the only currently available treatment.

Mahalaxmi et al. found steroid treatments for COVID-19 may also act to suppress the body’s immune response, contributing to these increased mucormycosis infection rates. “In this case,” explained Coleman, “there seems to be a suggestion that steroids may be playing a role in suppressing normal immune responses and allowing a fungus to invade.” India Today informs that Dr Ajay Swaroop, the chairman of the ENT department at the hospital, said the use of steroids in the treatment of COVID-19 coupled with the fact that many coronavirus patients have diabetes could be one of the reasons for this rise in the number of black fungus cases again. On the other hand, in the treatment of COVID-19, doctors have time and again warned against the misuse of steroids. Dr Randeep Guleria, AIIMS director, on Saturday blamed the misuse of steroids behind the rise of the cases of mucormycosis during post-coronavirus recovery. Recovery trials showed that steroids will benefit but it’s also important to know when they’re given. If given early before your oxygen saturation falls, it has a harmful effect. According to Dr Guleria, taking steroids at an early stage of the disease can further replicate the virus. Furthermore, taking high doses of steroids in mild cases may lead to severe viral pneumonia and they should be avoided in the first five days of the infection. Chairman of Institute of Liver Transplantation and Regenerative Medicine Dr Arvinder Singh Soin said steroids are one of the components of a vicious COVID-19 triangle, the other two being COVID-19 and diabetes. “Worse the diabetes, more severe the coronavirus and more the requirement for steroids. More the steroids, the worse the diabetes becomes,” he said. In the Union health ministry’s clinical guidance for COVID-19 patients, the use of anti-inflammatory therapy has been recommended only in moderate and severe cases, when the patient is either in the ward or in the ICU and the oxygen level is dropping. The steroid therapy is recommended only for a duration of five to 10 days, not more than that. Dr Suresh Kumar, medical director of LNJP hospital in New Delhi, has said overuse, misuse, and rampant use of steroids in COVID-19 patients are causing black fungus cases. “If given to patients with oxygen levels over 90, black fungus is a possible side-effect. Early diagnosis is critical. A CT scan of the face would detect this infection, after which antifungal drug amphotericin will be used for treatment,” he said.

It has also emerged that the cases of mucormycosis, which is a fungal infection and existed before pandemic, are increasing because of steroid misuse. Overall, it is difficult to determine the best course of action to simultaneously address both epidemics. The combined risks of SARS-CoV-2 virus and mucormycosis raise challenging issues and require careful coordination of patient care and treatment. Mahalaxmi et al. observes that a multidisciplinary approach should include prompt diagnosis, treatment with antifungals, any appropriate surgical consultation and treatment, which may reverse the underlying condition. Additional research in this area is recommended to investigate the mucormycosis in COVID-19 infected and recovered patients. Hence, vigorous investigations to emphasize the root cause of mucormycosis, specifically in COVID-19, should be under the scope of research. A diagnostic study for this opportunistic pathogen should not be ignored in case the patient is COVID-19 positive and immunosuppressed.