A systematic review was conducted to analyse the characteristics of patients with Covid-19 infection, who also had developed mucormycosis, and their outcomes. This review also aimed to examine the temporal association of mucormycosis with comorbidities and drugs being used to treat Covid-19. PubMed and Google Scholar were searched until May 13, 2021. Our search revealed 101 cases of mucormycosis in persons with Covid-19. This meta-analysis showed that more than 80% (82/101) of cases of mucormycosis at that time were reported from India and only around 18% cases were reported from outside India. Recently, there has been a sharp spike in the number of reported mucormycosis cases in India because of which mucormycosis, commonly referred to as the black fungus disease, has increasingly becoming a lead story since last few weeks. Currently there are more than 10,000 cases and the numbers continue to rise. Cases of white and yellow fungus have also been reported. The Central Government has declared mucormycosis as a notifiable disease while more than 10 states have declared it as an epidemic.
Mucormycosis is very uncommon in healthy persons. But, the risk of infection is increased in the presence of certain disease states and factors such as uncontrolled diabetes with or without diabetic ketoacidosis (DKA), hematological and other malignancies, organ transplantation, prolonged neutropenia, immunosuppressive and corticosteroid therapy, iron overload or hemochromatosis, deferoxamine therapy, severe burns, AIDS, intravenous drug abusers, malnutrition and traumatic open wounds. Rhino-orbito-cerebral mucormycosis (ROCM) is the commonest presentation of mucormycosis globally. The infection may be limited to nose and sinus or may extend to also involve the orbits. Lungs, GIT, skin, heart, and kidneys are the other organs affected. ROCM has been reported to be more common in patients with uncontrolled diabetes and DKA; lungs are more likely affected in patients with neutropenia, transplant patients and those with haematological malignancies, while GIT gets involved more in malnourished individuals.
The other key findings were:
- Mucormycosis was predominantly seen in males (78.9%), both in those who had active (59.4%) infection or those who had recovered (40.6%) from Covid-19.
- Hyperglycemia at the time of presentation – due to pre-existing diabetes mellitus or new-onset hyperglycemia or new-onset diabetes or diabetic ketoacidosis – emerged as the commonest risk factor for the majority of patients (83.3%). About 3% patients had malignancy as a risk factor.
- 76.3% of patients had received steroids as treatment for Covid-19; 20.6% had received remdesivir and 4.1% had been treated with tocilizumab.
- In this systematic review, the nose and sinus were found to be most commonly affected (88.9%), followed by rhino-orbital (56.7%), while the ROCM subtype was seen in 22.2% of cases.
- Overall mortality was noted in 30.7% of the cases.
This systematic review could not establish a cause and effect association between COVID-19 and mucormycosis with corticosteroids. This was due to lack of direct evidence that compared patients of mucormycosis in non-diabetic COVID-19, who were not given steroids against COVID-19 patients who received steroids and developed mucormycosis. Few triggers for precipitating mucormycosis in Covid-19 patients were however identified such as diabetes with or without diabetic ketoacidosis (DKA).
Steroids may disrupt glycemic control and cause uncontrolled hyperglycemia and precipitate DKA in diabetic patients. Low pH due to acidosis provides a fertile media for mucor spores to germinate. Steroids also impair the body’s natural defense system against infection. Covid-19 is characterised by high ferritin levels. Free available iron is an ideal resource for mucormycosis. Hence, a combination of factors such as high glucose, low pH, free iron and ketones and decreased phagocytic activity promotes the growth of mucor.
India has highest cases of the mucormycosis in the world. Three factors come into play in this outbreak of mucor cases in Covid-19 patients in India. They are Covid-19 (the disease itself characterised by cytokine storm, lymphopenia and endothelial storm), diabetes, particularly uncontrolled diabetes (India has the second highest diabetic population in the world) and indiscriminate use of steroids (which cause hyperglycemia and also weaken the immune system response). Other factors too have been implicated as sources of infections, use of tap water in oxygen humidifiers, which is not changed regularly, industrial grade oxygen, and overuse of antibiotics. The associated mortality is as high as 50%. Hence, mucormycosis is a matter of public health importance. To control the rising incidence of mucormycosis, it is important to carefully manage high blood sugar levels in patients with diabetes and use steroids only when and where indicated.
Source: Awadhesh Kumar Singh, Ritu Singh, Shashank R. Joshi, Anoop Misra. Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. Available online 21 May 2021.
When to suspect Mucor Mycosis
- Widespread use of steroids against COVID-19 may lead to the development / exacerbation of preexisting fungal diseases.
- Physicians should be aware of the possibility of invasive secondary fungal infections in patients with COVID-19 infections.
- Use of therapeutic agents should be monitored to achieve a therapeutic effect at the lowest dose and shortest durations.
- Use of broad-spectrum antibiotics, especially in the absence of infection, should be re-evaluated.
Dr Shashank R Joshi,
Chair, International Diabetes Federation Southeast Asia;
Consultant Joshi Clinic; Imm Past Dean Indian College of Physicians