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Dr. Sajitha Jasmin S L, MDS(OMR), FMC, FAD, PGACC(LASER)

OPPORTUNISTIC FUNGAL INFECTIONS IN COVID 19 PATIENTS: All YOU NEED TO KNOW

The Coronavirus disease 2019 (COVID-19) outbreak in Wuhan city, China has been announced as a pandemic on 11 March 2020 by World Health Organization (WHO). As the infection is airborne, it can easily be transmitted to others during close contact mainly through respiratory droplets formed by coughing, sneezing, and talking. Due to the higher transmissibility, increased infectivity, lack of effective treatment, and opportunistic infections, the fatalities are increasing day by day globally. This article reviews the Opportunistic fungal infections reportedin COVID patients like Black fungus, White fungus, and Yellow fungus in general, clinical presentation, prevention, diagnosis, and its management.

1. Introduction
2. What is an Opportunistic Infection?
3. What is a Fungus?
4. Opportunistic Fungal Infections
5. Fungal Infections in COVID Patients
A. Mucormycosis (Black fungal infection)
B. Candidiasis
C. Mucor septicus (Yellow fungal infection)
D. Aspergillosis
6. Summary

1. Introduction
The so-called Novel coronavirus is the cause of the Coronavirus disease 2019 (COVID- 19) pandemic has made severe harm across the globe. Common symptoms include fever, cough, shortness of breath, loss of taste, loss of smell and few patients report post-COVID syndrome/ Long COVID like extreme fatigue, difficulty in breathing, brain fog, joint pain, chest pain, impaired memory, loss of taste and/or loss of smell, Multisystem inflammatory syndrome in children( MIS-C) and sleep issues after recovery. In this challenging time of the COVID 19 pandemic, it is important to remember that we all are responsible and have to work hand in hand by following the protocols and preventive measures to stop the spread of this virus. People with severe COVID-19, such as those in an intensive care unit (ICU), are vulnerable to opportunistic bacterial and fungal infections. The most common fungal infections in patients with COVID-19 include mucormycosis, aspergillosis, and invasive candidiasis. Now, health experts have stated that diabetes and steroid intake, coupled with coronavirus infection could be the main reasons for the suddenspike of opportunistic fungal infections worldwide mainly in India.

2.What is an Opportunistic Infection?

Opportunistic infections are infections that occur more often or are more severe in people with weakened immune systems. These infections may occur due to bacteria, fungi, or viruses, that normally inhabit the human body and do not cause disease in healthy people, but become pathogenic when the body's defense system is impaired. More often, opportunistic fungal infection is a therapy-associated complication in patients needing immunosuppressive treatment and prolonged ICU stays. Malnutrition, AIDS, Uncontrolled Diabetes, Patients who have undergone bone marrow or organ transplantation, undergoing chemotherapy, and other leucopenia conditions are other contributing factors.

3. What is a Fungus?

Fungus is an organism separate from the plants and animal kingdoms. It is ubiquitous and found in soil, plants, decaying organic matter, water, air, damp places and also as commensal in humans and animals.Fungi play a very important role in our ecosystem along with bacteria, by degrading organic matter into simpler forms for the consumption of plants. The most common being Candida, Aspergillus, Cryptococcus,Histoplasma, Pneumocystis, and Mucormycetes. Our body’s defense mechanisms are continuously fighting against these fungi, and keep us infection-free.

4.Opportunistic Fungal Infections
Opportunistic Fungal Infections are caused by fungi that are nonpathogenic in the immunocompetent host and cause infection when the immunity is suppressed. Aspergillus, Candida, Cryptococcus, Mucormycetes are the most common opportunistic fungal infections. These fungal species are widely distributed in soil,plant debris, and other organic substrates or a part of the normal upper respiratory tract flora. Infection can be transmitted by inhalation of spores( aspergillosis, cryptococcosis), cutaneous/ subcutaneous infections, or penetration into the mucosa by commensal organisms such as Candida albicans. Infections may be mild or may cause life-threatening systemic illnesses such as candidiasis, aspergillosis, and mucormycosis.
Candida species can invade the local site(mucocutaneous or cutaneous candidiasis) or cause systemic infections( renal, liver abscess, brain, and lung infections). Allergic symptoms such as allergic bronchopulmonary aspergillosis were reported in infections with Aspergillus species. Mucormycosis is the most lethal opportunistic fungal infection among patients with diabetes mellitus, malignancies, immunosuppressants, or prolonged hospital stay.

5.Fungal Infections in COVID patients
Fungal coinfections mainly with Mucormycetes, Candida, and Aspergillus are common with hospitalized critically ill COVID patients on Steroids or other immunosuppressants such as Tozilizumab, Itolizumab which suppress the immune system coupled with uncontrolled Diabetes. Yellow fungus or Mucor septicus coinfection has also been reported among COVID patients.

A. Mucormycosis (Black fungal Infection)
Mucormycosis, known as zygomycosis previously, is an opportunistic infectious disease caused by a group of fungi belonging to the family "Mucorales". Fungi in this family are usually found in the environment, in soil, and/ or associated with decaying organic material such as fruits and vegetables. It’s a noncontagiousinfectious disease that occurs only in compromised immune conditions.

a. Pathophysiology
Immunosuppressive therapy ally with uncontrolled glycemic status is the risk factor, in which Mucormycosis is on the rise among COVID patients during or after recovery, Worldwide and in India. India is known as the world's diabetes capital and nearly one-sixth of people with diabetes in the world are from India. Also, the second wave of coronavirus disease has been more lethal in India. Administration of immunosuppressants early in the disease may suppress the body's natural immune mechanism to fight against the virus, viremia phase may be prolonged. Also, steroid therapy increases blood sugar in diabetics, and the prediabetic stage becomes frank diabetic. Mucorales can acquire iron from the host, which is essential for their growth. In conditions such as diabetic ketoacidosis, free iron are readily available in the serum which promote their increased growth. Other immunosuppressives can also predispose to this infection.
There are several forms of Mucormycosis, 1. Rhino-orbito- cerebral Mucormycosis, 2. Pulmonary Mucormycosis, 3. Gastrointestinal Mucormycosis, 4. Disseminated Mucormycosis and 5. Cutaneous Mucormycosis. Among these the most brutal, ruthless manifestation being with Rhino-orbito-cerebral
mucormycosis (ROCM), which is the common one associated with COVID patients; is a rare, invasive, and rapidly progressive type of Mucormycosis affecting the nose, paranasal sinuses, orbit, palate, and brain; linked to high morbidity and mortality. The fatality rate ranging from 40- 50%.
These fungi are angioinvasive, invade the surrounding blood vessels and destroy them leading to tissue necrosis and tissue death. These molds live throughout the environment and their spores get lodged in the nasal cavity and adjoining sinuses during inhalation. On reaching a favorable condition, the spores germinate, hyphae (filamentous processes) outgrow, and become rapidly growing fungi. As they grow in the nasal cavity they relentlessly destroy the surrounding soft tissue and bones in the nasal cavity and sinuses. Also, damages the hard palate, the orbital bones, and the skull base bones. Black masses may be seen in the nasal cavity, oral cavity, perioral, or periorbital areas. Once the orbit is destroyed and enters the eye socket it may cause bulging of the eyes, pain, restricted eye movements, blindness, or eventual loss of an eye. If the organism enters the cranial cavity by breaching the skull base it blocks major arteries and veins resulting in life-threatening brain strokes and bleeds. Also, spores may travel into the depths of the respiratory system, get lodged in the lung parenchyma, grow rapidly, destroying the lung tissue and compromising blood oxygenation.
b.Clinical Features
C/ Fs of ROCM( Rhino- Orbito- Cerebral Mucormycosis)
• Nasal congestion and discharge ( brown/black), foul smell
• Facial pain, numbness, facial swelling, headache, drowsiness, or seizures.
• Toothache, loosening of teeth, jaw bone involvement, and as the disease progresses the palate
may be destroyed as a large black necrotic mass.
• Pain and swelling over paranasal sinuses.
• Blurred or double vision, Periorbital discoloration, eye pain, conjunctival congestion, proptosis(
protrusion of the eyeball), loss of movement, and loss of vision.
• Fever, altered sensorium, and paralysis
• If the brain is invaded due to blood vessel blockage there will be strokes, hemorrhages, and even death.

C/Fs of Pulmonary Mucormycosis
• Fever, Cough, Chest pain, Pleural effusion, Haemoptysis, Haematemesis
• Worsening of respiratory symptoms.
c. Diagnosis
Diagnosis is based on the clinical presentation, lab investigation, culture, radiographs, and/ or biopsy.
o On endoscopic visualization of the nasal cavity, the presence of a black eschar (slough or dead
tissue) coated masses gives away the diagnosis.
o When the orbit is involved there will be proptosis (protrusion of eyeball), loss of movements of the eyeball with consequent double vision, or loss of vision.
o Endoscopic collection of debrided tissue or biopsy from the nose or PNS for microscopy and culture
o Based on clinical suspicion, MRI and high-resolution CT scan of the nasal cavity, sinuses, and brain is performed. These give a clear picture of the presence of the lesion along with its extent.
o CT lung helps to differentiate COVID-associated pulmonary Aspergillosis by Reverse halo sign

and more than 10 pulmonary nodules and pleural effusion is favorable in diagnosing COVID-
associated Mucormycosis.

o Broncho-alveolar lavage, a biopsy of the lung, CT-guided biopsy from the lung for laboratory
investigation, fungal staining, culture, and microscopic examination.
d. Prevention of Mucormycosis
o Steroid usage must be limited with strict blood glucose control and should be administered as per guidelines.
o Unnecessary use of broad-spectrum antibiotics to be avoided as it removes the normal commensal flora resulting in the growth of opportunistic microbes.
o Control of blood sugars and regular monitoring of blood sugar once discharged from the hospital
o Maintenance of good hygiene and cleanliness is a must, regular oral hygiene care with mouthwash and povidone-iodine gargles.
o Water for humidification must be sterile while administering oxygen and change the sterilized humidifier and tubes regularly.
o The surroundings must be clean, free of dust, rotten vegetables, and fruits, which helps the growth of the fungus.
o Universal masking reduces exposure to Mucorales.
o During discharge of the patients, advice the patients about the early symptoms of Mucormycosis, which may help for early intervention.
e.Treatment of COVID associated Mucormycosis
Team of Doctors and supporting staff including Physician, Microbiologist, ENT specialist, Neurologist,
Ophthalmologist, Radiologist, Dentist, and Surgeons can only effectively treat COVID associated
Mucormycosis. Early diagnosis and prompt treatment with medical and surgical intervention required to
reduce morbidity and mortality with Mucormycosis.
• Control Diabetes and Ketoacidosis
• Reduce administering steroids and other immunosuppressive drugs and prescribe steroids if required when active infection subsides or if the patient is critically ill.

• Necrotic tissue should be removed surgically because the penetration of antifungal medication is
suboptimal in the necrotic area. Sometimes need to exenterate the eye or surgical removal of the jawbone in case of extensive involvement of eye or jaw.
• Maintain adequate systemic hydration and infuse normal saline.
• Liposomal Amphotercin B( L- AmB) 5mg/ kg/day, dilute in 200 cc 5% dextrose, slow infusion for 2-3 hours( 10mg/kg/day in case of brain involvement) for 4-6 weeks.
• Monitor renal function and potassium level once treating with Amphotericin B.
• Alternative agents such as Posaconazole when the patient is intolerant to Amphotericin B
• Rehabilitating the patient with a prosthesis if required.

B.Candidiasis (White fungal Infection)
Candidiasis or Moniliasis is an infectious disease produced by Candida species, yeast-like fungi, a common inhabitant of the oral cavity, alimentary tract and causes infections in persons with a debilitating illness, immunosuppressive therapy, uncontrolled diabetes, and prolonged antibiotic therapy.
Candidiasis of the mucous membrane of the mouth is called thrush and that of the vagina is known as Candidal vaginitis, perleche is the candida infection at the corners of the mouth, and candidiasis of skin occurs mainly in the folds such as armpits. In severe immunosuppression, the fungi may invade the respiratory system, stomach, kidney, and brain. The tongue might be coated and become white.
COVID-19 patients with a weak immune system, diabetes, and those who are on steroids for a prolonged period and prolonged ICU stay are more at risk of deep candida infections. Also, patients who are on oxygen support, renal disease, or AIDS are more prone to white fungal disease and which produces lung infection and shows signs and symptoms similar to COVID 19 such as cough, fever, chest pain, and shortness of breath. Infections in joints that cause joint pain may be confused with rheumatoid arthritis. Candidal infections of the central nervous system may cause confusion, headache, and seizures.
a. Prevention, Diagnosis, and Treatment of White Fungus
White fungal infection can be prevented by wearing loose cotton garments, eat nutritious food that boosts our immunity, reduce the use of steroids and treat hyperglycemia. The disease can be diagnosed by either taking a small tissue sample or biopsy of the infected area of the body and blood tests also sometimes help in discovering the infection. Culture is the gold standard of diagnosis. Prompt diagnosis and treatment are of paramount importance for clinical success. Treatment of White Fungus disease is mainly done through topical and systemic antifungal medications like Echinocandins, fluconazole, and IV Amphotericin .
B Systemic antifungal therapy for deep candida infections of lung, kidney, or brain.

C. Mucor septicus (Yellow Fungal Infection)
Along with the cases of black fungus and white fungus, the first-ever reported case of Yellow fungus infection in Ghaziabad, Uttar Pradesh, India. Yellow fungus is otherwise known as Mucor septicus, a fungus commonly seen in reptiles. It's an opportunistic pathogen and causes disease once the immunity is lowered. There is no such terminology or references in the medical literature still regarding this fungus affecting human beings. Common symptoms of Yellow Fungus infection are lethargy, loss of appetite, weight loss,sunken eyes, abscess formation, and pus leakage. The wound of yellow fungus takes a longer time to heal than white and black fungal wounds. Severe systemic infection may lead to organ failure and death.
Irrational use of steroids coupled with diabetes and prolonged ICU admission are the risk factors of Yellow Fungal infection. High humidity beyond the range of 30-40%, and improper waste disposal can promote the growth of fungus. Poor hygiene is the primary cause and Yellow Fungal infection and it occurs when the person inhales the fungal spore present in the atmosphere.
a. Prevention and Treatment of Yellow Fungus keep the surroundings clean, remove stale food and excreta to prevent fungal growth. Keep the blood sugar under control, indiscriminate use of steroids and other immunosuppressants should be avoided, ensure clean water availability for patient's use, and maintain good personal hygiene. Amphotericin B, an antifungal is the drug of choice for the treatment of yellow fungus. Since this infection spreads internally and causes heavy internal damage, people are advised to seek treatment from the very beginning to prevent the case from being complicated.

D. Aspergillosis
Amidst of raising of mucormycosis cases, observing few cases of another invasive fungal infection called aspergillosis among recovered Covid-19 patients. The foremost reason for this opportunistic fungal infection among patients infected with the novel coronavirus in the second wave is extensive use of steroids and poor glycemic control. Other causes are immunosuppressive conditions, organ transplants, and malignancies. Aspergillosis is an infection caused by aspergillus, a common mold that lives indoors and outdoors. Symptoms of aspergillosis “mimics mucormycosis” spreads slowly, cause blindness, organ dysfunction, and invades the lungs. Immunocompetent people are not infected even if they breathe aspergillus spores due to high immunity.
There are different types of Aspergillosis such as Allergic Bronchopulmonary Aspergillosis, Invasive Aspergillosis, Aspergilloma, Chronic Pulmonary Aspergillosis, and Cutaneous Aspergillosis. Pulmonary Aspergillosis has been commonly seen in COVID patients. Invasive aspergillosis affects the lungs and causes cough with expectoration, blood-stained sputum, breathlessness, and fever. Involvement of the nose and paranasal sinuses results in symptoms similar to mucormycosis.
a. Prevention and Treatment of Aspergillosis
The preventive measures of Aspergillosis among COVID patients are, avoid areas with lots of dust, wear masks regularly, avoid activities that involve close contact with soil, maintain good hygiene, reduce intake of steroids, control diabetes and do the tests that help to find out early infection.
Make diagnosis by symptoms, risk factors, physical examination, lab test, Chest X-ray, and CT. Do perform a nasal endoscopy for all post-Covid-19 patients with low immunity for early diagnosis of invasive fungal infections like Aspergillosis. To rule out aspergillosis do a fungal culture. Patients with aspergillosis
are usually treated with an antifungal drug called Voriconazole, Isavuconazole, or Amphotericin B.

6. Summary
Opportunistic fungal infections may occur in COVID-19 patients with immunosuppressive therapy, immunosuppressive conditions, and poor glycemic control. Opportunistic infections carry more fatality rate than COVID infection. So, awareness among health care providers and the public is very important in earlydiagnosis and aggressive treatment; that is paramount for improving the outcome of the disease, together we can be able to win the battle against COVID 19 and Opportunistic Fungal Infections.

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