It’s a phenomenon first identified in India earlier this year: Patients who have or are recovering from COVID-19 who then contract a sometimes deadly fungal infection known as mucormycosis—also known as “black fungus.”
Now, the U.S. Centers for Disease Control and Prevention said isolated cases of the disease are hitting COVID patients in the United States.
The condition is caused by a variety of naturally occurring fungi that are typically harmless, but can trigger illness in folks whose immune systems have been depleted by illness, including COVID-19.
In a statement issued by the Indian Ministry of Health and Family Welfare in May, experts there explained that “people catch mucormycosis by coming in contact with the fungal spores in the environment [soil or decomposing leaves]. It can also develop on the skin after the fungus enters the skin through a cut, scrape, burn or other type of skin trauma.
“Mucormycosis begins to manifest as skin infection in the air pockets located behind our forehead, nose, cheekbones, and in between the eyes and teeth,” the Indian agency added. “It then spreads to eyes, lungs and can even spread to the brain. It leads to blackening or discoloration over the nose, blurred or double vision, chest pain, breathing difficulties and coughing of blood.”
Once established, “black fungus” disease is tough to treat. As the Indian experts explained, “treatment involves surgically removing all dead and infected tissue. In some patients, this may result in loss of upper jaw or sometimes even the eye.
Cure may also involve a 4-6-week course of intravenous antifungal therapy. Since it affects various parts of the body, treatment requires a team of microbiologists, internal medicine specialists, intensivist neurologists, ENT specialists, ophthalmologists, dentists, surgeons and others.”
Reporting in the Dec. 17 issue of the CDC journal Morbidity and Mortality Weekly Report, researchers led by CDC epidemiologist Dr. Jeremy Gold said they identified 10 lab-confirmed cases of black fungus illness in patients treated at six Arkansas hospitals between July 12 and Sept. 28, 2021. Nine of the 10 patients lived in the state, all were white, seven were men and the average patient age was 57.
Many cases were severe – four patients showed disease that had spread to the nose and mouth, with three of those patients also having the brain affected. In two cases, the illness attacked the lungs, and in one case the gastrointestinal system was affected, Gold’s team said.
None of the patients had been vaccinated against the new coronavirus.
Most patients did not survive their ordeal: “Five patients received surgical treatment to excise mucormycosis-affected tissue,” the CDC researchers said, and “six of the 10 patients died during hospitalization or within one week of discharge.”
The team noted that the outbreak in black fungus cases in Arkansas coincided with a midsummer statewide surge in COVID-19 cases, driven by the emergence and spread of the Delta variant.
In the absence of COVID-19, mucormycosis is exceedingly rare in Arkansas or other states. However, based on the summer outbreak, the Arkansas Department of Health “coordinated a statewide call on Oct. 11, 2021 to infection preventionists for COVID-19-associated mucormycosis cases,” the researchers said.
Dr. Amesh Adalja is senior scholar at the Center for Health Security at Johns Hopkins in Baltimore. He wasn’t involved in the new report, but said, “It is not surprising that mucormycosis is also able to ‘super-infect’ COVID-19 patients who have severe immune dysregulation.”
As they battle COVID-19, some of these patients may also be receiving medications that suppress their immune systems, such as dexamethasone or tocilizumab, and many will have already suffered lung damage, Adalja pointed out. That leaves them even more vulnerable to fungal infections such as mucormycosis.
Of course, many of the tragedies outlined in the Arkansas report could have been easily avoided, he added.
“The best prevention is to not have a case of severe COVID-19 in the first place, by being vaccinated,” Adalja said.
The surge in COVID-19–associated mucormycosis
Across borders, patients with COVID-19 experience notorious fungal coinfections during or after weeks or months of recovery. COVID-19–associated mucormycosis (CAM) has been reported in many countries like Austria, Brazil, Egypt, France, India, Iran, Italy, and the US [11,12].
A recent systematic review observed that CAM constitutes 0.3% of COVID-19 coinfections [13]. Mucormycosis is not unfamiliar to India; the case rate before 2019 was almost 70 times higher than in developed countries. The disease prevalence in India is predicted to be 140 cases per million population [8,14]. While India faces tough times during the second wave of COVID-19, there is a recent unexpected surge in CAM cases.
As a result, GoI has declared it a notifiable disease, while several state governments have declared it an epidemic [8]. Various control measures and guidance on procuring and allocating treatment drugs to all states were taken up quickly [15].
COVID-19–associated rhino-orbital-cerebral mucormycosis (CAROCM) is the most common type observed during the current epidemic, followed by the pulmonary form [16,17]. Prior to the COVID-19 pandemic, the mucormycosis mortality was 50%. However, during the current pandemic situation in India, it has increased to 85%, mainly due to crowded hospitals, unavailability of healthcare resources, overburdened healthcare workers, and poor diagnostic quality [18].
Notably, a recent systematic review of 7 global CAM cases observed 100% mortality, though 43% of them received antifungal monotherapy [19]. For India, a low doctor/patient ratio and practising by unqualified or nonregistered healthcare professionals are other key hurdles that the country faces to tackle CAM [20]. Lack of awareness and inadequate health infrastructure have introduced additional burden [16]. Globally, at least 6 systematic literature reviews are available on CAM, as of July 19, 2021. The majority of publications are from India (n = 4) [21–24]; the largest review has included 82 cases [24].
Besides, newer observational studies and case series have emerged. An Indian multicentric epidemiological study reported a 2-fold increase in mucormycosis cases year-over-year (2019 versus 2020). The CAM prevalence was 0.27% among hospitalised patients [25]. An in-press editorial from the Indian Journal of Medical Microbiology claims that a GoI website has mentioned more than 31,000 CAM cases by June 13, 2021 [16]. By July 2021, the case count reached 40,000 [26].
Extensive discussions and strategic actions are being promulgated from political, administrative, regulatory, and healthcare flagbearers during this unprecedented time as the country faces an epidemic within a ravaging pandemic. Recently, a staging system for CAROCM has been proposed, and a dedicated registry for CAM has been started.
The present critical review, which stands out from the limited reviews available as of July 19, 2021, attempts to comprehensively analyse recent evidence on CAM pathogenesis and its potential risk factors and intends to throw light on several India-specific treatment guidelines. We searched leading databases like PubMed, Web of Science, Ovid, Scopus, and Google Scholar for scholarly literature on CAM surge in India published until July 19, 2021, in English using the relevant keywords (“mucor*” OR “zygomycosis;” “COVID” OR “SARS-CoV” OR “coronavirus;” and “India”). Besides, we conducted a Google web search for CAM and COVID-19 statistics and potentially relevant news reports published before the above data cutoff period. We also reviewed the official websites of professional societies like the “Indian Medical Association” and governmental portals like the “Directorate General of Health Services–India” before the said date for any essential treatment and management guidelines. Later in September 2021, we had modified the post-submission manuscript based on the peer review comments and updated it with the recent references suggested by the reviewers.
Causes, characteristics, and diagnosis
Mucormycosis is caused by various saprophytic fungi in the order Mucorales, including Rhizopus, Lichtheimia, Mucor, and Rhizomucor species, and the first 3 species account for three-fourths of all cases [27]. It is an opportunistic infection affecting the lungs, skin, gut, rhino-cerebral areas, and central nervous system (CNS) and presents a clinical condition specific to the organ system. It may also be present in a disseminated form [28]; postmortem analysis in a few patients with disseminated disease revealed that they did not receive systemic or surgical treatment [19].
Rhizopus arrhizus (previously named Rhizopus oryzae) is the most common causative agent globally, although the fungi responsible for infection differ between geographies. In India, Apophysomyces is the second most familiar species causing mucormycosis [29]. Apophysomyces elegans and Rhizopus homothallicus are commonly reported fungi in this region, while other uncommon ones, including Mucor irregularis and Thamnostylum lucknowense, have also been observed. This deep fungal infection is wrongly termed a black fungus by local media and even by some learned academic researchers by confusing dematiaceous fungi with those that cause mucormycosis [30,31]. A unique form of isolated renal mucormycosis has also been reported in India [32,33].
Mucormycosis is not contagious. The entry of infective spores present in the environment into the human body is by inhaling, ingesting or direct inoculation through wounds, and germinating into angioinvasive hyphae [19,31]. The most extensive observational study reported on CAROCM in India, as of July 19, 2021, included 2,826 patients from 22 states. This research, named COSMIC, conducted jointly by the Oculoplastic Association of India and the Indian Journal of Opthalmology, described the epidemiological features and clinical characteristics along with details of predisposing factors for developing CAROCM and presenting various management strategies and their reported outcomes.
The most common CAROCM symptoms observed in that study included orbital/facial pain (23%) and oedema (21%), vision loss (19%), ptosis (11%), and nasal congestion (9%); the primary signs included periocular/facial oedema (33%), vision loss (21%), proptosis (11%), and nasal discharge (10%) [34]. Pulmonary mucormycosis mimics the symptoms of COVID-19, such as pyrexia, cough, and dyspnea [18].
The initial features of CAROCM appear in the paranasal sinuses before extending to the orbit and the cranial cavity. CAROCM can be suspected in patients with signs and symptoms as observed in the COSMIC study, along with the presence of necrotic ulcers in the nasal cavity/palate and orbital apex syndrome and cavernous sinus syndrome [34,35]. Mucormycosis involving the ear may have the characteristics of otitis externa, and the usual antibacterial therapy does not resolve the otological symptoms [36]. Double- and triple-mutant variants of SARS-CoV-2 have emerged in India during the second wave of COVID-19, which are more dreadful and are doubted to play a mightier role in CAM surge [37,38].
A recent systematic review that compared CAM cases of India (n = 233) with that of other countries (n = 42) suggested that pulmonary or disseminated disease form was associated with increased death rate, and treatment (in combination form) could improve survival [39]. Another cohort study identified cerebral involvement, and a higher HbA1c (≥8) level could significantly predict patient survival [40].
Diagnostic confirmation can be obtained by
- (a) direct microscopy with slides mounted with potassium hydroxide, particularly when it is necessary to start therapy immediately;
- (b) fungal culture;
- (c) biopsy of the affected lesions with adequate precaution;
- (d) radiological (computed tomography of ostiomeatal complex and magnetic resonance imaging with contrast) examinations;
- (e) matrix-assisted laser desorption/ionisation time of flight mass spectrometric analysis [35,41–45].
Florid sinusitis and bone erosion may not be identified on radiological examinations at an early stage; therefore, initial findings should not lead to missed diagnosis [42]. REBOVasC checklist may help radiologists not to miss any critical findings in the imaging examination [46]. It focuses on the rhinosinus, extrasinus, bones, orbital, vascular, and CNS areas for infection spread.
How does mucormycosis affect patients with COVID-19?
There are 3 possible theories for CAM related to immune and inflammatory processes: (1) COVID-19 causes significant lymphopenia, resulting in a dramatic reduction in the availability of T cells (CD4+ and CD8+) and opening the entry gate for opportunistic fungal infections; (2) increased pro-inflammatory markers in patients with severe disease; and (3) pronounced damage of pulmonary tissues by COVID-19 aids the invasive fungi, especially the airborne ones or those that attack through the respiratory system [47,48].
Hyperferritinemia caused by excess interleukin-6 (IL-6) release and macrophage activation results in increased availability of free iron within cells. This, in turn, causes endothelial destruction and inflammation called endothelitis. In addition, the hepcidin mimetic action of the virus further induces ferritin independent of the inflammatory reaction [17].
Thus, COVID-19–induced immunosuppression increases the risk of opportunistic infection, damages the endothelium and alveoles, easing the port of fungal invasion, and increases the glucose level due to the acute diabetes-like state caused by pancreatic damage; increased ferritin level supports fungal growth, and increased body temperature is optimal for thermotolerant fungi.
Another exciting hypothesis revolves around the dysregulation of angiotensin-converting enzyme 2 expression in various bodily organs, immunosuppression, and the creation of a microenvironment system that increases the risk of coinfection in COVID-19 [49]. Up-regulation of 78-kDa glucose-regulated protein (GRP78), a heat shock protein, in patients with COVID-19 (5 times more than controls) due to increased glucose and iron content caused by diabetic ketoacidosis (DKA) or induced by dexamethasone use also facilitates fungal entry. Besides, it promotes Mucorales’ pathogenicity and virulence [17,50].
https://doi.org/10.1371/journal.pntd.0009921.g001
reference link :https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0009921
More information: Find out more about mycormycosis and its link to COVID-19 at the American Society for Microbiology.
Theresa M. Dulski et al, Notes from the Field: COVID-19–Associated Mucormycosis—Arkansas, July–September 2021, MMWR. Morbidity and Mortality Weekly Report (2021). DOI: 10.15585/mmwr.mm7050a3
