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REVIEW ARTICLE
Year : 2022 | Volume
: 49
| Issue : 3 | Page : 223-228
Coronavirus disease 2019-associated mucormycosis of the head-and-neck area: A new rise of dreaded black fungus in the current pandemic
Santosh Kumar Swain1, Pragnya Paramita Jena2
1 Department of Otorhinolaryngology and Head and Neck Surgery, Siksha “O” Anusandhan University, Bhubaneswar, Odisha, India
2 Microbiology, IMS and Sum Hospital, Siksha “O” Anusandhan University, Bhubaneswar, Odisha, India
Correspondence Address:
Prof. Santosh Kumar Swain
Department of Otorhinolaryngology and Head and Neck Surgery, IMS and Sum Hospital, Siksha “O” Anusandhan University, K8, Kalinga Nagar, Bhubaneswar - 751 003, Odisha
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/jss.jss_56_21
Coronavirus disease 2019 (COVID-19) pandemic is currently evolving and associated with more complications with invasive fungal infection like mucormycosis. Classically, uncontrolled diabetes mellitus (DM) and other immunosuppressive conditions like corticosteroid therapy are known risk factors for causing mucormycosis in COVID-19 patients. Mucormycosis is an invasive fungal infection which rapidly spread to the orbit and brain from the nasal cavity and paranasal sinuses. Mucormycosis in COVID-19 is a fatal to the patient. There is possibility of COVID-19 as a trigger factor for diabetic ketoacidosis which predisposes to invasive fungal infections such as mucormycosis. Patients with poorly controlled DM and immunocompromised conditions increase the risk for development of COVID-19 infections in COVID-19 patients. During the current COVID-19 pandemic, a myriad of clinical manifestations and complications are emerged. Rhino-orbital-cerebral mucormycosis is a fatal clinical entity associated with COVID-19 infections resulting in higher morbidity and mortality. The treatment includes both medical and surgical interventions. It requires early and adequate treatment with amphotericin B and surgical debridement and control of risk factors. A multidisciplinary approach by otorhinolaryngologists, ophthalmologists, neurologists, and dentists is successful for treatment of COVID-19 patients with mucormycosis in the head-and-neck region. Identification of the risk factors and early preventive measures will minimize the incidence of life-threatening mucormycosis in the head-and-neck area of COVID-19 patients.
Keywords: Amphotericin-B, coronavirus disease 2019, coronavirus disease 2019-associated mucormycosis, head-and-neck area, mucormycosis, rhino-orbital-cerebral mucormycosis
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and now considered a global public health emergency.[1] COVID-19 infection is associated with a wide range of disease patterns which ranges from mild to life-threatening pneumonia. There are a wide number of bacterial and fungal infections that may be found and associated with preexisting morbidity like diabetes mellitus (DM) and lung diseases. India has a high prevalence of type 2 DM (approximately 8.9% of adults, approximately 77 million patients) which acts as a well-recognized risk factor.[2] Again, the widespread use of corticosteroids/monoclonal antibodies//broad-spectrum antibiotics as part of the armamentarium against COVID-19 infections may result in the development or exacerbation of preexisting fungal diseases or getting fatal infection like mucormycosis. Mucormycosis is an opportunistic fungal infection and rarely found in routine clinical practice. Mucormycosis is characterized by infarction and necrosis of the tissues of the patient which results from the blood vessels by the hyphae. The involvement of the rhino-orbital area is usually secondary to inhalation of the spores into the nose and paranasal sinuses of a susceptible host.[3] However, the incidence of non-COVID-19 rhinocerebral mucormycosis is 33%–50%.[4] Clinical suspicion, diagnosis, and early treatment with surgical debridement are key for preventing this fatal clinical entity. Histopathological study, direct, microscopy, and culture from the clinical samples are the important diagnostic modalities for mucormycosis.[1] COVID-19-associated mucormycosis (CAM) is less frequently documented in the literature. The objective of this review article is to discuss the details of CAM with its epidemiology, etiopathology, clinical presentations, diagnosis, and current treatment.
Methods of Literature SearchCurrent research articles regarding mucormycosis in the head-and-neck area of the COVID-19 patient were searched through a multiple systematic approach. First, we conducted an online search of the Scopus, PubMed, Medline, and Google Scholar databases. The abstract of the published articles was identified by this search method and other articles were identified manually from the citations. This manuscript reviews the details of the CAM specifically in the head-and-neck region of COVID-19 patients. This review article presents a baseline for further prospective trials toward this fatal fungal infection such as mucormycosis of the head-and-neck region or rhino-orbital-cerebral part among COVID-19 patients in the current pandemic. It will also help as a spur for further research in this dreaded fungal infection in COVID-19 patients and so protect from such fatal fungal infection, also called as mucormycosis or black fungus.
EtiopathogenesisThere are a variety of complications documented during and post-COVID infection. There has been an increase in number of sporadic cases of mucormycosis in the head-and-neck region in COVID-19 patients. Mucormycosis (previously called as zygomycosis) is an uncommon and devastating disease caused by a ubiquitous fungus which belongs to the class Zygomycetes and order Mucorales.[5] Fungi that belong to Mucorales cause infection called as mucormycosis. Rhizopus is the most common fungus seen in patients who have mucormycosis in diabetes patients.[6] Rhizopus is unable to sequester iron from nonbinding proteins.[6] In patients of poorly controlled DM, the long-standing elevated blood glucose levels result in impaired neutrophil function.[7] The fungi often get entry through inhalation into the nasal cavity and paranasal sinuses and may finally spread to the sphenoid sinus, palate, and cavernous sinus in COVID-19 infection; there will be dysregulation of the immune system with reduced number of T-lymphocytes, CD 4 + T, and CD 8 + T cells which impair the immunity of the patient.[7] In case of ketoacidosis, hyperglycemia and acidic pH may result in defect in motility and killing of the bacteria and fungi by the neutrophils. It is thought that pH becomes acidic and iron–protein complexes dissociate that allow for fungal cells to use raised free iron.[6] In patients of DM, rhino-orbital-cerebral mucormycosis is documented to be the most common type.[8] This fungus rarely affects immunocompetent persons but rather immunocompromised patients. The predisposing factors for mucormycosis are DM, neutropenia, systemic corticosteroids, hematological malignancies, organ transplant patients, and immunocompromised patients [Table 1].[9] In a patient with normal functioning immune cells, the spores and hyphae are usually readily taken up and destroyed by mononuclear and polymorphonuclear phagocytes. However, the patients have low phagocyte count, impaired phagocyte function, neutropenia, or poorly controlled DM; they are easily susceptible to invasive mucormycosis.[10] COVID-19 patients might show higher levels of inflammatory cytokines such as interleukin (IL)-2R, IL-6, IL-10, and tumor necrosis factor-alpha along with impaired cell-mediated immune response and affect both CD4+ T- and CD8+ T-cells. Hence, this clinical situation increases the susceptibility for fungal infections. Mucormycosis is characterized by infarction and necrosis of the tissues which leads to invasion of the vessels by the hyphae. On the basis of the anatomical sites, mucormycosis may present as different syndromes such as rhino-orbital-cerebral, pulmonary, cutaneous, and less commonly gastrointestinal, renal, and disseminated diseases.[11] The patients usually present a black and necrotic eschar in the affected sites.
Table 1: Predisposing factors for causing mucormycosis among coronavirus disease 2019 patients Epidemiology In the current pandemic, global attention is mainly on infected patients and its associated complications. In early December 2019, the first case of COVID-19 was identified in Wuhan.[12] It was declared as a public health emergency by the World Health Organization on January 30, 2020. By May 18, 2020, COVID-19 has spread to 212 countries of the world and it caused approximately 5 million confirmed cases (laboratory confirmed) and more than 310,000 deaths globally.[13] Similar to Middle East respiratory syndrome and SARS-CoV, SARS-CoV-2 is responsible for infecting the lower respiratory tract and results in acute respiratory distress syndrome.[14] As this is a novel virus, data related to the signs and symptoms indicative of COVID-19 disease are insufficient.[15] Currently, there is an increasing number of cases mucormycosis in COVID-19 patients those with DM, taking long time steroid or suffering from malignancy or organ transplant recipients. In the first wave of the COVID-19 pandemic, the incidence of CAM was low; however, in the current third wave of the pandemic, the incidence is rising. In Mexico, DM is the most common underlying comorbidity with approximately 72% of the cases reported, of which approximately 75% had rhinosinusitis with overall mortality by mucormycosis being approximately 51%.[16]
Clinical PresentationsMucormycosis is a dreaded fungal infection sporadically found in the head-and-neck area of COVID-19 patients. Mucormycosis is a serious and opportunistic fungal infection and usually affects elderly diabetic and immunocompromised patients.[17] It is a rapidly progressive disease and often ended in fatal outcome. The clinical presentations of mucormycosis depend on the site of the disease. In case of rhino-orbital and cerebral mucormycosis, patients complain blurring of vision, inflammatory swelling around the orbit [Figure 1], sinusitis, facial pain, numbness, proptosis, headache, ophthalmoplegia, or even periorbital cellulitis [Table 2].[18] Rhino-orbital-cerebral infection is a typical presentation of mucormycosis where fungi invade the paranasal sinuses to orbit and brain.[19] This clinical situation can result in orbital apex syndrome such as complete ophthalmoplegia with rapid loss of vision and involves cranial nerves such as II, III, IV, V, and VI which need urgent treatment with surgical intervention, antifungal drugs, and control of risk factors for preventing such morbidity and fatal outcome.[20],[21] During examination of the nasal cavity and oral cavity, a black eschar may be noted. Approximately 70% of the rhino-orbital-cerebral mucormycosis cases have been seen in patients of DM; majority of them have ketoacidosis at the time of presentation. Patients with mucormycosis usually present with acute sinusitis, nasal congestion, fever, purulent nasal discharge, and headache. All the paranasal sinuses are usually affected and spread to adjacent structures such as palate, orbit, and brain resulting in clinical manifestations. Spreading of the infection from the ethmoid sinus to the frontal lobe causes obtundation. Orbital involvement causes orbital compartment syndrome by expansile process with closed compartment of the orbit causing raised orbital pressure and results in ischemia and loss of vision. Delay in intervention (lateral canthotomy and inferior cantholysis) by ophthalmologists leads to permanent blindness. This diagnosis is done when patients present with acute proptosis, increased intraocular pressure, rapid loss of vision, ophthalmoplegia, fixed dilated pupil, or afferent papillary defect. Clinicians should be aware of the risk of invasive secondary fungal infections such as mucormycosis in COVID-19 infection particularly with preexisting morbidity or risk factors and so help early diagnosis and treatment. The use of therapeutic agents like corticosteroids, immunomodulators like tocilizumab should be monitored for getting therapeutic effect at the lowest dose with the shortest duration. The use of broad-spectrum antibiotics by clinicians, especially in the absence of any infection must be re-evaluated.
Figure 1: A 15-year-old girl with COVID-19-associated mucormycosis presenting with right-side facial and orbital swelling
Table 2: Early symptoms and signs of rhino-orbital-cerebral mucormycosis Diagnosis Clinical suspicion and early diagnosis with prompt treatment are key steps for preventing the morbidity of fatal condition like rhino-orbital-cerebral mucormycosis.[22] Proper history taking, physical examination, and imaging are important components for diagnosis of the suspected mucormycosis. In diabetes patients with COVID-19 infection and mucormycosis, computed tomography (CT) scan will often show bone destruction. Brain magnetic resonance imaging (MRI) is helpful to rule out any involvement of the brain, sinuses, and orbit. An MRI of the brain shows multiple areas of infarction and ischemia indicating invasive fungal disease. In case of unstable hemodynamic and poor respiratory status, patients often unable to sleep in supine position to perform MRI. In case of rhino-orbital mucormycosis, CT scan shows a soft tissue swelling affecting the face and eye with edema of the periorbital tissues and muscles. A further CT scan reveals evidence of cavernous sinus thrombosis which is better confirmed by MRI. An MRI angiogram shows partial occlusion of the common and internal carotid arteries or cavernous sinus involved with mucormycosis.[23] Bedside nasal endoscopy can be performed in a timely manner and histopathological processing in case of active COVID-19 infection is useful for starting the treatment for rhino-orbital mucormycosis. Mucor is usually demonstrated via a nasal biopsy and subsequent culture. Tissue is sent for histopathological examination and potassium hydroxide mount which confirm the mucormycosis.[24] Early identification of fungal co-infections may significantly reduce morbidity and mortality.[25] A biopsy should be done to confirm the mucormycosis. Fungal culture should be done in routine media at 30°C and 37°C or polymerase chain reaction also confirms the diagnosis. The biopsy at the time of the surgery can be sent for fungal staining and histopathological study. Histopathological examination, direct microscopy, and culture from the clinical samples are the major diagnostic modalities of mucormycosis.[26] The details of blood tests and diagnostic investigations of CAM are given in [Table 3].
Table 3: Investigations required in coronavirus disease 2019-associated mucormycosis patients Treatment The confirmed or suspected mucormycosis in the head-and-neck region of COVID-19 patients needs an immediate consultation with surgical team.[27] The patients have several challenges for getting prompt treatment. Poorly controlled DM and COVID-19 status may synergistically enhance the patient's susceptibility toward mucormycosis.[28] Proper control of hyperglycemia and early treatment with liposomal amphotericin B and surgical debridement are essential parts for successful management of mucormycosis [Table 4]. Patients often need surgical debridement in the emergency basis. If patients develop orbital apex syndrome secondary to paranasal sinus mucormycosis with COVID-19 infection require emergency endoscopic sinus surgery with debridement. It is always crucial for keeping clean margins at the time of the surgical debridement to stop the spread of this fungal infection. This will help as an immediate and effective surgical treatment. As endoscopic sinus surgery is an aerosol-producing procedure with a high chance of transmission of the coronavirus to the health professionals inside the operating room.. Hence, there must be precaution taken by the surgeon and other staffs inside the operating room.[29] However, there is no change in technique of the endoscopic sinus surgery. Hence, optimum safety measures of the health-care workers along with complete patient care are needed during the emergency surgical intervention of mucormycosis in the paranasal sinuses, orbit, and brain. The surgical and anesthesia team must wear personal protective equipment, surgical cap, N-95 mask, head shield, and double gloves. There should be strict donning and doffing measures.[30] The widely accepted treatment for mucormycosis is amphotericin B along with surgical debridement. Treatment of mucormycosis of paranasal sinuses requires aggressive and quick surgical intervention. It needs aggressive surgical debridement and antifungal therapy. After surgical debridement, the patient is usually left with a large bony defect. This bony defect demands reconstruction to protect the remaining vital structures, restore the function, and give a socially acceptable appearance.[31]
During administering amphotericin B, it is essential for monitoring renal function because of its risk toward nephrotoxicity. In case of extensive disease, second-line therapies may be considered. A combination of echinocandins and amphotericin B is recommended as a secondary line of therapy.[32] If echinocandins are added with amphotericin B, they will add a polyene backbone which enhances the success of treatment. Some second-line antifungals include triazoles, posaconazole, and isavuconazole.[32] Triazoles inhibit the 14-α-demethylation which increase in toxic 14-α-methyl sterols which alter the fungal membrane's permeability. Patients who are intolerant to amphotericin B are given posaconazole. Isavuconazole has an extended spectrum of effect. Due to its extended spectrum, it is the only antifungal agent used in the treatment of invasive mucormycosis.[11] The current guideline of treating mucormycosis recommends liposomal amphotericin B at a dose of 5–10 mg/kg per day. In the absence of central nervous system involvement, a dose of 5 mg/kg is helpful.[33] In a randomized controlled study of 201 patients having invasive mucormycosis, liposomal amphotericin used at a dose of 3 mg/kg/day was equally effective and safer and well tolerated than 10 mg/kg/day dose of amphotericin B.[34] In case of patients with kidney disease, liposomal amphotericin must be advised in place of amphotericin B. The optimal duration of treatment in mucormycosis is not usually clear and often guided by the treatment regimen's clinical response and tolerability by the patient. Early identification and prompt treatment of mucormycosis in COVID-19 patients help to assure a good prognosis. In case of uncontrolled DM, it is highly important to correct hyperglycemia and ketoacidosis.[32] The prompt control of hyperglycemia and the reversal of ketoacidosis result in best outcome.[35] In addition to this, tapering of the immunosuppressive medication may play an additional role for effective treatment of mucormycosis. The use of steroids/glucocorticoids in mild cases of COVID-19 (without hypoxemia) or utilization of higher doses of steroids must be avoided. As per current guidelines in India, the recommended intravenous methylprednisolone 0.5–1 mg/kg/day for 3 days in moderate cases and 1–2 mg/kg/day in cases of a severe variety of COVID-19 infections.[36] As per the recommendation by the National Institutes of Health, dexamethasone (6 mg/day for maximum 10 days) in COVID-19 patients can be used in patient with a ventilator or patient with supplementation of oxygen but not in milder cases.[37] This guideline mentions the risk of secondary infection. In the absence of clear benefit, certain medications targeting immune pathways like tocilizumab must be discouraged.[38]
PrognosisThe global mucormycosis case fatality rate is approximately 46%.[39] The diagnosis of mucormycosis is often difficult. However, early diagnosis and treatment is always essential and delay of even 6 days is associated with doubling of mortality from 35% to 66%.[39] Despite early diagnosis and aggressive surgical and medical treatment, the prognosis for getting recovery from mucormycosis is poor. A high suspicion of mucormycosis is considered in immunocompromised patients. In case of high-risk persons, the diagnosis of mucormycosis can be suspected if there is associated with unilateral facial swelling, facial pain, orbital swelling, or proptosis. The late sign is tissue necrosis which acts as a hallmark for mucormycosis and occurs due to angioinvasion and vascular thrombosis.[40] Once the diagnosis is done, prompt surgical opinion is required followed by antifungal agents. One study showed 20% chances of recurrence in head-and-neck mucormycosis where 20 patients presented with rhinocerebral mucormycosis.[41] Early diagnosis and prompt treatment are necessary for improvement of the outcome of mucormycosis.
ConclusionCOVID-19 infection is spreading quickly all the continents of the world. Currently, mucormycosis, a fatal fungal infection, is associated with COVID-19 patients. Patients of DM or taking systemic steroids or under any immunosuppressive medication with COVID-19 are at higher susceptibility for fungal infection. Mucormycosis is a life-threatening fungal disease resulting in vascular invasion by the hyphae leading to thrombosis and necrosis of the host tissue. In COVID-19 patients, the severity of mucormycosis is due to its rapid progression and angioinvasive nature. Health-care professionals should act promptly to identify mucormycosis, particularly in immunocompromised patients or poorly controlled DM. There should be a multidisciplinary approach for this fatal clinical entity such as prompt diagnosis and early treatment with antifungal and appropriate surgical debridement plus reversal of the underlying risk factor condition.
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