COVID-19 is associated with a significant incidence of secondary infections, both bacterial and fungal probably due to immune dysregulation. Additionally, the widespread use of steroids/monoclonal antibodies/broad-spectrum antibiotics as part of the armamentarium against COVID-19 may lead to the development/exacerbation of preexisting sinonasal infections, therefore, it might be suggested that SARS-CoV-2 infection by itself can induce an immunosuppressive state that exposes the patient to the risk of developing opportunistic infections, such as mucormycosis.
Pathophysiology
Besides, the diffuse alveolar damage with severe inflammatory exudation, COVID-19 patients always have immunosuppression with a decrease in CD4 + T and CD8 + T cells. Critically ill patients, who require mechanical ventilation, or longer duration of hospital stays are more likely to develop fungal sinonasal co-infections. The main fungal pathogens documented in literature are Aspergillus and Candida; however, COVID-19 patients with uncontrolled diabetes mellitus (persistent acidotic state), glucocorticosteroids (GC) use in moderate-severe COVID infections, requirement of prolonged humidified oxygen therapy, are more likely to develop mucormycosis, which can be life threatening to the patient. Various other immunocompromised states in an individual namely diabetic ketoacidosis, hematological malignancies, neutropenia, solid organ malignancies, high dose corticosteroids, post-organ transplantation, deferoxamine therapy, trauma, and burns also act as predisposing factors for mucormycosis. A study of 929 cases of zygomycotic showed prevalence and mortality of 36% and 44% resp. in patients with underlying diabetes [10, 11]. The immunocompromising effects of corticosteroids with microangiopathy in diabetic patients and possible peripheral microthrombi in COVID-19 provide the ideal host for invasive fungal rhinosinusitis, which due to its inherent angioinvasive nature leads to its increased incidence in such patients. Tissue necrosis, often a late sign, is a hallmark of mucormycosis, resulting from angioinvasion and vascular thrombosis.
Hyperglycemia especially along with acidosis is an ideal environment for fungal growth which is aided by weakened immune system secondary to altered chemotaxis and ineffective phagocytosis of PMNs and macrophages resp. due to impaired glutathione pathway [12, 13]. For Mucorales, iron appears to be a growth factor. Normally, transferrin, a serum iron binding protein clubs with iron and deprives the fungus of the same thus inhibiting their growth. In such situations microbes secretes siderophores which binds with the serum iron and in turn is utilized by the growing fungus. The excessive glycosylation of transferrin and ferritin protein in cases of uncontrolled diabetes leads to its decreased affinity for iron and thus its free availability to the growing fungus [14]. Deferoxamine, an iron and aluminum chelator in humans used in cases of iron overload in renal patients on dialysis also acts as a false siderophore for Rhizopus thus enabling their iron uptake and augmenting their hyphal growth [15, 16]. Patients with hematological malignancies, solid organ, or hematopoietic stem cell transplant (HSCT) recipients, which are continuously under the effects of immunosuppressants also lead to increase in the incidence of mucormycosis infection.
Comparison with other studies
Very few reports in literature have been documented so far, wherein complicated sinusitis has occurred in patients having concomitant COVID-19 infection [17]. One of the main pathophysiological mechanisms described is the occurrence of a generalized pro-thrombotic state resulting into microvascular and macrovascular thromboembolism. Han et al. wrote that certain coagulation parameters like raised D-dimers, fibrin degradation products, and fibrinogen correlate with severity of COVID-19 infection [18]. The pathophysiology of thrombophilia in SARS-CoV-2 infection is still debatable; however, some mechanisms have been proposed, which includes a pro-coagulable cytokine storm, role of viral affinity for angiotensin converting enzyme 2 (ACE2) receptors situated in vascular endothelium and also raised antiphospholipid antibodies. Reports of complications like pulmonary embolisms, deep vein thrombosis, cerebral infarction, and cerebral venous sinus thrombosis associated with ongoing COVID-19 infection are increasing in recent literature [19]. This may explain the intracranial complications including a case of cavernous sinus thrombosis in two patients of our case series.
In our review of literature, we came across various case reports but very few case series reporting complicated rhino sinusitis in COVID-positive patients. Despite the tropism of COVID-19 to both upper and lower respiratory mucosa, a very limited number of reports have studied its association with the development of complicated sinusitis. Turban et al. reported two cases of COVID-19-associated complicated sinusitis with orbital cellulitis [20].
White et al. reported an incidence of 26.7% for invasive fungal infections in his case series of 135 adults having COVID-19 infection [21]. Song et al. described association between COVID-19 and invasive fungal sinusitis in April 2020, and came to conclusion that a large number of patients either affected by or recovered from COVID-19 are at greater risk of developing invasive fungal diseases, and also devised a management algorithm for such cases [14, 22].
Pediatric rhinosinusitis
Disease spectrum of COVID-19 in pediatric population is a gray zone. Xu et al. found that patients in pediatric age group were 2.7 times less likely to contract the illness as compared to adults. Although data has suggested less severe disease form in the pediatric population, but still pediatric mortalities have been documented in the USA [23]. Conor H et al. have described two different approaches for dealing with complicated pediatric rhinosinusitis in COVID-positive patients in their case series [24]. Though we saw and successfully managed only one case of complicated CRS in a 10-year-old boy, but we hope that even a small contribution may result in a better understanding of disease progression in children.
Invasive fungal rhinosinusitis
Mucormycosis is a highly aggressive and relentlessly progressive invasive fungal infection with high mortality rates and its incidence has tremendously increased in patients who are suffering from COVID-19 or just recovered from it. In diabetic patients who are being treated for moderate-severe COVID Disease, Mucor infection has become very rampant owing to acidotic state providing an excellent media for mucor growth. Majority of cases have no prior history suggestive of rhino sinusitis. The intraorbital invasion by Mucor often leads to irreversible loss of vision as a part of post-COVID sequelae, making it famous as black fungus. The dilemma lies in distinguishing opportunistic invasive Mucor from other commensal fungus in nose and paranasal sinuses, thus highlighting a very important role of molecular biology, and other pathological and microbiological tests. Rhizopus, Mucor, Rhizomucor, Absidia, Saksenaea, Apophysomyces, and Cunninghamella are the commonly recovered genera with Rhizopus oryzae as the most frequent pathogen associated with mucormycosis and is being accounted for approximately 60% of all the mucormycosis infections and a contributor of approximately 90% of rhino cerebral cases [25, 26].
Management in a nutshell
These sinonasal infections manifest themselves more commonly in immunocompromised states, thus requiring a multispeciality involvement and treatment of comorbid conditions apart from treating the primary sinonasal pathology. Since appearance of tissue at endoscopy as well the radiological findings lag behind the clinical progression of the disease, a prompt biopsy should be taken keeping a high index of suspicion in order to promptly diagnose and instigate the treatment at the earliest. The principle of management of any sinonasal disease depends upon four factors namely (a) rapidity of diagnosis (b) reversal of underlying predisposing factors, if any (c) surgical debridement (d) appropriate medical therapy including antibiotics and antifungals [27,28,29,30,31,32]. Early diagnosis is an important factor as a small lesion can be effectively treated surgically prior to encroachment onto vital structures thus preventing any severe iatrogenic morbidity. In case of an active orbital fungal invasion, exenteration might be lifesaving. Many studies have come to a conclusion that exenteration should be considered for an actively inflamed orbit with an immobile blind eye [33]. Even after the intracranial spread has occurred, orbital exenteration conducted with the motive of decreasing the fungal load is still helpful.
For medical management of Mucormycosis, Amphotericin B (AmB) remains the mainstay of treatment. Though, Amphotericin B deoxycholate is the crux of treatment its usage is associated with renal toxicity therefore, a careful monitoring of blood urea nitrogen, serum electrolytes, serum creatinine along with creatinine clearance should be done. An infectious disease specialist or physician should be kept in loop to avoid any untoward reaction.
Outcomes
Appropriate diagnosis and timely intervention is quintessential for better outcomes.
Prognosis of invasive fungal rhino sinusitis patients remains poor despite aggressive surgery and intravenous anti-fungal therapy, with documented mortality rates of 33.3–80%, which may go up to 100% in disseminated infections.
