Code Mucor: Guidelines for the Diagnosis, Staging and Management of Rhino-Orbito-Cerebral Mucormycosis in the Setting of COVID-19

“Fungi are the interface organisms between life and death.” -- Paul Stamets

Mucormycosis is a potentially lethal, angioinvasive fungal infection predisposed by diabetes mellitus, corticosteroids and immunosuppressive drugs, primary or secondary immunodeficiency, hematological malignancies and hematological stem cell transplantation, solid organ malignancies and solid organ transplantation, iron overload, etc.[¹] The increasing incidence of rhino-orbito-cerebral mucormycosis (ROCM) in the setting of COVID-19 in India and elsewhere has become a matter of immediate concern.[²³⁴] From the time that we first reported a series of six cases of ROCM in February 2020,[²] there has been an exponential increase in incidence in India, in sync with the soaring second wave of COVD-19.[⁵⁶]

ROCM being a rapidly progressive disease, even a slight delay in the diagnosis or appropriate management can have devastating implications on patient survival.[⁷] However, the outcome can be optimized by early diagnosis prompted by awareness of warning symptoms and signs and a high index of clinical suspicion, confirmation of diagnosis by appropriate modalities, and initiation of aggressive medical and surgical treatment by a multidisciplinary team.[¹⁷] This article aims to provide a succinct list of red flags to suspect ROCM, propose a working disease staging system to help choose an appropriate diagnostic modality and tailor therapy, describe an evidence-based management algorithm, and outline possible preventive measures.

Red Flags of ROCM in the Setting of COVID-19

The COVID-19 care teams must be aware of the warning symptoms and signs of ROCM. If a patient currently under active treatment for COVID-19 or on follow-up after completion of treatment exhibits any of the symptoms and signs listed in Table 1, there should be a very high index of suspicion for ROCM, and an immediate ophthalmology and otorhinolaryngology consultation is warranted.[¹⁷] Explanation of early warning signs to patients and the family on discharge following treatment of COVID-19 and a carry-home list of warning symptoms may prompt them to seek early medical attention.

Table 1: Warning symptoms and signs of rhino-orbito-cerebral mucormycosis

Diagnosis of ROCM

ROCM can be categorized as Possible, Probable, and Proven. A patient who has symptoms and signs of ROCM [Table 1] in the clinical setting of concurrent or recently (<6 weeks) treated COVID-19, diabetes mellitus, use of systemic corticosteroids and tocilizumab, mechanical ventilation, or supplemental oxygen is considered as Possible ROCM. When the clinical symptoms and signs are supported by diagnostic nasal endoscopy findings, or contrast-enhanced MRI or CT Scan, the patient is considered as Probable ROCM. Clinico-radiological features, coupled with microbiological confirmation on direct microscopy or culture or histopathology with special stains or molecular diagnostics are essential to categorize a patient as Proven ROCM. Table 2 lists specifications and criteria for microbiological, histopathological, molecular, and radiological diagnosis of ROCM.

Table 2: Supportive evidence for the diagnosis of rhino-orbito-cerebral mucormycosis (ROCM)[^{7 8}]

Staging of ROCM

There is no good staging system to categorize the disease severity of ROCM and stratify the diagnostic modalities and management. As the critical care teams start receiving and caring for increasing number of ROCM patients in the setting of COVID-19, a working staging system may help triage these patients and customize their care. The proposed staging system is simple and follows the general anatomical progression of ROCM from the point of entry (nasal mucosa) on to the paranasal sinuses, orbit and brain, and severity in each of these anatomical locations [Fig. 1]. There is an attempt to plug in the symptoms, signs, and preferred diagnostic tools for each of these stages. The next logical step could be to validate it, propose the preferred management for each stage, and then correlate the outcomes.

Figure 1: Proposed staging of Rhino-Orbito-Cerebral Mucormycosis with clinical symptoms and signs, evaluation and diagnosis

Logical Management of ROCM

Optimizing the outcome, minimizing the morbidity, and improving the survival in ROCM needs concerted action and rapid response by a multi-disciplinary team comprising of experts in diagnosis (radiology, microbiology, pathology, molecular biology), and medical (infectious disease, neurology, critical care) and surgical (otorhinolaryngology, ophthalmology, neurosurgery) care.[⁷⁸] Evidence-based and clear management guidelines help synergize the management within the team. The European Confederation of Medical Mycology (ECMM) and the Mycoses Study Group Education and Research Consortium (MSG ERC) have issued comprehensive management guidelines.[⁷] Fig. 2 provides diagnostic and management algorithms with salient aspects of the elaborate ECMM-MSG ERC guidelines adapted to standard disease definitions and customized to ROCM in the setting of COVID-19.[⁷⁹] Expeditious clinical or clinico-radiological diagnosis, supported by quick direct microscopy, and induction with full-dose liposomal Amphotericin B is the definitive first step in the long and arduous management of ROCM. In situations with resource-constraint, it may be acceptable to use Amphotericin B Deoxycholate or Amphotericin B Lipid Complex in patients with good renal function. These have relatively lower efficacy and higher systemic toxicity as compared to liposomal Amphotericin B. There is no convincing data to support combination antifungal therapy, and it is not recommended as part of major treatment guidelines.[¹⁷⁸] However, prolonged step-down oral antifungal therapy is warranted.[¹⁷⁸]

Figure 2: Management algorithm for Rhino-Orbito-Cerebral Mucormycosis (ROCM)

Can ROCM be Prevented?

It may be possible to reduce the incidence of ROCM in the setting of COVID-19 by optimizing the indications for systemic corticosteroids, judicious use of tocilizumab, proactive metabolic control, and by minimizing the patient exposure to potential sources of infection [Table 3]. There may be a role for prophylactic oral Posaconazole in high-risk individuals.

Table 3: Prevention of rhino-orbito-cerebral mucormycosis in the setting of COVID-19

Conclusion

Awareness of, and due attention to warning symptoms and signs, and a high index of clinical suspicion, early diagnosis by a diagnostic nasal endoscopy and direct microscopy of the high nasal swab or an endoscopically guided nasal swab, supported by contrast-enhanced MRI or CT scan, initiation of full-dose liposomal Amphotericin B while awaiting the results of culture and histopathology, identification of indications for paranasal sinus surgery and orbital exenteration and meticulous post-surgical management, and continued step-down oral antifungals until clinical and radiologically monitored resolution and beyond, may help optimize the outcome of ROCM in the setting of COVID-19. Inculcating a protocol-based strategy by a multidisciplinary team and a prioritized Code-Mucor approach may be the key to success.