Taxonomically, the term 'zygomycosis' was used to describe invasive fungal infections caused by Zygomycetes, which are ribbon-shaped (about 5-15 microns in diameter) irregularly branched pauciseptate or aseptate molds which reproduce sexually via formation of zygospores. Subsequently, a reclassification was followed, dividing the above species into two orders, Mucorales and Entomopthorales.
The term mucormycosis denotes the acute or subacute rapidly progressing infections caused by the angioinvasive fungi in the order of Mucorales, though there are rare reports of indolent disease. The fungus is unique to cause devastating disease in patients with poorly controlled diabetes mellitus and immunocompromised patients, and often causes significant morbidity and mortality. The rare incidence of mucormycosis in apparently immunocompetent patients has also been documented. The commonest clinical manifestation is rhino-orbital cerebral mucormycosis.
Though mucormycosis exhibits a variety of clinical syndromes with isolated involvement of the gastrointestinal system, skin, kidney, and central nervous system, the commonest and most devastating manifestations are rhino-orbital cerebral, and pulmonary syndromes. Isolated presentations of mucormycosis have also been reported predominantly involving the middle ear, parotid gland, mediastinum, heart and valves, uterus, urinary bladder, and lymph nodes. Disseminated mucormycosis is reported rarely in immunocompromised patients and premature infants.
The ubiquitous fungi in the order Mucorales often thrive on decaying plant debris and soil. The most common genera causing human infections include Rhizopus, Lichtheimia, Apophysomyces, Mucor, and Rhizomucor. Human infections are less commonly caused by Cunninghamella and Saksenaea. The most commonly isolated mucormycosis species in the world is Rhizopus arrhizus, though Apophysomyces variabilis is most common in Asia, and Lichtheimia species is predominant in Europe. A large review of 929 patients from 1940 to 2003 identified poorly controlled diabetes mellitus as the commonest risk factor (36%), followed by hematologic cancers (17%), and hematopoietic stem cell or solid organ transplant (12%). Subsequently, the RetroZygo study done over 3 years in France has shown hematologic malignancy as the risk factor in almost half of the patient population followed by diabetes mellitus (23%) and trauma(18)%.
The most common clinical presentation is rhino-orbital cerebral mucormycosis, and the commonest etiology for rhino-orbital cerebral mucormycosis is Rhizopus oryzae. Rhino-orbital cerebral mucormycosis almost always occurs in immunocompromised persons, including uncontrolled diabetes mellitus, especially with acidosis or ketoacidosis, steroid therapy, solid organ or hematopoietic stem cell transplant recipients, chemotherapy, hematologic dyscrasias, retroviral disease, and malnourishment. The preponderance is also noted in patients on deferoxamine therapy, iron overload state, and intravenous drug abuse. Cases of rhino-orbital cerebral mucormycosis occurring following facial burns or scleral buckling procedures have been reported. Rare reports of rhino-orbital cerebral mucormycosis have also been published in immunocompetent hosts.
The rapidly growing saprophytic fungi release a large number of spores to the environment. These sporangiospores are commonly inhaled by the host, and in hosts with normal immune status, the ciliary system directs the spores towards the pharynx, thereby eliminating them via the gastrointestinal system. The spores might also get colonized in the oral mucous membranes, nose, throat, and paranasal sinuses. Mucorales do not cause disease in the host with an intact immune system where phagocytosis could effectively contain the invasion and infection. When the phagocytosis is impaired due to immune deficiency, the germination of spores into hyphae with resultant angioinvasion gets initiated. The initial site of infection in rhino-orbital cerebral mucormycosis is the nasal turbinates. An acute episode of sinusitis progresses into pan sinus involvement within a few days with contiguous spread to the palate, orbit, and brain resulting in severe tissue ischemia and necrosis due to the angioinvasive nature of the fungus.
Accuracy of epidemiologic analysis is challenging since mucormycosis is not a notifiable disease and is further compounded by considerable variation of risk factors among the different populations. With the available data, the global epidemiology of mucormycosis has been showing not only an increase in the incidence but also reporting of new causative agents along with a change in the susceptible population characteristics. Though the rise has been noted globally, it is significantly higher in the Asian continent, especially in India and China. The Leading International Fungal Education (LIFE) portal estimates the annual global prevalence of mucormycosis approximately as 10,000 cases when Indian data is not included. When Indian data is added, it becomes 910,000 cases annually. The estimated incidence burden in the USA is about 3 cases per million population, the UK being 0.9 cases per million, and Canada and Australia being 1.2 and 0.6 cases per million, respectively. Wide variation has been noted among European countries, eg.incidence of 0.2 cases per million in Denmark versus 95 cases per million in Portugal. Rhino-orbital cerebral mucormycosis is the commonest presentation seen in 40% of the cases. There is no age or sex predilection.
A 7-year review of 851 cases showed that the incidence is higher in Europe (34 %), and 31 % in Asia, 28 % in North and South America, 3% in Africa, and 3% Australia and New Zealand. The higher values in the European continent could have been due to under-diagnosis and under-reporting in the Asian continent during the study period. The most common risk factor for rhino-cerebral mucormycosis all over the world is diabetes mellitus, whereas hematologic malignancies and transplants more commonly predispose to pulmonary mucormycosis. Though diabetes mellitus has been the most common susceptibility factor in Asia, post tuberculosis state and chronic renal failure have emerged as new risk factors. The RetroZygo study in France found hematologic malignancy as the major predisposition to mucormycosis in 50 % of the cases, followed by diabetes mellitus (23 %) trauma (18%).
Rhizopus grows rapidly in the hyperglycemic environment because phagocytosis is significantly impaired in a high blood sugar state. The ketone reductase system in the fungus helps to successfully survive the acidotic environment in diabetic ketoacidosis. Moreover, acidosis causes dissociation of iron from sequestering proteins in the serum, which could promote virulence and survival. Phagocytosis is notoriously impaired also in neutropenia and steroid therapy. The iron-rich state caused by deferoxamine, an iron-chelating agent, also favors the fungal growth by acting as a siderophore to the fungus. Many patients with diabetes mellitus with rhino-orbital cerebral mucormycosis present with minimal or no acidosis. The hyperglycemia itself favors fungal growth by at least three mechanisms, which include hyper-glycation of iron sequestering proteins with impaired iron sequestration, enhanced expression of GRP 78, a mammalian protein receptor, which increases binding to Mucorales, and finally the decreased phagocytosis associated with high blood sugar state.
Mucormycosis is an angiotropic fungus having a high tendency to damage the internal elastic lamina of blood vessels, especially the arteries by mechanical and toxic means, and subsequently spreading to lymphatics and veins. After inhalation of spores into the sinuses, the angioinvasive infection gets established via the spores germinating into multiple hyphae in the immunocompromised patient. The pterygopalatine fossa is believed to be the largest reservoir. Vascular and neuronal spread along with vessel wall infiltration ensues rapidly in the coming hours. Direct invasion results in thrombosis and nerve dysfunction. The involvement of blood vessels, bone, cartilage, nerves, perineural areas, and meninges are quite common. The tissue necrosis at the palate results in palatine eschars and the destruction of nasal turbinates. The bone is eroded by the spread of infection from the sinuses, which subsequently extends into the orbital structures, thereby spreading to the brain via a retro-orbital route. Spread to the frontal lobes could also happen via the ethmoid sinuses. Infection spreading along the sphenoid sinuses to the nearby cavernous sinus results in cranial nerve palsies. This is followed by extensive thrombosis of the cavernous sinus, jugular veins, and carotid artery. The blockage of the carotid artery is well reported.
Smears can be examined under potassium hydroxide (KOH) wet preparation. Hematoxylin-eosin (H&E) and Papanicolau stains are used in scrape smears, and air-dried smears are examined with periodic acid Schiff (PAS) and May-Grünwald-Giemsa stains. Surgical sections are processed in paraffin and examined with H&E and PAS stains. Histopathology evaluation of the debrided tissue will reveal elongated broad ribbon-like hyphae irregularly branching at right or obtuse angles, with no or scanty septations. Thrombosed blood vessels with significant necrotic areas and giant cells are also noted. Widespread infiltration with lymphocytes, eosinophils, and occasional plasma cells is seen. Calcofour-white or Grocott-Gomori's methenamine silver staining demonstrates twisted septate hyphae.
The symptoms of rhino-orbital cerebral mucormycosis are often non-specific with varying spectrum and severity. Background history of diabetes mellitus or underlying immunosuppression is usually revealed. Fever, headache, nausea, and generalized weakness may be the initial complaints. Purulent discharge with or without epistaxis might be present with onset of sinusitis, along with congestion and decreased sensation inside the nose. Nasal ulceration and necrosis are often reported. Facial symptoms include pain and numbness. Periorbital or retro-orbital pain, double or blurred vision, and partial or complete loss of vision in one or both eyes might progress to blindness. The involvement of the brain can manifest with altered consciousness, unstable gait, and/or seizures. Rare reports of rhino-orbital cerebral mucormycosis leading to mucormycosis of the retina misdiagnosed as coats disease in young patients exist.
Nasal or palatine findings of rhino-orbital cerebral mucormycosis include grey or reddish mucosa, which will progress to black areas of eschar as necrosis ensues. Eschar may be seen in the nasal septum, palate, eyelid, face, or orbital areas. The absence of eschar does not rule out rhino-orbital mucormycosis. Examination of the eyes may reveal pain and swelling of the eyelids, and evidence of orbital invasion in the form of painful proptosis. Ptosis, abscess of eyelids, and corneal numbness with edema are often noticed. A closer examination may reveal features of vitritis and/or endophthalmitis, and optic disc edema. Evidence of ophthalmoplegia (internal as well as external) with the latter being partial or complete, afferent pupillary abnormalities, fixed pupils, nystagmus, and a loss of vision secondary to fungal invasion or retinal artery occlusion can occur. Superior orbital fissure syndrome and superior ophthalmic vein thrombosis have been known to occur. A painless orbital apex syndrome has also been well described. Cranial nerve palsies with varying involvement of II, III, IV, V, VI, and VII nerves are common. Cerebral edema may lead to coma, and vascular occlusion progresses to cerebral infarcts. Cavernous sinus thrombosis with loss of vision is believed to be a characteristic feature of mucormycosis where cavernous sinus thrombosis without loss of vision is observed in bacterial infections.
A high index of suspicion in the appropriate clinical setting and a low threshold for further evaluation is imperative for early diagnosis and treatment, which significantly reduces morbidity and mortality. Laboratory findings are often non-specific and may show a high blood sugar reading with/without evidence of acidosis or ketoacidosis. An arterial blood gas report can rule out acidosis, dyselectrolytemia, and serum or urine ketone tests can screen for ketone bodies. A complete blood cell count can rule out a neutropenic state. Iron studies might be required to rule out suspected iron overload states in the form of low total iron-binding capacity and high ferritin values.
CT scan can demonstrate the nature and extent of soft tissue abnormalities in the sinuses, orbits, and brain. Mucosal thickening of sinuses along with opacification is often noted. Edema, inflammation, and infarcts in the brain are also detected. CT scan is advantageous over MRI on its ability to detect bony erosion and necrosis though such findings indicate an advanced disease with poor prognosis. A contrast CT scan also shows evidence of cavernous sinus thrombosis and enhancement of vessels. MRI is more helpful over the CT brain in clearly delineating early vascular invasion, intracranial spread, and also in the assessment for early perineural spread. A T2 weighted MRI with fat saturation sequences or short- TI Inversion Recovery(STIR) images is ideal.
Definite diagnosis is arrived only by demonstrating the characteristic ribbon-shaped non-septate or pauciseptate, irregularly branching hyphae in the tissue specimens, and the finding is further strengthened by demonstrating thrombosis of the vessels signifying angioinvasion. Fresh tissue specimens subjected to PCR techniques often show high sensitivity and specificity in the diagnosis. The biopsy specimens could be fresh, frozen, and/or permanent. If safe and feasible, an arterial biopsy needs to be considered, if all the available tissue specimens come negative for fungal hyphae despite a high degree of suspicion.
Tissue cultures are rarely positive, and extreme caution needs to be exercised to avoid the homogenization process, which will destroy the fragile hyphae. Fine mincing of the tissues is preferred over-grinding or crushing to preserve the hyphae. The culture positivity could be challenging at times since the differentiation between colonization versus contamination versus pathogenicity could be difficult. It is a well-accepted fact that Mucorales could be a colonizer in airways or could often contaminate microbiology specimens.
PCR techniques can help in identifying the fungal species in histologic specimens, even when the culture is negative. MALDI -TOF mass spectrometry can be used for species identification in culture specimens.
Management of rhino-orbital cerebral mucormycosis is a medical as well as surgical emergency. Reaching an early definite diagnosis is pragmatically challenging, whereas the delay in initiating the treatment will further aggravate the morbidity and mortality. Early antifungal administration and extensive surgical debridement are carried out empirically whenever the possibility of rhino-orbital cerebral mucormycosis is suspected based on risk factors, clinical features, and/or radiologic findings. A three-pronged approach of reversal of immunosuppressive state, administration of IV antifungals, and extensive surgical debridement is usually undertaken.
The immune-suppressive factors are reversed by reversal of hyperglycemia, acidosis, hypoxemia, and dyselectrolytemia. Discussions are made with relevant experts regarding reducing or stopping of immunosuppressive agents. Granulocyte colony-stimulating factor may increase white cell count and may help to improve host defenses.
IV amphotericin (liposomal) is administered in the dose of 5-10 mg per Kg body weight per day. After initial treatment with IV amphotericin for several weeks along with the achievement of clinical improvement, the amphotericin is usually stepped down to oral posaconazole or isavuconazole. In the step-down therapy, oral posaconazole (delayed-release tablet) is given at a dose of 300mg twice daily on the first day, followed by 300 mg once daily. Oral posaconazole suspensions are not advisable since their bioavailability is inadequate and requires fatty meals for better absorption. Serum trough concentration of oral posaconazole needs to be monitored after a week of treatment and has to be kept at least above 1 mcg/ml. Oral isavuconazole is given at a dose of 200 mg (2 x 100mg capsules) thrice daily for two days, followed by 200 mg once daily.
IV or oral posaconazole or isavuconazole has been used as salvage therapy in certain patients who do not tolerate amphotericin or who do not respond to it. There no evidence for the benefit of a combination of drug therapy in the form of combining amphotericin with an echinocandin at this stage. Although echinocandins do not have an in vitro activity against mucormycosis, R.oryzae, the commonest etiology for mucormycosis, expresses the target enzyme for echinocandins raising the theoretical possibility for a potential benefit. A retrospective study had observed a potential benefit for the above combination therapy in mucormycosis patients with brain involvement, though the conclusion is debatable. Amphotericin is also used for local instillation or irrigation of debrided cavities in surgical management.
Surgical debridement includes extensive resection of infected and necrotic tissues as a part of source control and reduction of fungal load. Debridement also provides adequate tissue biopsy specimens for definite histopathologic confirmation. Dissection is usually continued until normal, well-perfused bleeding tissue is reached since mucormycotic tissues are less likely to bleed due to extensive thrombosis of vessels. Removal of the palate, nose cartilage, and orbit would cause significant disfigurement. The orbital involvement may need orbital decompression or exenteration. The role of routine orbital exenteration or the timing exenteration is currently unclear, and cases with orbital involvement have also been successfully managed without exenteration.
Deferasirox and deferiprone are iron-chelating agents which do not act as a siderophore to the fungus. The studies have been small, and the results have been mixed. The DEFEAT mucor (Deferasirox-AmBisome Therapy) for Mucormycosis randomized trial showed increased mortality in patients who received a combination of amphotericin and deferasirox than those who received amphotericin alone.
A high degree of suspicion is a must and any delay in diagnosis with the subsequent delay in initiation of IV amphotericin can worsen morbidity and mortality. The differential diagnosis may vary based on the presenting symptoms and signs and include:
DEFEAT Mucor was a small randomized double-blinded placebo-controlled study where 20 patients with proven or probable mucormycosis were randomly given IV liposomal amphotericin alone or liposomal amphotericin plus deferasirox for the first 2 weeks of therapy. The 90-day mortality was found to be significantly higher in the deferasirox group (82% versus 22%). Adverse events were similar in both groups. It is difficult to make strong conclusions given the population imbalances in this small phase II trial. The patients who received deferasirox were having hematologic cancers, neutropenia, or/and pulmonary involvement where the expected mortality is significantly high.
The current survival of patients without brain involvement could be up to 50-80% but the survival drops to 20% with brain involvement. The morbidity and mortality in rhino-orbital cerebral mucormycosis is determined by the reversibility of underlying risk factors, the time of initiation of IV amphotericin, and the time of initiation of surgical debridement. A delay in any of the above measures could affect survival. No survival was reported before 1954 when amphotericin was not in use. Delay from diagnosis to treatment for more than 6 days is associated with poor survival. The factors associated with poor survival include delay in initiation of treatment, hemiparesis or hemiplegia, sinus involvement on both sides, blood cancer, renal disorder, and deferoxamine treatment. The involvement of the brain, cavernous sinus, and carotid artery is usually associated with poor outcomes. The best prognosis is expected in those patients where the disease is confined to sinuses. Patients with diabetes mellitus have better survival than patients with no history of diabetes mellitus or patients with CNS involvement. A recent meta-analysis observed no change in overall survival of rhino-orbital cerebral mucormycosis patients in the past 20 years although the mortality in patients with chronic renal disease is better (decreased from 52 % to 19%), likely due to the use of liposomal amphotericin which is less nephrotoxic. The study also found enhanced survival in patients with leukemia (from 13% to 50%). Facial necrosis and hemiplegia continue to be poor prognosticators.
There is significant associated morbidity in survivors. The duration of antifungal treatment could be approximately 7 months. Significant post-surgical disfigurement can psychologically impair many patients as well as relatives. Neurologic deficits of variable degrees could persist if there is a delay in treatment. Long term prophylaxis may be required in certain immunosuppressed patients.
Major complications include cavernous sinus thrombosis, carotid artery obstruction, central nervous system infarction secondary to mycotic intravascular thrombosis, manifesting with hemiparesis, hemiplegia, coma, and death. CNS hemorrhage, abscess, inflammation, and blindness have been well reported. Airway obstruction from head and neck infections is possible.
The antifungal agent IV amphotericin is associated with significant nephrotoxicity and dyselectrolytemia, especially when given in the conventional amphotericin B deoxycholate form. Disfigurement following surgical debridement is common in survivors who often need psychological or psychiatric support. Residual sequelae of the disease occur in up to two-thirds of the patients.
Management of rhino-orbital cerebral mucormycosis requires close interaction and coordination between various medical and surgical clinicians. There could a certain overlap between various specialties in the management of suspected or proved rhino-orbital cerebral mucormycosis patients. Suggested specialties to be involved include the following:
A hospitalist could be in charge of the overall general management of the patient. Infectious disease or endocrinology opinions could be asked for if further inputs regarding the diagnosis and antimicrobial management, or diabetic ketoacidosis treatment are required. An urgent otorhinolaryngology opinion is needed for extensive debridement and tissue biopsy of the affected nose and sinuses where the former procedure is expected to reduce the fungal load, while the latter helps to achieve a definite tissue diagnosis. Opthalmology review for assessment of ophthalmoplegia and optic neuropathy is advisable. Oculoplasty surgeons can help in orbital debridement, decompression, or exenteration and reconstruction. Neurosurgery consult would be ideal if orbital or intracranial disease is present. Many times the different surgical teams have to intervene together in single or multiple settings. Pharmacotherapists often help in the proper dosing of IV amphotericin.
Psychiatry or psychology counseling or treatment may be required for patients and relatives who often get crippled with the significant post-surgery disfigurement. Rehabilitation help might be required to combat residual neurologic sequelae.
Rhino-orbital cerebral mucormycosis has significant morbidity and mortality despite available medical and surgical management. Education of patients and relatives is of paramount importance to reduce certain preventable factors, and for ensuring early presentation to the clinician, thereby preventing a delay in diagnosis and treatment.
Rhino-orbital cerebral mucormycosis is most commonly seen in patients with diabetes mellitus, especially when their glucose is uncontrolled. These patients must constantly monitor and control their blood sugar, which could help reduce the incidence in the general population. All immunocompromised patients and their relatives need to be adequately advised regarding seeking urgent medical attention in case of any ear, nose, eye issues even when they are subtle. Neutropenic patients fail to show any sign of inflammation, and hence a very high index of suspicion on the part of patients and relatives is again advisable. Once rhino-orbital cerebral mucormycosis is diagnosed, the patients and family need to be adequately counseled regarding poor prognosis, and the pros and cons of extensive surgical debridement, including the potential for severe disfigurement after the procedure. Varying residual neurologic sequelae are seen in up to two-thirds of the patients.
Rhino-orbital cerebral mucormycosis is an angioinvasive disease with high morbidity and mortality despite treatment. Suspicion or diagnosis of rhino-orbital cerebral mucormycosis is a medical as well as surgical emergency. A high index of suspicion among caregivers, a rapid workup, and early initiation of amphotericin and surgical debridement in all suspected cases are a must for improved outcomes. Surgical debridement reduces the fungal load as well as enables tissue diagnosis. Significant disfigurement is common after debridement. An interprofessional team approach with close interaction and coordination among various medical and surgical specialties indisputably ensures a better outcome.
Management of rhino-orbital cerebral mucormycosis illustrates the classic example of an interprofessional team approach in improving patient outcomes. The management starts in the emergency department. A meticulous history taking and close examination of the patient, along with a high index of suspicion is required. After a quick ABC evaluation and stabilization, there is a need to undergo urgent imaging, and it is extremely important to provide adequate inputs to the radiology team for early, accurate reporting. Once rhino-orbital mucormycosis is suspected based on clinical presentation and radiology, it is important to involve an otorhinolaryngologist for urgent extensive nasal/sinus debridement, and tissue biopsy for histopathologic diagnosis. An ophthalmology evaluation is often followed, and subsequent involvement of an oculoplastic surgeon will help in orbital exploration, decompression, or exenteration. Neurosurgery opinion is often sought whenever there is intracranial involvement. Hospitalists, infectious disease physicians and endocrinologists are involved in the medical management of the patient. There will be an overlap of roles between different medical and surgical specialties, and close interaction and coordination among the interprofessional team are essential to ensure better patient outcomes. Surgical procedures may have to be done in single or multiple stages. Psychologists or psychiatrists may have to be involved in the counseling of the patient and family to overcome the stress of severe disfigurement following surgical debridement. Rehabilitation opinion is often asked to effectively minimize residual neurologic deficits. Close coordination and interaction between various medical, surgical, nursing, and paramedical professionals help to achieve a better outcome. [Level 5]
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