*Corresponding Author E-mail:
ABSTRACT:
Mucor mycosis is an angio invasive fungal infection, due to fungi of the order Mucorales. Its incidence cannot be measured exactly, since there are few population-based studies, but multiple Studies have shown that it is increasing. The prevalence of mucor mycosis in India is about 80 times the prevalence in developed countries, being approximately 0.14 cases per 1000 population. Diabetes mellitus is the main underlying disease globally, especially in low and middle-income countries. In developed countries the most common underlying diseases are hematological malignancies and transplantation. The epidemiology of mucor mycosis is evolving as new immune modulating agents are used in the treatment of cancer and autoimmune diseases, and as the modern diagnostic tools lead to the identification of previously uncommon genera/species such as Apophysomyces or Saksenaea complex. In addition, new risk factors are reported from Asia, including post-pulmonary tuberculosis and chronic kidney disease. New emerging species include Rhizopus homothallicus, Thamnostylum lucknowense, Mucor irregularis and Saksenaea erythrospora. Diagnosis of mucormycosis remains challenging. Clinical approach to diagnosis has a low sensitivity and specificity, it helps however in raising suspicion and prompting the initiation of laboratory testing. Histopathology, direct examination and culture remain essential tools, although the molecular methods are improving. The internal transcribed spacer (ITS) region is the most widely sequenced DNA region for fungi and it is recommended as a first-line method for species identification of Mucorales. New molecular platforms are being investigated and new fungal genetic targets are being explored. Molecular-based methods have gained acceptance for confirmation of the infection when applied on tissues. Methods on the detection of Mucorales DNA in blood have shown promising results for earlier and rapid diagnosis and could be used as screening tests in high-risk patients, but have to be validated in clinical studies. More, much needed, rapid methods that do not require invasive procedures, such as serology-based point-of-care, or metabolomics-based breath tests, are being developed and hopefully will be evaluated in the near future.
KEYWORDS: Mucormycosis, Epidemiology, Diagnosis.
INTRODUCTION1:
American pathologist R.D. Baker coined the term Mucormycosis. It is also known as Zygomycosis. It can be defined as an insidious fungal infection caused by members of Mucorales and zygomycotic species. Mucormycotina are the common saprobes originating from the rotten matter or soils. Infections with Mucorales are categorized by rapid progression.
This can lead to serious disease with warning sign and symptoms as follows:
· Pain and redness around eyes and/or nose
· Fever
· Headache
· Coughing
· Shortness of breath
· Bloody vomits
· Altered mental status
When to Suspect2
(In COVID-19 patients, diabetics or immunosuppressed individuals):
Sinusitis – nasal blockade or congestion, nasal discharge (blackish/bloody), local pain on the cheek bone
One sided facial pain, numbness or swelling Blackish discoloration over bridge of nose/palate Toothache, loosening of teeth, jaw involvement Blurred or double vision with pain; fever, skin lesion; thrombosis and necrosis (eschar) Chest pain, pleural effusion, haemoptysis, worsening of respiratory symptoms.
Dos:
· Control hyperglycemia Monitor blood glucose level post COVID-19 discharge and also in diabetics
· Use steroid judiciously – correct timing, correct dose and duration
· Use clean, sterile water for humidifiers during oxygen therapy
· Use antibiotics/antifungals judiciously
Don’ts:
· Do not miss warning signs and symptoms
· Do not consider all the cases with blocked nose as cases of bacterial sinusitis, particularly in the context of immune suppression and/or COVID-19 patients on immune modulators
· Do not hesitate to seek aggressive investigations, as appropriate (KOH staining and microscopy, culture, MALDI-TOF), for detecting fungal etiology
· Do not lose crucial time to initiate treatment for mucormycosis
History:
In 1885, the German pathologist Paltauf, reported the first case of Mucormycosis and described it as Mycosis Mucorina. During 1980s and 1990s Mucormycosis was increasingly seen among immuno compromised individuals. Based on the prevalence rate, a study carried out in France reported amplification by 7.4% per year. Worldwide occurrence along with the possibility of seasonal variation of mucorales infection has been reported.
Etiopathogenesis3
Mucorales attack deep tissues by means of ingestion or inhalation of spores, and percutaneous injection of spores. As soon as the spores penetrate into lung or cutaneous tissues, the first line of defence in the healthy
Host is capable of destroying the spores via oxidative metabolites and cationic peptides. Risk factors include uncontrolled diabetes mellitus, especially ketoacidosis, steroid use, extremes of age, neutropenia; especially with haematological malignancy, AIDS, renal insufficiency, organ or stem cell transplantation, iron overload, skin trauma, broad-spectrum antibiotics, intravenous drug abuse, prophylactic voriconazole for aspergillosis and malnutrition. In diabetic patients, mucormycosis occurs as a destructive and potentially critical condition due to augmented availability of micronutrients and diminished defence mechanism of the body. Various hypotheses include (i) Low serum inhibitory activity against Rhizopus species, (ii) Improved availability of iron for the pathogen at decreased PH level and (iii) Pulmonary macrophages of persons with diabetes mellitus show diminished facility to inhibit germination of Rhizopus species. Ketone reductase in Rhizopus allows the organism to increase the glucose and acidic environment. In DM particularly with ketoacidosis all types of mucormycosis will occur. Neutrophils play a major role in host defence against mucorales. Its function is impaired at different level in DM10. Ketoacidosis in diabetes accelerate the fungal invasion. The acidic milieu produces more free iron by reducing its binding to transferrin and low level of dialyzable inhibitory factor in diabetics present suitable conditions for fungal duplication. Mortality rate was reported 90% or even more with Mucormycosis, before the administration of amphotericin B and radical surgery. Severely neutropenic patients and those who lack phagocytic function are more prone for mucormycosis. But it’s not same in the case of AIDS patients. It implies that the T lymphocytes are not significant for inhibiting fungal proliferation but only the neutrophils. Prolonged administration of voriconazole, principally among the patients with haematological malignancies and hematopoietic stem cell transplants are more prone for mucormycosis. Moreover mucormycosis is also seen in patients without any obvious immune-deficiency. In such conditions, it may be related with burns, trauma and or allied with iatrogenic factors.
Radiographic Features4
Opacification of the sinuses may be observed in conjunction with patchy effacement of bony walls of sinuses. In cavernous sinus thrombophlebitis mucor infection can interpret with “Black turbinate sign” which refers to an area of non-enhancing mucosa on MRI. A radiographic or CT scan of the head may show thickened mucosa or cloudy sinuses, densely crowded extra ocular muscles, enlarged compactness of the orbital apex, proptosis and inflammation of the optic nerve. The development of micro nodules along with additional ten nodules were found out in the visualization of lung in pulmonary Mucormycosis, which is in accordance with the findings of Chamilos
Histopathological Features:
On examination, the affected tissue with lesions show extensive necrosis with numerous large branching pale-staining, wide, flat non-septal hyphae with branching at right or obtuse angles. Round or ovoid sporangia are also frequently seen in culture. Thin - walled hyphae (infrequently septae) with non - parallel sides ranging from 3 to 25μm in diameter, branching irregularly and often with bulbous hyphal swelling. Necrotic tissue containing hyphae might be seen with signs of angio – invasion and infarction are seen; in non granulocytopenic conditions, infiltration of the neutrophils and with chronic infection granuloma formation will also be observed.39 Gomori Methamine Silver (Grocott) or Periodic - acid Schiff are the staining of choice5
Diagnostic Method:
Diagnosis of mucormycosis includes cautious evaluation of clinical manifestations, magnetic resonance imaging modalities, utilization of computed tomography (CT) in the early stages, specialist assessment of cytological and histological provision, finest application of clinical microbiological technique and execution of molecular detection. Detection of host factors contribute extensively to the estimation of a patient’s possibility for invasive mucormycosis. PAS stains, direct examination, calcofluor, histopathological examination, Gomori methen amine silver stain, culture, molecular methods and fluorescent in situ hybridization are the various laboratory techniques for detecting mucor40. According to Kontoyiannis., a major problem in the identification of mucormycosis includes its indefinable clinical appearance and recurrent occult distribution, and hence a need for a sensitive nonculture-based investigative method is required. Gold standard analytic technique for confirmation is the tissue based analysis.
Differential Diagnosis:
Differential finding of mucormycosis include maxillary sinus neoplasia, maxillary sinus aspergillosis, soft tissue infarction, soft tissue radio necrosis, other deep fungal infections6
Treatment:
Successful treatment for mucormycosis includes rapid accurate diagnosis, surgical debridement, and administration of drugs, adjunctive application of hyperbaric oxygen, recombinant cytokines or transfusion of granulocyte and prosthetic obturator. According to Spellberg, currently available monotherapy shows high mortality rate especially with haematology patients and hence proposed the choice of “Combination therapy” forMucormycosis. Antifungal therapies include AmB Dexycholate, Liposomal AmB (5-10mg/kg), AmB lipid complex, AmB colloidal dispersion, Posaconazole (400mg bid) and manage of core conditions. Second-line treatment includes combination of caspofungin and lipid AmB, mixture of lipid AmB and Posaconazole, not grouping with Deferasirox is suggested7, 8, 10,11
CONCLUSION:
To conclude, mucormycosis is a disease which usually shows aggressive and an alarming mortality rate. However the actual etiopathogenesis remains varied throughout the world, diagnosis of this disease remains a challenge for the clinicians. But still in the view of its high mortality rate, (i) early and prompt diagnosis, (ii) recovery from the predisposing factors, (iii) early intervention with surgical debridement and therapeutic drugs are the only hopes to improve the condition from this divesting disease.
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Received on 26.05.2021 Modified on 28.06.2021
Accepted on 22.07.2021 ©AandV Publications All right reserved
Res. J. Pharmacology and Pharmacodynamics.2021; 13(3):89-92.
DOI: 10.52711/2321-5836.2021.00019