Mucormycosis


Article Author:
Jorge Hernández


Article Editor:
Clifford Buckley


Editors In Chief:
Dustin Constant
Donald Kushner


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
6/16/2019 12:27:38 PM

Introduction

Mucormycosis is an opportunistic fungal infection of the zygomycete family that can cause various types of infections.  In most cases, there exist underlying conditions that predispose the hosts to the infection. There are several clinical forms of infection: pulmonary, gastrointestinal, cutaneous, encephalic, and rhinocerebral. Mucormycosis is characterized by tissue necrosis due to an invasion of blood vessels and subsequent thrombosis, which usually follows a rapid progression. The key to treatment is early and aggressive surgical debridement, along with high doses of intravenous antifungal therapy.[1]

Etiology

Mucormycosis is an infectious disease caused by a fungus of the class of Zygomycetes and the order of Mucorales.

The species most frequently isolated from patients are: Apophysomyces (A. variabilis), Cunninghamella (C. bertholletiae), Lichtheimia [Absidia] (L. corymbifera L. raosa), Mucor  (M. circinelloides), Rhizopus (R. arrhizus (oryzae) R. microsporus), Rhizomucor (R. pusillus), and Saksenaea (S. vasiformis).[1][2]

Epidemiology

Mucorales are thermotolerant fungi found in soil and decaying matter and rarely cause disease because of low virulence.  Rhizopus is considered the most frequent fungal infection in immunocompromised populations. Mucormycosis has increased its frequency because of the increased prevalence of immunosuppression states in the general population.

The primary route of infection is via air spore inhalation, which deposits in the paranasal sinuses and the lung. Other routes less frequently encountered result from ingestion or direct skin inoculation.

Risk factors include diabetes mellitus,  malnutrition, malignancies (lymphomas and leukemias), renal failure, organ transplant, burns, immunosuppressive therapy, cirrhosis, and AIDS. Patients with diabetic ketoacidosis and patients on dialysis who receive treatment with iron chelator deferoxamine are also more susceptible to mucormycosis.

The most commonly encountered clinical form is rhinocerebral mucormycosis and mortality, even with pharmacological and/or surgical treatment is high.[1][3]

Pathophysiology

Mucorales are present in soil and decaying matter, in immunocompetent people, the spores of Mucorales that reach the respiratory tract adhere to the nasal mucus and are eliminated either by swallowing or sneezing, if there is any wound in the mucous membranes, the polymorphonuclear neutrophils phagocytose and destroy the fungal structures. Neutrophils are the host defense against these infections; therefore, individuals with neutropenia or neutrophil dysfunction are at the highest risk.

Rhizopus arrhizus have demonstrated that the ketone bodies present in these patients are metabolized by a ketone reductase, which allows them to survive in conditions with an acid medium thus the fungi become hyphal forms in tissues then invade blood vessels, this extensive angioinvasion results in vessel thrombosis and tissue necrosis.  Diabetes patients usually present with a large amount of glucose in tissues and exudates, providing excellent conditions for the rapid development of filamentous structures that first bind to blood vessels and then penetrate them completely clogging them in a few days, causing extensive areas of necrosis.

Also, metabolic acidosis prevents chemotaxis of polymorphonuclear leukocytes, causes decreased phagocytic activity, and reduces local inflammatory activity.[3][4]

Histopathology

The microscopic examination and culture of samples of the affected tissue are the main pillars in the histological evaluation of mucormycosis in its different forms. Diagnosis occurs through observing non-septate or minimally septated broad, ribbon-like hyphae (10 to 20 micrometers) invading blood vessels. The microscopic examination should evaluate morphology, width, branching angle, and septation.

It is challenging to get the proliferation of these fungi from the infected tissues. Once achieved, proliferation is rapid and diffuse in most culture media at room temperature. The biopsy is obtainable by imaging-guided biopsy, transbronchial biopsy, endoscopy with biopsy of the sinuses or gastrointestinal tissue, and skin biopsy. As such, histopathology allows the differentiation of mucormycosis from aspergillosis. Notably, the absence of hyphae should not dissuade from the diagnosis when the presence of risk factors and the clinical findings suggest this infection.[3][5]

History and Physical

Mucormycosis can invade different body systems. Sites of infection include the lung, central nervous system, paranasal sinuses, gastrointestinal system, and the skin. Its clinical manifestations are varied but characteristically demonstrate rapid progression.  The clinical manifestations largely depend on the route of entry of the fungus and the predisposing disease.

Rhinocerebral mucormycosis initiated with inhalation of spores into the paranasal sinuses and the invasion of blood vessels in the tissue. The infection stars with fever, nasal congestion, facial numbness, blurry vision, nasal discharges, nasofrontal headache, ocular pain, diplopia, and chemosis. Dermatological lesions in the nostrils characteristically have ulcerations and necrotic tissue, usually progress rapidly over days.

Pulmonary mucormycosis consists of the development of bilateral pneumonia, which is rapidly progressive and the result of the inhalation of infectious material.  The most common clinical features are fever, hemoptysis, dyspnea, and cough. This clinical form is seen more frequently in patients with hematological diseases. This pulmonary condition can present as bronchitis, bronchopneumonia, and even pulmonary embolism. The infection can spread to contiguous tissues, such the mediastinum, and heart. 

Cutaneous mucormycosis presents in both primary and secondary disease. In primary disease, the skin infection results from direct inoculation and in secondary form, by dissemination from other locations. The primary form often occurs in patients with burns and traumatic skin wounds, usually appears as a single and indurated area of cellulitis that progresses a necrotic lesion, other forms of manifesting are abscesses, skin swelling, and necrosis.

Gastrointestinal form occurs via the ingestion of contaminated food and the use of contaminated herbal medicines have been linked to gastrointestinal disease development, there may be nausea, vomiting, ulceration, and thrombosis of the gastric, esophageal and intestinal mucosa, manifested by diarrhea, hematemesis, and melena. Perforation and peritonitis can result from necrotic ulcers. Also, the presence of bowel infarctions and hemorrhagic shock lead to poor prognosis.  

Disseminated form of mucormycosis may originate from any primary sites of infection, manifestations are nonspecific, which makes diagnosis even harder, but a metastatic skin lesion is undoubtedly a sign to suspect disseminated mucormycosis.[3][4][6][7][8]

Evaluation

Routine blood work is rarely diagnostic but can find the presence of neutropenia as a correlating risk factor.   

Imaging can be valuable in evaluating the extent of the disease. Radiological imaging studies are required to investigate areas with suspected mucormycosis, specifically in the brain, paranasal sinuses, lungs, and abdomen, always guided by the clinic.

The first imaging study in the suspicion of rhinocerebral mucormycosis is with the endoscopic evaluation of the sinuses to look tissue necrosis and to obtain examples of tissue, the presence of characteristic hyphae provides a presumptive diagnosis. A computed tomography scan helps us to evaluate contiguous structures such as the eyes and brain, findings in CT scan included soft tissue edema of cavity mucosa, sinus mucoperiosteal thickening, bone erosions, and orbital invasions.

Patients with immunosuppression and respiratory symptoms should have a CT chest for possible pulmonary mucormycosis. The presentation of the infection does not differ from pneumonia; therefore, the diagnosis is difficult. Chest radiologic findings are pleural effusion, nodules, consolidation, and ground glass infiltrates. Bronchoalveolar lavage can show broad nonseptate hyphae.

If there is a concern for gastrointestinal mucormycosis (abdominal pain, gastrointestinal bleeding), a CT scan to evaluate for colitis is necessary.  Once confirmed, colitis should be further investigated by endoscopy with biopsy.  The presence of characteristic hyphae in the biopsy provides a presumptive diagnosis.[6][9]

Treatment / Management

The standard management of mucormycosis requires early diagnosis, a reversal of risk factors and underlying illness, surgical debridement and prompt administration of intravenous amphotericin B.  This entails the prompt management of hyperglycemia, acidosis, and cessation of immunosuppressive agents when possible.

Amphotericin B is considered the first line therapy for mucormycosis. The lipid formulation of amphotericin B is administered in high doses intravenously once a day as initial therapy. The initial starting dose is 5 mg/kg IV daily, with a maximum dose of 10 mg/kg IV. Treatment duration depends upon the patient's clinical picture. 

Surgical debridement of infected tissue should be urgently performed to limit the further spread of infection. Aggressive surgical debridement of necrotic tissue should take place immediately. 

Posaconazole or isavuconazole has some evidence as second-line therapy in mucormycosis. For salvage treatment posaconazole 200 mg IV four times daily is recommended. The guidelines do not support the combination of amphotericin and posaconazole. 

Other adjuncts include hyperbaric oxygen.  The increased oxygen pressure improves the ability of neutrophils to kill the organism and facilitates wound healing.[9][5]

Differential Diagnosis

In a case of mucormycosis in its rhinocerebral form, one must consider different pathologies such as orbital cellulitis and cavernous sinus thrombosis.

When we consider the diagnosis of pulmonary mucormycosis, we should think about aspergillosis, nocardiosis, and Wegener's granulomatosis.[10]

Prognosis

The prognosis is dependent upon the timing of therapeutic intervention, as well as the degree of the underlying immunodeficiency of the patient with mortality ranging from 25 to 87% depending on the site of infection.

Severity and poor prognostic indicators include disseminated infection, renal injury, central nervous system disease, and inadequate response to medical treatment.[10]

Complications

Complications of mucormycosis subdivide into those that result from the disease itself and those that are caused by the antifungal treatment. Complications associated with the disease are cavernous sinus thrombosis, disseminated infection, periorbital destruction, palatine ulcers, osteomyelitis, and death.

Complications due to treatment are nephrotoxicity, hypokalemia, prolonged hospitalization (specifically with the use of deoxycholate amphotericin B).

Pearls and Other Issues

The key to the diagnosis is the identification of key risk factors and hallmark symptoms. The "classic" presentation is the immunocompromised patient, with rhinosinusal involvement, demonstrating a very rapid progression of infection, and the presence of tissue necrosis.

Depending on the degree of immunosuppression and predisposing conditions, the progression of the disease can be acute, fulminant, or chronic.

The identification of the exact species that cause mucormycosis is not straightforward due to the difficulty of isolating the fungus in culture media. However, regardless of the causative species and clinical presentation, therapeutic management is the same.

Enhancing Healthcare Team Outcomes

Mucormycosis is a life-threatening fungal infection, with very high mortality. Interdisciplinary management typically consists of infectious disease, otolaryngology, hematology/oncology, endocrinology, microbiology, specialty-trained nursing, and pharmacist assistance of therapeutic drug administration and monitoring, all collaborating across disciplines to achieve optimal patient results. [Level V] However, even with prompt, adequate evaluation and treatment by the interdisciplinary team, the prognosis remains poor.


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Mucormycosis - Questions

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A 55-year-old male with poorly controlled diabetes mellitus is admitted with a severe infection of his face and started on broad-spectrum antibiotics. Shortly after admission, the patient develops a high fever and hypotension despite empiric therapy with antibiotics, and the entire right face appears necrotic. What is the next step in the management of this patient?



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A 45-year-old patient with diabetes mellitus presents complaining of chills, fevers, and malaise for 1 day. A chest x-ray reveals a large mass. CT shows pleural effusion, consolidation, a nodule, and ground-glass opacities. During exploration, a dimorphic fungal organism is seen adjacent to thrombosed vessels. Which of the following is the treatment of choice?



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Which of the following is not true of a mucormycosis infection?



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A diabetic patient with hemoptysis, fever and dyspnea has a lung biopsy. The fresh sample shows hyphae branching at right angles with vascular invasion and necrosis. What is the most likely pathogen in the diagnosis?



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A diabetic patient undergoing chemotherapy for lung cancer suddenly develops hemoptysis and a gangrenous infection of the chest wall and surrounding tissue. What feature on the CT scan of the chest may suggest the presence of rhizopus?



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A 66-year-old man with a history of type 2 diabetes and non-compliance with insulin therapy presents with a 2 to 3 days' complaint of right facial and eye pain, blurred vision, proptosis, and a necrotic lesion of the palate. Which of the following best explains the appearance of necrotic injury in the palate area?



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A 23-year-old woman with a recent diagnosis of acute myeloid leukemia undergoes induction chemotherapy. She develops nausea, diarrhea, right iliac fossa pain and tenderness during the neutropenic phase. A CT scan of the abdomen showed an inflamed ascending colon and ileum. She undergoes a biopsy guided by computerized tomography of the involved area and confirms the diagnosis of Mucormycosis. Which of the following is the most likely expected result of the biopsy?



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A 35-year-old male with a diagnosis of chronic myeloid leukemia undergoes induction chemotherapy resulting in prolonged neutropenia. His course is complicated with neutropenic fever, for which he is treated with vancomycin for seven days. Fever resolves in 48 hours, and the antibiotics are stopped. He now has a dry cough, occasional hemoptysis, and febrile episodes. CT scan of the chest reveals nodular pulmonary infiltrates, which do not respond to empiric therapy with voriconazole. Which of the following is the most appropriate management of the pulmonary infection?



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Mucormycosis - References

References

Lewis RE,Kontoyiannis DP, Epidemiology and treatment of mucormycosis. Future microbiology. 2013 Sep;     [PubMed]
Binder U,Maurer E,Lass-Flörl C, Mucormycosis--from the pathogens to the disease. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2014 Jun;     [PubMed]
Farmakiotis D,Kontoyiannis DP, Mucormycoses. Infectious disease clinics of North America. 2016 Mar;     [PubMed]
Sahota R,Gambhir R,Anand S,Dixit A, Rhinocerebral Mucormycosis: Report of a Rare Case. Ethiopian journal of health sciences. 2017 Jan;     [PubMed]
Lin E,Moua T,Limper AH, Pulmonary mucormycosis: clinical features and outcomes. Infection. 2017 Aug;     [PubMed]
Skiada A,Lass-Floerl C,Klimko N,Ibrahim A,Roilides E,Petrikkos G, Challenges in the diagnosis and treatment of mucormycosis. Medical mycology. 2018 Apr 1;     [PubMed]
Katragkou A,Walsh TJ,Roilides E, Why is mucormycosis more difficult to cure than more common mycoses? Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2014 Jun;     [PubMed]
Castrejón-Pérez AD,Welsh EC,Miranda I,Ocampo-Candiani J,Welsh O, Cutaneous mucormycosis. Anais brasileiros de dermatologia. 2017 May-Jun;     [PubMed]
Long B,Koyfman A, Mucormycosis: what emergency physicians need to know? The American journal of emergency medicine. 2015 Dec;     [PubMed]
Kang JW,Kim JH, Dark necrotic mucosa in sinonasal mucormycosis. British journal of hospital medicine (London, England : 2005). 2016 Jan     [PubMed]

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