Mucorales/Mucormycosis

General Characteristics

Basic features of Mucorales

Taxonomy:

• Order: Mucorales
• Genera most commonly associated with human infection: 
  • Rhizopus
  • Rhizomucor
  • Mucor
  • Cunninghamella
  • Lichtheimia (formerly Absidia)
  • Apophysomyces
  • Saksenaea

Morphology:

• Colonies:
  • Fast growing
  • Cottony
  • White-to-yellow color → becomes gray 
• Microscopic features:
  • Wide hyphae Hyphae Microscopic threadlike filaments in fungi that are filled with a layer of protoplasm. Collectively, the hyphae make up the mycelium. Mycology 
  • Lack of or rare septations
  • Branching at right angles
  • Sporangiophores:
    • Upright hyphae Hyphae Microscopic threadlike filaments in fungi that are filled with a layer of protoplasm. Collectively, the hyphae make up the mycelium. Mycology
    • Support sac-like sporangia filled with asexual sporangiospores

Associated diseases

Mucormycosis is caused by many species within the Mucorales order, which can be classified based on the site of infection:

• Rhinocerebral mucormycosis (most common) 
• Pulmonary mucormycosis
• Cutaneous mucormycosis
• Gastrointestinal mucormycosis

Epidemiology

• Very rare infection; the true incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency is unknown.
• Approximately 500 annual cases in the United States
• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency is increasing due to a rising number of immunocompromised immunocompromised A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. Gastroenteritis patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.
• No gender Gender Gender Dysphoria predilection
• No racial predilection
• No age predilection
• Mortality Mortality All deaths reported in a given population. Measures of Health Status rate: 50%–85%

Pathogenesis

Reservoir Reservoir Animate or inanimate sources which normally harbor disease-causing organisms and thus serve as potential sources of disease outbreaks. Reservoirs are distinguished from vectors (disease vectors) and carriers, which are agents of disease transmission rather than continuing sources of potential disease outbreaks. Humans may serve both as disease reservoirs and carriers. Escherichia coli

Mucorales are common in the environment and are found on:

• Decaying vegetation
• Soil

Transmission

• Inhalation of spores Spores The reproductive elements of lower organisms, such as bacteria; fungi; and cryptogamic plants. Anthrax (primary method)
• Ingestion of contaminated food 
• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions inoculation

Host risk factors

Almost all infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease occur in the presence of an underlying condition:

• Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus (especially diabetic ketoacidosis Ketoacidosis A life-threatening complication of diabetes mellitus, primarily of type 1 diabetes mellitus with severe insulin deficiency and extreme hyperglycemia. It is characterized by ketosis; dehydration; and depressed consciousness leading to coma. Metabolic Acidosis)
• Hematological malignancies
• Solid-organ cancer
• Organ transplant
• Stem-cell transplant
• Immunosuppressive therapy 
• Chronic corticosteroid use
• HIV HIV Anti-HIV Drugs/ AIDS AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS
• Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia ( neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation are the key host defense against the fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology)
• Iron-overload conditions (e.g., hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis and deferoxamine Deferoxamine Natural product isolated from streptomyces pilosus. It forms iron complexes and is used as a chelating agent, particularly in the mesylate form. Hereditary Hemochromatosis therapy)
• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions injury due to surgery, burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns, or trauma
• Use of injection drug
• Malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries

Pathophysiology

• Most spores Spores The reproductive elements of lower organisms, such as bacteria; fungi; and cryptogamic plants. Anthrax enter through the respiratory tract → adhere to mucus
• Healthy individuals:
  • Usually clear by coughing, sneezing Sneezing The sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. Rhinovirus, or swallowing Swallowing The act of taking solids and liquids into the gastrointestinal tract through the mouth and throat. Gastrointestinal Motility
  • Neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation phagocytize → destroy the fungus
• Susceptible patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship:
  • Spores Spores The reproductive elements of lower organisms, such as bacteria; fungi; and cryptogamic plants. Anthrax transform into the hyphal form in nasal turbinates Turbinates The scroll-like bony plates with curved margins on the lateral wall of the nasal cavity. Turbinates, also called nasal concha, increase the surface area of nasal cavity thus providing a mechanism for rapid warming and humidification of air as it passes to the lung. Nose Anatomy (External & Internal) or alveoli Alveoli Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place. Acute Respiratory Distress Syndrome (ARDS).
  • Hyphae Hyphae Microscopic threadlike filaments in fungi that are filled with a layer of protoplasm. Collectively, the hyphae make up the mycelium. Mycology invade blood vessels → tissue infarction and thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
  • Leads to rhinocerebral or pulmonary disease Pulmonary disease Diseases involving the respiratory system. Blastomyces/Blastomycosis
• Other routes of infection → disease at those sites:
  • Traumatic inoculation or contamination → cutaneous disease
  • Ingestion → gastrointestinal disease

Clinical Presentation

Rhinocerebral disease

Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship start with symptoms of acute sinusitis Sinusitis Sinusitis refers to inflammation of the mucosal lining of the paranasal sinuses. The condition usually occurs concurrently with inflammation of the nasal mucosa (rhinitis), a condition known as rhinosinusitis. Acute sinusitis is due to an upper respiratory infection caused by a viral, bacterial, or fungal agent. Sinusitis. Symptoms progress due to the spread of the infection to contiguous structures.

• Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
• Nasal congestion (may have black discharge)
• Unilateral retro-orbital headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
• Facial pain Facial pain Pain in the facial region including orofacial pain and craniofacial pain. Associated conditions include local inflammatory and neoplastic disorders and neuralgic syndromes involving the trigeminal, facial, and glossopharyngeal nerves. Conditions which feature recurrent or persistent facial pain as the primary manifestation of disease are referred to as facial pain syndromes. Trigeminal Neuralgia
• Numbness
• Hyposmia Hyposmia reduced ability to smell Cranial Nerve Palsies
• Orbital swelling Swelling Inflammation with proptosis Proptosis Retinoblastoma and chemosis Chemosis Conjunctivitis
• Facial cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis
• Eschar formation can occur on:
  • Nasal mucosa Nasal mucosa The mucous lining of the nasal cavity, including lining of the nostril (vestibule) and the olfactory mucosa. Nasal mucosa consists of ciliated cells, goblet cells, brush cells, small granule cells, basal cells (stem cells) and glands containing both mucous and serous cells. Nose Anatomy (External & Internal)
  • Palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy
  • Overlying skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions

Pulmonary disease Pulmonary disease Diseases involving the respiratory system. Blastomyces/Blastomycosis

Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with pulmonary disease Pulmonary disease Diseases involving the respiratory system. Blastomyces/Blastomycosis develop rapidly progressive pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia (often bilateral).

• Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
• Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
• Cough
• Hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis

Cutaneous disease

• Cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis
• Dermal necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage
• Formation of black eschar

Gastrointestinal disease

The condition causes necrotic ulcers in the gastrointestinal tract (most commonly in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy), which can lead to perforation Perforation A pathological hole in an organ, blood vessel or other soft part of the body, occurring in the absence of external force. Esophagitis. Signs and symptoms include:

• Abdominal pain Abdominal Pain Acute Abdomen
• Distention
• Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
• Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
• Hematemesis Hematemesis Vomiting of blood that is either fresh bright red, or older ‘coffee-ground’ in character. It generally indicates bleeding of the upper gastrointestinal tract. Mallory-Weiss Syndrome (Mallory-Weiss Tear)
• Hematochezia Hematochezia Gastrointestinal Bleeding
• Obstruction
• Peritoneal signs

Rare manifestations

• Disseminated disease:
  • Can present with nonspecific signs and symptoms
• CNS mucormycosis:
  • Usually direct spread from a sinus infection
  • Signs and symptoms:
    • Lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia
    • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
    • Focal neurologic deficits Neurologic Deficits High-Risk Headaches

Diagnosis and Management

Diagnosis

A high index of suspicion is required to make the diagnosis.

• Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma specimen:
  • Histopathologic identification Identification Defense Mechanisms of the causative organism establishes the diagnosis.
  • Tissue necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage can be seen.
• Fungal cultures Fungal cultures Dermatophytes/Tinea Infections (often negative)
• Imaging (e.g., head or chest CT) to assess the extent of infection and tissue damage
• 1,3-β-D-glucan is not useful (not a component of the Mucorales cell wall Cell wall The outermost layer of a cell in most plants; bacteria; fungi; and algae. The cell wall is usually a rigid structure that lies external to the cell membrane, and provides a protective barrier against physical or chemical agents. Cell Types: Eukaryotic versus Prokaryotic).

Management

• Treat the underlying condition when possible (e.g., diabetic ketoacidosis Ketoacidosis A life-threatening complication of diabetes mellitus, primarily of type 1 diabetes mellitus with severe insulin deficiency and extreme hyperglycemia. It is characterized by ketosis; dehydration; and depressed consciousness leading to coma. Metabolic Acidosis).
• If possible, management should occur in a tertiary care center.
• Antifungal Antifungal Azoles therapy should be started immediately:
  • Liposomal amphotericin B Liposomal Amphotericin B Polyenes (1st line)
  • Isavuconazole Isavuconazole Azoles 
  • Posaconazole Posaconazole Azoles
• Surgical resection of necrotic tissue is indicated to limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation further spread:
  • Associated with improved survival
  • Can lead to significant disfigurement

Comparison of Species

Differential Diagnosis

• Bacterial orbital cellulitis Orbital cellulitis Orbital and preseptal cellulitis are infections differentiated by the anatomic sites affected in the orbit. Infection posterior to the septum is orbital cellulitis. Inoculation with the pathogen can occur through trauma or surgery. Cellulitis also occurs via extension from a nearby structure (such as from sinus infection or sinusitis). Orbital and Preseptal Cellulitis: infection of the orbital tissues, which can occur from hematogenous Hematogenous Hepatocellular Carcinoma (HCC) and Liver Metastases spread, extension Extension Examination of the Upper Limbs from adjacent sinuses, or traumatic inoculation. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with swelling Swelling Inflammation and redness Redness Inflammation, conjunctival erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion, pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways from eye movement, and proptosis Proptosis Retinoblastoma. Diagnosis is clinical. The mainstay of treatment is antibiotic therapy and surgery is reserved for severe cases. 
• Cavernous sinus thrombosis Cavernous sinus thrombosis Formation or presence of a blood clot (thrombus) in the cavernous sinus of the brain. Infections of the paranasal sinuses and adjacent structures, craniocerebral trauma, and thrombophilia are associated conditions. Clinical manifestations include dysfunction of cranial nerves III, IV, V, and VI, marked periorbital swelling, chemosis, fever, and visual loss. Cranial Nerve Palsies: a rare, life-threatening condition occurring from a facial infection. Cavernous sinus thrombosis Cavernous sinus thrombosis Formation or presence of a blood clot (thrombus) in the cavernous sinus of the brain. Infections of the paranasal sinuses and adjacent structures, craniocerebral trauma, and thrombophilia are associated conditions. Clinical manifestations include dysfunction of cranial nerves III, IV, V, and VI, marked periorbital swelling, chemosis, fever, and visual loss. Cranial Nerve Palsies is usually bacterial in etiology. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, proptosis Proptosis Retinoblastoma, and ophthalmoplegia Ophthalmoplegia Paralysis of one or more of the ocular muscles due to disorders of the eye muscles, neuromuscular junction, supporting soft tissue, tendons, or innervation to the muscles. Orbital and Preseptal Cellulitis. Diagnosis is confirmed with CT or MRI. Management includes antibiotics and, occasionally, steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors. Anticoagulation Anticoagulation Pulmonary Hypertension Drugs is controversial.
• Community-acquired pneumonia Community-Acquired Pneumonia Pneumonia in Children: infection of the lung parenchyma most often caused by a bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology or virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, and a productive cough. Chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests typically shows lobar consolidation Consolidation Pulmonary Function Tests. Management involves empiric antibiotics, which can be tailored if the causative organism is identified. Antivirals are used when a viral cause is suspected.