Zygomycosis (Mucormycosis) – Causative Agent, Symptoms, Prevention, Treatment

• Zygomycosis is an infection caused by saprophytic fungi, such as Mucor, Rhizopus, and Absidia.
• These fungi are ubiquitous and generally saprophytic in nature. They are the third most common cause of invasive fungal infection in immunocompromised people.
• Rhizopus species are the most prevalent zygomycosis-causing pathogens in humans. Rhizopus arrhizus is the most prevalent cause of zygomycosis among all Rhizopus species.
• Zygomycosis fungi have a strong propensity to infect major blood arteries, resulting in ischemia, necrosis, and infarction of nearby tissues.
• In addition, they are known to affect people with acidosis due to renal failure, diarrhoea, or aspirin consumption. The majority of Zygomycetes infections are acute and typically deadly despite early identification and treatment.
• Zygomycosis is transmitted through the air by means of asexual spores. In humans, they infiltrate the tissues of patients with a compromised immune system.
• From there, they penetrate the blood vessels and proliferate in the blood vessel walls, especially in the paranasal sinuses, lungs, and intestines.
• This causes tissue infarction and necrosis distal to the occluded arteries. Depending on the immunological status of the host and the entrance point, zygomycetes can cause a variety of diseases in humans.
• These induce rhinocerebral, pulmonary, and gastrointestinal zygomycosis, respectively. Rhinocerebral zygomycosis is the most prevalent manifestation of illness in diabetic acidosis patients.
• Frequent symptoms include fever, unilateral facial pain or headache, nasal congestion, epistaxis, vision disturbances, and tiredness. Frequently, the clinical diagnosis of zygomycosis is problematic.
• It demands a high level of suspicion and an adequate risk profile for the host. Microscopy, culture, and histopathology are used for laboratory diagnosis:
• Microscopy must reveal the presence of wide, nonseptate hyphae with branching at right angles in the material. In cases of rhinocerebral zygomycosis, a KOH mount of discharge scrapings may reveal wide, irregularly arranged hyphae with right-angled branching.
• Cultures grown without antibiotics on SDA media are thick and bushy. The LPCB preparation of the colony reveals that the hyphae are coenocytic and that the sporangia contain sporangiophores. The majority of fungal cultures are negative. Fungi are difficult to cultivate because their cells are solitary and very lengthy, and any damage to the cells limits their growth.
• Since culture frequently fails to demonstrate growth, histopathology of afflicted tissue is quite valuable for validating the diagnosis. The diagnosis is confirmed by a fungal stain of biopsy material collected from the afflicted tissue that reveals nonseptate hyphae with broad, irregular branches that develop more or less at right angles.
• Blood cultures are useless.
• There are no serological testing available.
• Amphotericin B is the recommended treatment for mucormycosis. Frequently, surgical excision of necrotic, diseased tissues is beneficial.

Causative Agent

• Multiple species of fungus are capable of causing mucormycosis. These fungi are known as mucormycetes and are classified as Mucorales.
• Mucormycosis is most commonly caused by Rhizopus species and Mucor species.
• Rhizomucor, Syncephalastrum, Cunninghamella bertholletiae, Apophysomyces, Lichtheimia (previously Absidia), Saksenaea, and Rhizomucor are more instances.

Habitat

• Mucormycetes, the genus of fungi that causes mucormycosis, are widespread, especially in soil and in connection with decomposing organic matter such as leaves, compost piles, and animal manure.
• They are more prevalent in the soil than in the air and in the summer and autumn than in the winter and spring.
• It is virtually hard to totally avoid coming into touch with mucormycetes, as most people come into contact with fungus spores on a daily basis.
• These fungus are generally harmless to humans. Breathing in mucormycete spores can induce an infection in the lungs or sinuses that can spread to other parts of the body in those with compromised immune systems.

Transmission

• The majority of zygomycetes have a broad geographic distribution and utilise a variety of substrates as food sources. All pathogens are thermotolerant in the sense that they can grow at temperatures over 37 °C.
• Mucorales can be found in decaying vegetables, foodstuffs, fruits, dirt, and animal excrement.
• Most of them, especially Rhizopus spp., can grow rapidly on substrates with a high content of carbohydrates.
• Sporangiospores are released into the environment in the form of airborne propagules that can adhere to a variety of surfaces.
• Due to the intake of sporangiospores and subsequent diffusion from the respiratory system, the principal clinical settings are rhinocerebral and pulmonary.
• Large quantities of airborne propagules may cause pollution. Sporangiospores and hyphae present in contaminated air conditioning systems and wound dressings have led to nosocomial infections.
• Peritonitis following peritoneal dialysis, disseminated infections after infusion of contaminated fluids, skin infection after intravenous catheter use, and various infections associated with foreign bodies such as prosthetic heart valves and contact lenses have been recorded.
• Mucoraceous fungi are not as common as Aspergillus spp. in causing nosocomial infections; the majority of reported cases involve patients with hematologic malignancies.
• There is no transfer between individuals.

Risk factors 

• In the development of an infection, the underlying condition is more essential than other host characteristics such as race, age, or gender.
• In spite of the fact that the infection rate in males and females is normally equivalent, a recent meta-analysis revealed a small male predominance of 65%.
• The median age of patients with these infections is 40 years, and while infections caused by mucoraceous fungus can occur in newborns through the elderly, the proportion of children among patients without underlying illnesses is larger than in any other group.
• Traditional descriptions of predisposing factors are presented in Table. In recent years, the incidence of these diseases has increased exponentially in immunocompromised groups, such as stem cell and solid organ transplant recipients, who are profoundly immunocompromised.
• Diabetes, metabolic acidosis, or hyperglycemia, corticosteroid therapy, immunosuppressive therapy for organ or bone marrow transplantation, neutropenia, trauma, HIV, and deferoxamine therapy for iron or aluminium overload are additional risk factors.
• Diabetes mellitus is one of the most significant risk factors, especially when ketoacidosis is present. Increased glucose concentration encourages fast zygomycete development.
• Due to the rapid development rate, it appears that these fungi have neither the time nor the need to create septa in their hyphae.

Types of mucormycosis (Zygomycosis)

• Rhinocerebral (sinus and brain) mucormycosis: Rhinocerebral (sinus and brain) mucormycosis is an illness that can move to the brain from the sinuses. This is more prevalent in persons with uncontrolled diabetes and kidney transplant recipients.
• Pulmonary (lung) mucormycosis: Pulmonary (lung) mucormycosis is the most prevalent form of mucormycosis among cancer patients and those who have undergone an organ transplant or stem cell transplant.
• Gastrointestinal mucormycosis: Young children are more susceptible to gastrointestinal mucormycosis than adults. Premature and low-birth-weight infants less than one month old who have received antibiotics, surgery, or drugs that weaken the immune system are at risk.
• Cutaneous (skin) mucormycosis: Cutaneous (skin) mucormycosis is caused by the entry of fungus into the body through a skin breach. After a burn, scrape, cut, surgery, or other form of skin trauma, this sort of infection may develop. This is the most prevalent form of mucormycosis among individuals with healthy immune systems.
• Disseminated mucormycosis: Disseminated mucormycosis develops when the infection travels through the circulation and affects a different portion of the body. The infection typically affects the brain, but it can also damage the spleen, the heart, and the skin.

Symptoms of Zygomycosis (Mucormycosis)

The symptoms of mucormycosis vary on where the fungus is growing in the body. 1,4 Contact your healthcare practitioner if you believe you have mucormycosis-related symptoms.

The following are symptoms of rhinocerebral (sinus and brain) mucormycosis:

• one-sided facial enlargement
• Headache
• nasal congestion or sinusitis
• Rapidly worsening black lesions on the nasal bridge or upper interior of the mouth
• Fever

The following are symptoms of pulmonary (lung) mucormycosis:

• Fever
• Cough
• Chest pain
• Insufficiency of breath

Cutaneous (skin) mucormycosis may manifest as blisters or ulcers, and the diseased region may darken. Other symptoms around a wound include pain, warmth, extreme redness, and swelling.

The following are symptoms of gastrointestinal mucormycosis:

• Abdominal discomfort
• sickness and vomiting
• gastrointestinal haemorrhage

Typically, disseminated mucormycosis occurs in people who are already ill, thus it can be difficult to determine which symptoms are caused by mucormycosis. Patients with a disseminated infection in the brain may experience alterations in mental status or coma.

Prevention

Because fungi that cause mucormycosis are prevalent in the environment, it is difficult to avoid inhaling fungal spores. There is no preventative vaccination for mucormycosis. There may be ways for immunocompromised individuals to reduce their risk of acquiring mucormycosis.

Protect yourself from the environment.

• Importantly, although these actions are advised, they have not been demonstrated to prevent mucormycosis.
• Avoid dusty environments such as construction and excavation sites. Wear a N95 respirator (a form of face mask) if you cannot avoid these regions. Click here for additional details on respirators.
• After hurricanes and other natural catastrophes, avoid direct contact with flooded buildings and flood water.
• Avoid activities involving close contact with soil or dust, such as gardening and yard maintenance. Unless this is feasible,
• Wear shoes, long pants, and a long-sleeved shirt when engaging in outside activities like gardening, yard labour, or forest exploration.
• When handling things such as soil, moss, or manure, use gloves.
• To lessen the likelihood of getting a skin infection, thoroughly cleanse skin wounds with soap and water, particularly if they have been exposed to soil or dust.

Antifungal medication

• Your healthcare practitioner may recommend medication to prevent mucormycosis and other mould infections if you are at high risk for acquiring mucormycosis (for instance, if you have had an organ transplant or stem cell transplant).
• Doctors and scientists are still discovering which transplant patients are at the most risk for fungal infections and how to best prevent them.

Laboratory diagnosis

Due to the dismal prognosis of zygomycosis, even the slightest suspicion of the disease in a patient at risk should induce a biopsy to obtain tissue samples for direct microscopic examination, histopathologic analysis, and culture. Because the fungi responsible for these illnesses can be laboratory contaminants, it is difficult to evaluate isolated cultures without evidence of wide hyphae in tissues or materials unless the patient is neutropenic or diabetic. A positive culture of zygomycetes from sputum, skin scrapings, or nasal discharge is more significant in the presence of predisposing circumstances or direct microscopy of the material.

Direct examination 

• Samples should be collected from infected-looking locations. In the rhinocerebral type, nasal mucosa scrapings and sinus aspirates should be acquired.
• For lung infections, sputum or centrifuged bronchoalveolar lavage fluid is beneficial.
• Necrotic, infected tissues must be biopsied from any location. Observe specimens through a microscope after mounting the material in a few drops of potassium hydroxide (KOH) and warming the slide gently to clean the tissue.
• Visible are broad (7–15 m), sparsely septate hyphae. Frequently observed are enlarged cells (up to 50 m) and twisted hyphae.
• In contrast to Aspergillus spp., branching frequently occurs at an angle of 90 degrees to the main hyphae.
• The diagnosis cannot be ruled out by other appearance (thinner hyphae, less than 5 m in diameter, or sharper branching) or absence of hyphae, as fungal elements are frequently dispersed throughout tissues.
• In fluid specimens, yeast forms of Mucor circinelloides can be confused for Paracoccidioides brasiliensis due to the peculiar appearance of zygomycetes.

Histology 

• During acute infections caused by mucoraceous fungi, necrotic, hemorrhagic, or pale tissue results from the fungus’ invasion of blood vessels, which causes thrombosis, necrosis, and infarction.
• In the majority of cases, inflammation is absent. The fungus can be stained with either hematoxylin and eosin or periodic acid-Schiff. Using the GMS stain, silver discoloration is inconsistent.
• Observable are broad, irregularly branched, twisted hyphae. Some narrow hyphae may be observed, but they lack the typical dichotomous branching characteristic of Aspergillus.
• Septation is uncommon in comparison to that of Aspergillus. Large hyphae in tissue can superficially resemble yeast cells similar to those observed during an Aspergillus infection.
• Typically, fungal elements invade blood vessels and surrounding tissue. In chronic infections caused by mucoraceous fungi and in almost all cases of infections caused by members of the Entomophthorales, small abscesses surrounded by granulomatous tissue reactions indicate a chronic inflammatory process.
• A strong eosinophilic perihyphal reaction of variable size (2–2 m) is frequently observed (Splendore–Hoeppli phenomenon).
• Individually or in clusters, broad, irregular hyphae (4–30 m) with thin walls and rare septation are visible. In contrast to acute infections caused by members of the genus Mucorales, there is no invasion of blood vessels or infarction of tissue.

Culture 

• All zygomycosis-causing fungi should be grown on standard laboratory media devoid of cycloheximide.
• Particularly for highly contaminated materials such as nasal discharge and sputum, antibiotics may be added to the isolation medium.
• Instead of submitting exudate from the surface of a lesion for culture, tissue should be submitted to differentiate colonisation from infection and increase culture yield.
• Fluids must be spread on agar plates, and biopsies of tissue must be minced and not homogenised. Homogenization with a tissue grinder should be avoided because destroying hyphae reduces culture yield.
• Some authors have reported that a piece of sterile bread without preservatives placed on the surface of the inoculated agar plate can facilitate the recovery of zygomycetes.
• Negative cultures can occur as frequently as forty percent of the time. In cases of negative culture and positive histology, repeated sampling is beneficial.
• Rapid growth is typically evident after 24 hours of incubation at 25–37°C. Again, zygomycosis cannot be diagnosed or ruled out based solely on culture results.
• It is contingent upon a panel of evidence compiled by both the clinician and the microbiologist. After isolation, fungus identification frequently requires the assistance of a mycologist.
• Transferring the sterile isolates to saline agar46 or to plates containing water supplemented with 1% filter-sterilized yeast extract solution may assist in obtaining the identifying reproductive structures.
• Sometimes, zygospore production is the only way to correctly identify certain of these organisms. To combat the loss of sporulation in Basidiobolus species, glucosamine hypochloride and casein hydrolysate-containing media have been proposed.

Other means 

• There is no reliable serologic test for diagnosing zygomycosis. In 1989, Kaufman and colleagues reported that an enzyme-linked immunosorbent assay (ELISA) procedure employing R. homogenates had a high degree of specificity (94%) and sensitivity (81%). arrhythmia and R. pusillus.
• However, cross-reactivity was observed with sera from patients with aspergillosis and candidiasis, limiting the diagnostic utility of the test.
• Because zygomycetes spores are present in the environment, it will be difficult to interpret the presence of antibodies reactive with antigens prepared at home from these fungi in patients at risk for other invasive fungal infections, such as neutropenic patients.
• Due to the rapid progression and frequently fatal outcome of acute zygomycosis, the development of DNA-based diagnostic methods, antigen detection, or specific serologic procedures could improve the prognosis for these infections.

Treatment for Zygomycosis (Mucormycosis)

• Mucormycosis is a serious infection that requires treatment with antifungal prescription drugs, typically amphotericin B, posaconazole, or isavuconazole.
• These medications are administered intravenously (amphotericin B, posaconazole, isavuconazole) or orally (posaconazole, isavuconazole) (posaconazole, isavuconazole).
• Other medications, including fluconazole, voriconazole, and echinocandins, are ineffective against mucormycosis-causing fungi. Frequently, mucormycosis necessitates surgical removal of infected tissue.

Mucormycosis Statistics

• Mucormycosis is uncommon, but it is difficult to determine the exact number of cases because there is no national surveillance in the United States.
• During 1992–1993, laboratory surveillance in the San Francisco Bay Area yielded population-based incidence estimates for mucormycosis that suggested an annual rate of 1.7 cases per 1 million population.
• Mucormycosis was the third most common type of invasive fungal infection in stem cell transplant recipients and accounted for 8% of all invasive fungal infections, as determined by prospective surveillance of 16,808 transplant recipients at 23 institutions between 2001 and 2006. (77 mucormycete cases occurred among 983 stem cell transplant recipients who developed any fungal infection).
• 2% of all invasive fungal infections in solid organ transplant recipients were caused by mucormycosis (28 mucormycete cases occurred among 1,208 solid organ transplant recipients who developed any fungal infection).
• The number of cases varied widely among institutions that participated.
• If healthcare professionals are concerned about an unusually high number of new cases, they should contact their state or local department of public health.
• Although the majority of cases of mucormycosis are sporadic (not part of an outbreak), outbreaks have occurred.
• In healthcare settings, it can be challenging to determine whether mucormycosis is healthcare-associated or if it was acquired elsewhere.
• Mucormycosis outbreak sources include adhesive bandages, wooden tongue depressors, hospital linens, negative pressure rooms, water leaks, poor air filtration, non-sterile medical devices, and building construction.
• Community-onset epidemics have been linked to traumatic injuries sustained during natural disasters.
• Mucormycosis is often a potentially fatal infection. A review of published cases of mucormycosis revealed an overall mortality rate of 54%.
• The mortality rate varied based on the underlying patient condition, the type of fungus, and the affected body site (for instance, the mortality rate was 46% among patients with sinus infections, 76% for pulmonary infections, and 96% for disseminated mucormycosis).

References

• Ostrosky-Zeichner, L., Smith, M., & McGinnis, M. R. (2009). Zygomycosis. Clinical Mycology, 297–307. doi:10.1016/b978-1-4160-5680-5.00012-8 
• https://www.cdc.gov/fungal/diseases/mucormycosis/index.html#:~:text=Mucormycosis%20(previously%20called%20zygomycosis)%20is,to%20fight%20germs%20and%20sickness
• https://en.wikipedia.org/wiki/Zygomycosis
• https://dermnetnz.org/topics/zygomycosis