Zygomycosis

Zygomycosis also known as mucormycosis, phycomycosis or hyphomycosis, is a broad term for a multitude of severe angioinvasive fungal infections caused by common filamentous fungi in the order Mucorales and Entomophthorales, which generally occurs in immunocompromised hosts as opportunistic infections ¹. Previously, the term zygomycosis was used to denote invasive fungal infections caused by the fungi belonging to the phylum Zygomycota, class Zygomycetes, orders Mucorales and Entomophthorales. The Mucorales order contains 2 families—Mucoraceae and Cunninghamellaceae ². Since the majority of human infections are caused by Mucorales fungi, the term Mucormycosis is now used to designate this infection ³.

It is extremely rare for zygomycosis or mucormycosis to occur in healthy individuals ⁴. The most common species that cause zygomycosis infection are the Rhizopus species from the Mucoraceae family ⁵. The disease is aggressive and commonly fatal despite appropriate treatment ⁶. These ubiquitous opportunistic fungi can cause infections with high lethality in immunocompromised or diabetic patients especially people with diabetes who are in ketoacidosis as acidic environment contributes to fungal growth ⁷. Whatever the route of infection (inhalation of airborne spores, ingestion, or direct skin inoculation), the zygomycetes fungi invade blood vessels, causing tissue infarction and necrosis ⁸. In healthy persons, innate immunity is sufficient to prevent zygomycosis infection, except in cases of massive contamination after traumatic inoculation of contaminated soil ⁹. For reasons unknown, two-thirds of zygomycosis occurs in males. The occurrence is equal across race, age, and geography.

Host risk factors include diabetes mellitus, phagocytic dysfunctions caused by neutropenia, sustained immunosuppressive therapy, chronic prednisone use, patients with high iron serum concentrations and treatment with the iron chelating agent deferoxamine, broad-spectrum antibiotic use, severe malnutrition, and primary breakdown in the integrity of the cutaneous barrier such as trauma, surgical wounds, needle sticks, or burns ⁸. These underlying conditions can influence clinical presentation and outcome ¹⁰. Zygomycosis disease manifestations reflect the mode of transmission, with rhinocerebral and pulmonary diseases being the most common manifestations. Cutaneous, gastrointestinal, and allergic diseases are also seen. The rhinocerebral presentation is the most frequently reported localized symptom followed by pulmonary, cutaneous, cerebral, gastrointestinal, and disseminated infections ¹¹. In the rhinocerebral or pulmonary zygomycosis, patient death rates are reported to be as high as 60% because of delayed diagnosis or delayed therapeutic management ¹².

The Mucorales fungi are associated with angioinvasive disease, often leading to thrombosis, infarction of involved tissues, and tissue destruction mediated by a number of fungal proteases, lipases, and mycotoxins. If the diagnosis is not made early, dissemination often occurs. Therapy, if it is to be effective, must be started early and requires combinations of antifungal drugs, surgical intervention, and reversal of the underlying risk factors.

There are several different classifications of zygomycosis: rhinocerebral, pulmonary, gastrointestinal, cutaneous, and disseminated. Rhinocerebral is the most common form and initially resembles sinusitis with congestion, sinus pain, and drainage. The exam will vary depending on how advanced the infection is. Patients may present with erythema, periorbital swelling, and black necrotic eschars. History and physical will also vary depending on the underlying immunosuppressive disorder. For example, a patient with diabetic ketoacidosis may present with nausea, vomiting, and abdominal pain.

Invasive zygomycosis is simply bad news for patients as well as treating physicians. Despite recent medical advances, this aggressive fungal infection still carries poor prognosis. Since deep mucormycosis encompasses many syndromes, the mortality rate varies greatly from 33.3% in a Korean study ¹³, to a worse rate of 63% in an Italian study ¹⁴, to a staggering 96% rate in case of disseminated form ¹⁵. This extreme variation in mucormycosis mortality rate can be explained by many factors, including early diagnosis, site of the infection, patient’s immune status, correction of other co-morbid factors, and the type of therapy instituted among others.

If the patient, struck with aggressive zygomycosis, survives this horrible initial infection; he has high probability of carrying some of its terrible and severe debilitating consequences. Spontaneous blindness due to bilateral ophthalmic artery occlusion in rhino-orbito-cerebral mucormycosis has been reported ¹⁶. Facial disfiguration is a common result of aggressive surgery in cases of rhino maxillary or orbital mucormycosis ¹⁷. With aggressive pulmonary zygomycosis, complete pneumonectomy and even partial chest wall resection can be performed ¹⁸. In the case of bilateral renal mucormycosis, both kidneys had to be removed to save the patient’s life ¹⁹. Obviously, these patients will need physical and psychological support and occasionally rehabilitation with their daily activities.

Treatment strategies are based on high doses of any lipid formulation of amphotericin B, associated with large surgical resections when possible. Most triazole agents are not effective in vivo ²⁰, except for posaconazole, which shows some efficacy both experimentally and in patients as second-line therapy ²¹. The clinical contribution of new iron chelating agents remains controversial ²².

The Mucorales fungi are ubiquitous. They are found outdoors in soil and vegetation. They are also a common mold found in homes. One study from Denmark showed that it was present in 98% of samples taken from house dust. Studies have also shown the mold to be present on molded bread, other foods, dirty carpets, and vacuum cleaner systems ²³.

Zygomycosis causes

Mucormycosis, previously called zygomycosis, is a broad term for a multitude of diseases caused by infection with different fungi in the order of Mucorales. The most common causative organisms are from the Rhizopus species. Other species include, in descending order, include Rhizomucor, Cunninghamella, Apophysomyces, Saksenaea, Absidia, Mucor, Syncephalastrum, Cokeromyces, and Mortierella ²⁴. These fungi are ubiquitous in nature and have world-wide distribution. Mucor is a rapidly growing fungus that is usually dark gray or light olive gray when grown on typical laboratory media. It is easily recognizable microscopically by its tall needle like sporangiophores and large sporangium. The mold grows and spreads quickly. Like other members of the class Zygomycetes, Mucor fungi can reproduce asexually with spores, or sexually by fusing to create zygospores which contain a mixture of genetic material. Mucor can be present in the outdoor or indoor settings. In the outdoors, it can be found in soil, decaying vegetation, hay, stored seeds or horse manure. Indoors, it can be found in house dust, and poorly maintained vacuum systems or dirty carpets. One study looking at the most frequent molds found in house dust found Mucor in 98% of the samples from homes in Denmark and 31% of the samples in homes in Canada ²⁵. Heavy inhalation of the Mucor spores can cause extrinsic allergic alveolitis and ultimately pulmonary fibrosis if the fungus exposure persists. The supreme danger of Mucor, however, lays in the fact that it can become an opportunistic pathogen causing deep fungal infection when conditions are right. Ripe conditions for aggressive zygomycosis include significantly compromised immunity such in malignancy, neutropenia, use of immunosuppressive agents, metabolic acidosis, uncontrolled diabetes, starvation, severe trauma or other forms of debilitation. It is well documented that they can cause a multitude of pathologies not only in humans but also in cattle, sheep, swine and dogs ²⁶. In Australia, mucormycosis was documented to cause severe skin lesions in frogs ²⁵ and the Tasmanian platypus ²⁷.

The histopathologic hallmark of this infection is the mycotic invasion of the blood vessels and cause destruction quickly, often leading to thrombosis, followed by tissue infarction and necrosis mediated by fungal proteases, lipases and mycotoxins ²⁸. The infection rapidly accelerates and extends into adjacent tissues and structures. Necrotic and black tissue develops in the nares, palate, or orbit. The organisms can invade vessels and initiate a clotting response that leads to infarction. This tissue death leads to acidosis, which continues to feed the growth and destruction of the fungal organisms. This lack of blood flow also makes treatment with antifungals more difficult. Due to angioinvasion, the infection can quickly progress to fungemia and the disseminated form. This aggressive vasculature invasion can not only affect the small vessels such as arterioles but can also reach large arteries causing devastating results such as rupture of the aorta ²⁹.

Risk factor for zygomycosis

Almost all patients with invasive mucormycosis have some underlying disease that both predisposes to the infection and influences the clinical presentation. The most common underlying diseases are ³⁰:

• Diabetes mellitus, particularly with ketoacidosis
• Treatment with glucocorticoids
• Hematologic malignancies
• Hematopoietic cell transplantation
• Solid organ transplantation
• Treatment with deferoxamine
• Iron overload
• AIDS
• Injection drug use
• Trauma/burns
• Malnutrition

Invasive zygomycosis can rarely occur in healthy individuals without any apparent predisposing factors ⁴. It is usually a disease of the immune-compromised patient or those with chronic debilitating conditions. Some of these predisposing conditions include: ketoacidosis and uncontrolled diabetes mellitus ³¹, other forms of acidosis ³², hematologic malignancies ¹⁴ or solid cancers ³³, immunosuppressive therapy even for a short period of time ³⁴, after solid organ ³⁵ or following bone marrow transplantation ³⁶, patients with congenital or acquired neutropenia ³⁷ or anemia such as thalassemia or aplastic anemia ³⁸. Individuals with acquired immunodeficiency syndrome (AIDS) are also prone to invasive phycomycosis among other fungal infections ³⁹, persons with history of intravenous drug abuse ⁴⁰ or history of alcoholism ⁴¹; it can be seen following trauma ⁴² or with different degrees of burns ⁴³. Hospital acquired zygomycosis can occur following invasive procedures such as central line catheter or pace-maker wire implantation ⁴⁴ or frank surgical intervention ⁴⁵. Other potential predisposing factors include chronic infections such as tuberculosis ⁴⁶, septicemia with multi-organ failure ⁴⁷, fever of unknown origin ⁴⁸, use of antibiotic therapy, chronic renal failure ⁴⁹, sarcoidosis ⁵⁰ or patients suffering from starvation and severe malnutrition ⁵¹. Iron metabolism is another important predisposing factor for invasive zygomycosis. Even partially understood, many studies demonstrated that increased serum iron and treatment with the iron chelating agent deferoxamine predispose to such condition. The Rhizopus species actually utilize deferoxamine as a siderophore to supply previously unavailable iron to the fungus; this increased iron uptake is linearly correlated with its growth in the serum ⁵². The list of potential predisposing factors for invasive zygomycosis will certainly keep on growing with the advent of new biologic therapeutic agents that adversely affect patients’ immunity.

Zygomycosis symptoms

Classically, invasive zygomycosis has been classified into six different clinical syndromes. This classification is based on the general location of the disease. These locations are: rhinocerebral, pulmonary, gastrointestinal, cutanous, disseminated and miscellaneous. But keep in mind the wide variety of combinations and presentations that can be adopted by mucormycosis.

Rhinocerebral zygomycosis

Rhinocerebral zygomycosis is the most common form of all invasive mucormycoses form with one third to half of all cases ⁵². It is seen primarily in uncontrolled diabetic patients. It occurs by inhalation or hematogenous or lymphatic dissemination. The classical form involves the sinuses, especially maxillary, but can easily spread to the neighboring tissue including nose, orbits, eyes, brain, cranial nerves, hard and soft palates, both mandibles and the rest of the face. It has great variety of clinical presentations from that of a simple acute sinusitis with purulent rhinorrhea ⁵³, where the initial exam of the nasal mucosa may be normal, to a more dramatic presentation caused by progressive thrombosis and infarction. The exam might reveal violaceous discoloration, black eschar or frank tissue necrosis. Fever can be present or absent. Another well-recognized and severe form of rhino-cerebral zygomycosis is the presentation of periorbital cellulitis. It can be uni or bilateral. Initially it presents with tissue edema and erythema around the eye(s), later proptosis, ophtalmoplegia, and visual loss can ensue ⁵⁴. The spread of the infection to the hard palate can cause perforation ⁵⁵. Its extension towards the brain can cause utmost devastation; cases with brain abscesses ⁵⁶, cerebral arteries aneurysms ⁵⁷, hydrocephalus ⁵⁸ and stroke ⁵⁹ have been reported. Even the rare Garcin syndrome, where multiple cranial neuropathies occur, was documented in mucormycosis ⁶⁰.

Pulmonary mucormycosis

Pulmonary mucormycosis is thought to be second most common form. It occurs by inhalation or hematogenous or lymphatic spread. It can present with mild to severe symptoms including fever, cough, sputum production, dyspnea, hypoxia, chest pain and hemoptysis ⁵⁹. Mucormycosis can cause lobar consolidation ⁶¹, multiple disseminated lung nodules ⁶², fungal ball ⁶³ or mycotic abcess formation ⁶⁴. It can also present as a single tracheal ⁶⁵ or multiple endobronchial lesions ⁶⁶. Obviously, and because of its proximity, pulmonary zygomycosis can disseminate to the pleural space ⁶⁷, chest wall ⁶⁸ or the mediastinum where it can cause catastrophic rupture of large vessels ²⁹.

Gastrointestinal zygomycosis

Gastrointestinal zygomycosis is relatively rare. It is thought to be caused by ingestion of zygospores especially in the malnourished and alcoholics ⁶⁹ or it can be secondary to trauma ⁴². It can cause fever, abdominal pain and bloating, nausea and vomiting, hematemesis, melena or bowel perforation. It can be observed in the stomach where it can cause ulceration, bleeding or perforation ⁷⁰. It is interesting to notice that cases of iatrogenic gastric mucormycosis were reported after use of naso-gastric tubes or even tongue depressors colonized by the fungus ⁷¹. Other possible gastrointestinal sites include terminal ileum ⁷² and large bowel ⁷³. Mucor can infect other parts of the digestive system including liver ⁷⁴, bile duct ⁷⁵. It can be severe enough to involve many adjacent organs including pancreas ⁷⁶.

Cutaneous mucormycosis

Intact skin forms a barrier against mucor penetration. Cutaneous zygomycosis takes hold when this barrier is disrupted. This disruption can be caused by skin maceration, burns ⁴³ or trauma ⁷⁷. It usually carries a better prognosis than other forms of mucormycosis until the fungal reaches deeper into muscle, bone or fascia where it causes severe necrosis; the mortality rate then becomes very high ⁷⁸.

Disseminated zygomycosis

Disseminated zygomycosis has the worse prognosis. Its mortality rate approaches 100%. Since mucor is an angiotropic fungus, any prior form of this mycosis can cause severe fungemia in immune compromised individuals with subsequent hematogenous spread to many body organs including brain, heart, lungs, and kidneys among others. Moreover, disseminated mucormycosis was described with intravenous drug use ⁷⁹ and diabetics utilizing self-monitoring material ⁸⁰. Antemortem diagnosis can be very challenging. Blood cultures, in these severely ill patients, are usually negative. The diagnosis is suspected in the presence of disseminated organ infarction and necrosis ⁸¹. Cases of endocarditis ⁸² and myocarditis ⁸³ were observed.

Miscellaneous mucormycosis

In miscellaneous mucormycosis, the infecting agents from the mucorales order can infect any part of the body. Indeed, documented cases of this fungal infection were reported in the ear ⁸⁴ or limited to the parotid gland ⁸⁵ or in the intravascular system where it can cause severe micro-aneurysms or migratory thrombi ⁸⁶, adjacent to the spinal cord ⁸⁷, inside joints like the knee ⁸⁸ or affecting whole upper or lower limbs ⁸⁹, within the urinary tract ⁹⁰ and genital organs and pelvic floor ⁹¹. The consequences can be disastrous regardless of the affected site.

Zygomycosis diagnosis

Diagnosing invasive zygomycosis is not an easy task. Its clinical picture can be extremely variable. Further, because of its relative rarity, it is usually missed in its early stage when the chances of cure are still reasonable. Unfortunately, close to half of phycomycosis cases are diagnosed post-mortem ⁹². A high index of suspicion should always be kept when facing these variable presentations of mucormycosis especially when dealing with immune-compromised patients. When this infection is suspected, physicians have nowadays an extensive armamentarium at their disposition to try to pin down its elusive diagnosis. Initial blood work can reveal non-specific findings such as leukocytosis, hyperglycemia or acidosis. Frequently, stigmata of immunosuppression, including neutropenia, are encountered. Blood cultures are usually negative but, exceptionally, fungal growth in the blood can be observed ⁹³. Until now, there is no specific serologic test for mucormycosis. Radiological investigations, such plain x-rays or computed tomography, can be completely normal or demonstrate variable abnormal findings depending on the infection size and location. That location will guide the clinician to use further diagnostic tools in order to further clarify the diagnosis. Examples of such tools include bronchoscopy with bronchoalveolar lavage in case of pulmonary disease, upper or lower endoscopy for gastric or bowel lesions, or video assisted device for abdominal or thoracic infection ⁹⁴. However, obtaining tissue biopsy remains the gold standard for diagnosing invasive zygomycosis. Indeed, clinicians should not hesitate to obtain a good sample of the infected tissue as soon as possible to clinch the diagnosis. This task is relatively easy in cutaneous and rhinomaxillary mucormycosis; it becomes more challenging with deeper forms. Histopathology will reveal irregular broad non-septate hyphae and spores pathognomonic of mucor; with evidence of surrounding neutrophilic infiltration, necrosis and vasculature invasion.

Zygomycosis treatment

Most medical textbooks and literature emphasizes three important cornerstones in the treatment of invasive zygomycosis. They are: reversal of the underlying condition(s), medical therapy and surgical debridement.

1. Reversal of underlying condition(s): any predisposing factor, such as hyperglycemia or acidosis or malnutrition or immunosuppression, must be corrected if possible. This easy initial intervention improves the chances of survival ⁹⁵.
2. Medical therapy: until recently, the natural course of mucormycosis was usually fatal. A breakthrough in the treatment of deep mycoses occurred in 1953 when Drs Charles Smith and William Winn discovered amphotericin B from a soil isolate brought from the Orinoco Basin in Venezuela ⁹⁶. This discovery opened doors to the parenteral therapy for such mycoses including histoplasmosis, cryptococcosis, and mucormycosis. The first case of cure from this severe disease was reported by Harris in 1955 ⁹⁷. There are two types of antifungal treatment for invasive zygomycosis:
   1. Standard therapy: amphtericin B is a polyene macrolide. It continues to play a major role in the treatment of invasive zygomycosis. Both conventional and liposomal amphotericin B are effective against it; the liposomal form offers less infusion site side effects and milder nephrotoxicity, however, it generally costs more ⁹⁸. The duration of therapy varies from weeks to months depending on the site and severity of the infection.
   2. Experimental therapy: newer antifungal medications are being currently developed. The orally administered posaconazole, from the family of azoles, recently showed promising results against the mucorales species ⁹⁹. Iron chelation is a novel adjunctive therapy that has potential role in the treatment of mucormycosis ¹⁰⁰. Future immunotherapy will probably hold some key answers in the management of zygomycosis.
3. Surgical intervention: surgical debridement is another cornerstone in treating invasive zygomycosis. It is usually extensive and can be disfiguring. It has to be done in earnest in addition to other therapeutic interventions.
4. Psychological support: patients infected with invasive mucomycosis face many difficult challenges. This infection can be prolonged and exhausting, it adds to the heavy burden(s) of their uncontrolled chronic condition, such as diabetes and its complications, immunosuppression from malignancy or AIDS, etc. These patients are clearly prone to psychological setbacks and major depression. Health care providers must pay special attention to these possibilities and provide necessary supportive and therapeutic treatment.
5. Physical rehabilitation: if the infected person with invasive zygomycosis escapes death he could carry severe stigmata, from the infection or its treatment, such as disfigurement, partial/complete loss of an extremity or organ function. In many instances, these patients need prolonged course of physical or occupational rehabilitation depending on the degree of their disability.

The current standard of care for zygomycosis treatment includes aggressive surgical debridement and treatment with liposomal amphotericin B. If there is any suspicion for mucormycosis, amphotericin B should be initiated immediately. Correction of any underlying pathophysiology, such as diabetic ketoacidosis, should be done as well ¹⁰¹.

Hyperbaric oxygen therapy is commonly used for necrotizing soft tissue infections, chronic osteomyelitis, and compromised grafts and flaps ⁶. Hypoxia is a problem when it comes to nonhealing tissue. hyperbaric oxygen allows for saturation of oxygen within the blood and hemoglobin and a 10-fold increase of dissolved oxygen in plasma. Oxygen delivery to compromised tissue is increased, and normal tissue oxygenation for healing is restored. Hyperbaric oxygen therapy has also been shown to improve vascularity and stimulate new blood vessel growth. These factors are important in zygomycosis because of the angioinvasive nature of the infection, tissue becomes hypoxic and blood vessels become thrombosed. In addition, zygomycosis patients often undergo extensive debridement surgery. In cases of rhinocerebral murcomycosis, patients can be left disfigured. Addition of postsurgical hyperbaric oxygen therapy could help the formation of granulation tissue and bone healing ¹⁰².

Due to the rareness and severity of this rapidly progressive infection, it is extremely difficult to conduct randomized, controlled trials on human patients. Therefore, the majority of the research on using hyperbaric oxygen therapy for zygomycosis largely relies on case reports and retrospective studies. In a review of the literature done by Ferguson et al. ¹⁰³, 12 patients with rhinocerebral mucormycosis were investigated. They were all treated with surgery and amphotericin B. Half of the patients were treated with adjunctive hyperbaric oxygen therapy. Of the patients who did not receive hyperbaric oxygen therapy, 4 out of the 6 patients died as a result of the infection. Of the 6 patients who received adjunctive hyperbaric oxygen therapy, only 2 died. However, this case review is too small to draw any statistical conclusions.

One of the most interesting case reports comes from Couch et al. in which 2 diabetic patients with rhinocerebral mucormycosis were treated with adjunctive hyperbaric oxygen therapy. A high fatality rate occurs when the cerebral extension of the infection occurs. Both of these patients were critically ill and had aggressive brain mucor abscesses and one patient even had total occlusion of the internal carotid artery. Despite surgical debridement and medical therapy, their infections progressed and hyperbaric oxygen therapy was added as salvage therapy. Both patients had marked clinical improvement upon addition of hyperbaric oxygen therapy. They each received treatments 6 days a week at 2.5 atmosphere absolute (ATA) for 90 minutes. One received 79 total treatments and the other received 85 treatments. Both patients remained disease free 21 months after discharge. De La Paz et al. and Melero et al. also published case reports on successfully treating bilateral rhinocerebral mucormycosis with adjunctive hyperbaric oxygen therapy. A more recent review of cases done in 2004 by John BV et al. explored the use of hyperbaric oxygen therapy in 28 cases. The hyperbaric oxygen treatment sessions 90 minutes long at a pressure of 2 to 3 ATA, ranging from 90 to 120 minutes. In general, hyperbaric oxygen therapy was not started until after surgical debridement. The survival rate was 86% with diabetic patients having a much higher survival rate of 94%. There is a higher rate of survival when the underlying condition is correctable such as diabetic ketoacidosis. Conversely, 2 out of the 3 patients with malignancies died as a result of the infection.

Considering the pathophysiology of invasive zygomycosis, its high morbidity and mortality, and the benefits of hyperbaric oxygen treatment, it is reasonable to consider hyperbaric oxygen therapy as adjunctive therapy in the treatment of this disease.

Mucormycosis prognosis

The prognosis of mucormycosis depends on several factors, including the infection site, rapidity of diagnosis, and type and severity of immunosuppression.

Even with prompt diagnosis and treatment, overall mortality rates average about 50%, although rhinocerebral and gastrointestinal forms of the infection carry a mortality rate of approximately 85%. Mortality rates are high because of the difficulty in establishing the diagnosis and the lack of adequate antifungal therapy. By the time a diagnosis of mucormycosis is confirmed, it has frequently spread via either local invasion with extensive tissue destruction or widely disseminated infection. Mortality is higher in patients who have hematological disorders or malignancies as their underlying conditions are more difficult to treat. The disseminated form has a mortality of over 90%. Patients who do survive are often left disfigured due to extensive debridement surgeries.

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