EPIDEMIOLOGY OF MUCORMYCOSIS – SCIENCE LABORATORY TECHNOLOGY PROJECT TOPICS

TABLE OF CONTENT

COVER PAGE…………………………………………………………………..1
DEDICATION…………………………………………………………………..2
ACKNOWLEDGMENT………………………………………………………….3
TABLE OF CONTENT……………………………………………………………4
ABSTRACT……………………………………………………………………….5
CHAPTER ONE
INTRODUCTION………………………………………………………………..6
SIGNS AND SYMPTOMS……………………………………………………….7
CHAPTER TWO
HISTORY AND PHYSICAL EXAMINATION…………………………………8
CHAPTER THREE
DIAGNOSIS ……………………………………………………………………..10
TREATMENT ……………………………………………………………….….12
PROGNOSIS…………………………………………………………………….14
EPIDEMIOLOGY ………………………………………………………………15
ETIOLOGY AND PATHOPHYSIOLOGY……………………………………16

CHAPTER FOUR
CONCLUSION…………………………………………………………………18
RECOMMENDATION………………………………………………………..18
REFERENCE…………………………………………………………………19

ABSTRACT

Mucormycosis is an emerging angioinvasive infection caused by the ubiquitous filamentous fungi of the Mucorales order of the class of Zygomycetes. Mucormycosis has emerged as the third most common invasive mycosis in order of importance after candidiasis and aspergillosis in patients with hematological and allogeneic stem cell transplantation. Mucormycosis also remains a threat in patients with diabetes mellitus in the Western world. Furthermore, this disease is increasingly recognized in recently developed countries, such as India, mainly in patients with uncontrolled diabetes or trauma. Epidemiological data on this type of mycosis are scant. Therefore, our ability to determine the burden of disease is limited.

CHAPTER ONE

INTRODUCTION

Mucormycosis is any fungal infection caused by fungi in the order Mucorales.[1]:328 Generally, species in the Mucor, Rhizopus, Absidia, and Cunninghamella genera are most often implicated. This disease is often characterized by hyphae growing in and around vessels.

“Mucormycosis” and “zygomycosis” are sometimes used interchangeably. However, zygomycota has been identified as polyphyletic, and is not included in modern fungal classification systems.

Also, while Zygomycosis includes Entomophthorales, mucormycosis excludes this group.

Mucormycosis refers to several different diseases caused by infection with fungi in the order of Mucorales. Rhizopus species are the most common causative organisms. In descending order, the other genera with mucormycosis-causing species include Mucor, Cunninghamella, Apophysomyces, Absidia, Saksenaea, Rhizomucor, and other species.[1, 2]

Most mucormycosis infections are life-threatening, and risk factors, such as diabetic ketoacidosis and neutropenia, are present in most cases. Severe infection of the facial sinuses, which may extend into the brain, is the most common presentation. Pulmonary, cutaneous, and gastrointestinal (GI) infections are also recognized.

Successful mucormycosis treatment requires correction of the underlying risk factor(s), antifungal therapy with liposomal amphotericin B, and aggressive surgery.

The following is a postmortem image of a patient who had diabetic ketoacidosis and left rhinocerebral mucormycosis.

SIGNS AND SYMPTOMS

Mucormycosis frequently involves the sinuses, brain, or lungs as the areas of infection. While oral or cerebral mucormycosis are the most common types of the disease, this infection can also manifest in the gastrointestinal tract, skin, and in other organ systems.[6] In rare cases, the maxilla may be affected by mucormycosis. The rich vascularity of maxillofacial areas usually prevents fungal infections, although more virulent fungi, such as those responsible for mucormycosis, can often overcome this difficulty.

There are several key signs which point towards mucormycosis. One such sign is fungal invasion into the vascular network which results in thrombosis and death of surrounding tissue by loss of blood supply. If the disease involves the brain then symptoms may include a one-sided headache behind the eyes, facial pain, fevers, nasal stuffiness that progresses to black discharge, and acute sinusitis along with swelling of the eye Affected skin may appear relatively normal during the earliest stages of infection. This skin quickly progresses to an erythemic (reddening, occasionally with edema) stage, before eventually turning black due to necrosis.[8] In other forms of mucormycosis, such as pulmonary, cutaneous, or disseminated mucormycosis, symptoms may also include dyspnea (difficulty breathing), and persistent cough; in cases of necrosis, symptoms include nausea and vomiting, coughing blood, and abdominal pain.

CHAPTER TWO

HISTORY AND PHYSICAL EXAMINATION

Based on anatomic localization, mucormycosis can be classified as 1 of 6 forms: (1) rhinocerebral, (2) pulmonary, (3) cutaneous, (4) gastrointestinal, (5) disseminated, and (6) uncommon presentations.[11] Manifestations of mucormycosis depend on the location of involvement.

Rhinocerebral disease

Rhinocerebral disease may manifest as unilateral, retro-orbital headache, facial pain, numbness, fever, hyposmia, and nasal stuffiness, which progresses to black discharge. Initially, mucormycosis may mimic sinusitis.[19, 20]

Late symptoms that indicate invasion of the orbital nerves and vessels include diplopia and visual loss (see the following image). These late symptoms indicate a poor prognosis and are usually followed by reduced consciousness. Most patients with rhinocerebral disease have diabetes (especially with ketoacidosis) or have malignancies in combination with neutropenia and who may be receiving broad-spectrum antibiotics.

Orbital swelling and facial cellulitis are progressive. Black pus discharges from the necrotic palatine or nasal eschars. Necrotic eschars can be noted in the nasal cavity, on the hard palate, or as facial lesions; although these lesions are suggestive of mucormycosis, their absence does not exclude the possibility of this disease.

Proptosis, ptosis, chemosis, and ophthalmoplegias indicate retro-orbital extension. Cranial nerves V and VII are the most commonly affected. Loss of vision can occur with retinal artery thrombosis.

A reduced conscious state denotes brain involvement.

PULMONARY DISEASE

Pulmonary mucormycosis manifests nonspecifically as fever, dyspnea, and cough. Hemoptysis may occur in the presence of necrosis. Most patients with pulmonary disease have malignancies and a history of neutropenia. Pulmonary disease frequently occurs with concurrent sinus involvement.

The signs of pulmonary disease are nonspecific. Fevers are often noted. The lung examination may reveal decreased breath sounds and rales. Occasionally, chest wall cellulitis can occur adjacent to the underlying parenchymal disease, given the ability of this infection to cross tissue planes.

Cutaneous disease

Cutaneous disease manifests as cellulitis, which progresses to dermal necrosis and black eschar formation. The progressive black necrotic lesion of cutaneous mucormycosis reflects the vessel invasion characteristic of all forms of the disease.

Patients with skin disease may have had previous trauma or have been exposed to contaminated medical equipment, such as bandages.[5, 6] Rare cases have occurred at catheter sites or insulin or drug-use injection sites.

Gastrointestinal

Gastrointestinal (GI) mucormycosis usually affects severely malnourished individuals. Some case reports have described GI mucormycosis in transplant patients (eg, renal transplant). This infection may occur throughout the GI tract but most commonly affects the stomach, ileum, and colon. Again, the presentation is nonspecific, with abdominal pain, distention, nausea, and vomiting. Hematochezia or obstruction may occur. Some patients have tenderness to palpation or a mass; rupture may lead to signs of peritonitis.

Disseminated disease

Other disseminated forms of mucormycosis may involve the kidneys, bones, heart, and other locations, with symptoms attributed to these organ systems. Peritonitis in the setting of continuous ambulatory peritoneal dialysis has also been described.[23]

CHAPTER THREE

DIAGNOSIS

This photomicrograph reveals a mature sporangium of a Mucor sp. fungus, which can be responsible for mucormycosis

As swabs of tissue or discharge are generally unreliable, the diagnosis of Mucormycosis tends to be established by a biopsy specimen of the involved tissue.

When evaluating a patient with suspected rhinocerebral mucormycosis, also consider the following:

  • Bacterial orbital cellulitis
  • Cavernous sinus thrombosis
  • Aspergillosis
  • Pseudallescheria boydii infection (Pseudallescheriasis)
  • Rapidly growing orbital tumor

Aspergillosis, P boydii infection (pseudallescheriasis), nocardiosis, Wegener granulomatosis, and pulmonary embolism are also considered when evaluating a patient with suspected pulmonary mucormycosis.

Cutaneous disease considerations include ecthyma gangrenosa associated with pseudomonal infection and anthrax, and gastrointestinal disease considerations include bowel obstruction and ileocecal tuberculosis.

Pulmonary disease

Obtain chest radiography and chest high-resolution CT scanning. The most common finding is consolidation, usually unilobar; with disease progression, multilobar involvement may develop. Cavitation, especially producing an air crescent or halo sign (or reverse halo sign),[29] is highly suggestive of fungal infection, but does not distinguish it from aspergillosis. Nodular lesions (especially multiple nodules, ie, >10) and pleural effusions may be present. See the images below.

Chest computed tomography (CT) scan showing pulmonary mucormycosis with left basal consolidation and widespread nodules due to Rhizopus oryzae infection. The patient was receiving cytotoxic chemotherapy for myelodysplastic syndrome and had iron overload from numerous blood transfusions. Chest computed tomography (CT) scan showing pulmonary mucormycosis with left basal consolidation and widespread nodules due to Rhizopus oryzae infection. The patient was receiving cytotoxic chemotherapy for myelodysplastic syndrome and had iron overload from numerous blood transfusions. This CT scan of the patient shows resolution of pulmonary mucormycosis after 5 months of antifungal treatment.

Gastrointestinal disease

In gastrointestinal (GI) disease, abdominal CT scans may show a mass associated with the GI tract.

Central nervous system

CT scanning or MRI of the central nervous system may reveal abscesses (especially in the setting of intravenous drug use) or extension of rhinocerebral disease into the brain. Additionally, cavernous and, less commonly, sagittal sinus thrombosis may be seen.

Biopsy and Histologic Features

The critical test procedure for diagnosing mucormycosis is obtaining a biopsy specimen of the involved tissue. A rapid histologic assessment of a frozen tissue section should be performed in order to promptly institute surgical and medical management for the infection.

Biopsy of necrotic tissue

Biopsy of necrotic tissue may be obtained from nasal, palatine, lung, cutaneous, gastrointestinal (GI), or abscess wall site.

Stains of fixed tissues with hematoxylin and eosin (H&E) or specialized fungal stains, such as Grocott methenamine-silver (see the following image) or periodic acid-Schiff (PAS) stains, show pathognomonic changes of broad-based (typically 10- to 20-µm diameter), irregular, ribbonlike, nonseptate hyphae with irregular branching that may occur at right angles. Vascular invasion and necrosis are the characteristic consequences of the infective process. Thus, neutrophil infiltration, vessel invasion, and tissue infarction are often observed. A granulomatous reaction may also be observed.

Histologic findings from an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Findings show the typical Mucorales hyphae on Grocott methenamine-silver staining. The hyphae are the dark structures with budlike, right-angle hyphae. (Courtesy of A. Allworth, MD, Brisbane, Australia.)

Culture of biopsy samples is required to determine the species of Mucorales. Do not crush or grind the specimen, because the nonseptate hyphae are prone to damage. Growth usually occurs in 2-3 days. The genus and species are determined via examination of the fungal morphology (eg, the presence and location of the rhizoids).

TREATMENT

If mucormycosis is suspected, prompt amphotericin B therapy should be administered due to the rapid spread and mortality rate of the disease. Amphotericin B (which works by damaging the cell walls of the fungi) is usually administered for a further 4–6 weeks after initial therapy begins to ensure eradication of the infection. Posaconazole has been shown to be effective against mucormycosis, perhaps more so than amphotericin B, but has not yet replaced it as the standard of care.

Liposonal drug is also available in the market, but this drug is very expensive.

After administration of either amphotericin B or Posaconazole, surgical removal of the “fungus ball” is indicated. The disease must be monitored carefully for any signs of reemergence.

Surgical therapy can be very drastic, and in some cases of Rhinocerebral disease removal of infected brain tissue may be required. In some cases surgery may be disfiguring because it may involve removal of the palate, nasal cavity, or eye structures.[9] Surgery may be extended to more than one operation.[6] It has been hypothesised that hyperbaric oxygen may be beneficial as an adjunctive therapy because higher oxygen pressure increases the ability of neutrophils to kill the organism.

Patients with mucormycosis should be treated in a tertiary referral center with subspecialty units experienced in the care of the condition and the underlying causes. Correction of the underlying abnormality and prompt institution of liposomal amphotericin B therapy and surgical resection are critical.[1, 27, 30]

Other important considerations in medical management include the following:

  • Diabetic ketoacidosis requires insulin, correction of acidosis with sodium bicarbonate, and rehydration
  • Neutropenia in association with hematologic malignancy and its treatment should be reversed, if possible, with the use of colony-stimulating factors and the withdrawal of cytotoxic chemotherapy
  • Wean glucocorticosteroids and other immunosuppressive drugs
  • Interrupt deferoxamine therapy; hydroxypyridine chelating agents may be substituted for deferoxamine

For prevention, avoid the use of contaminated medical bandages and other equipment to prevent cutaneous disease; frequently check the wound(s). The use of contaminated bandages and other dressings has caused cutaneous mucormycosis. Failure to examine areas under dressings or to recognize the significance of deterioration in preexisting wounds may produce severe cutaneous and, ultimately, disseminated disease. Place patients with severe prolonged neutropenia in rooms equipped with high-efficiency particulate air (HEPA) filters, where practicable. Secondary prophylaxis is often used after therapy among patients who remain immunocompromised.

PROGNOSIS

In most cases, the prognosis of mucormycosis is poor and has varied mortality rates depending on its form and severity. In the rhinocerebral form, the mortality rate is between 30% and 70%, whereas disseminated mucormycosis presents with the highest mortality rate in an otherwise healthy patient, with a mortality rate of up to 90%. Patients with AIDS have a mortality rate of almost 100%.[10] Possible complications of mucormycosis include the partial loss of neurological function, blindness and clotting of brain or lung vessels.

EPIDEMIOLOGY

Mucormycosis is a very rare infection, and as such it is hard to note histories of patients and incidence of the infection.[6] However, one American oncology center revealed that mucormycosis was found in 0.7% of autopsies and roughly 20 patients per every 100,000 admissions to that center.[10] In the United States, mucormycosis was most commonly found in rhinocerebral form, almost always with hyperglycemia and metabolic acidosis.[11] In most cases the patient is immunocompromised, although rare cases have occurred in which the subject was not; these are usually due to a traumatic inoculation of fungal spores. Internationally, mucormycosis was found in 1% of patients with acute leukemia in an Italian review.

A cluster of infections occurred in the wake of the 2011 Joplin tornado. As of July 19, a total of 18 suspected cases of cutaneous mucormycosis had been identified, of which 13 were confirmed. A confirmed case was defined as 1) necrotizing soft-tissue infection requiring antifungal treatment or surgical debridement in a person injured in the tornado, 2) with illness onset on or after May 22, and 3) positive fungal culture or histopathology and genetic sequencing consistent with a Mucormycete. No additional cases have been reported since June 17. Ten patients required admission to an intensive-care unit, and five died.

Cutaneous mucormycosis has been reported after previous natural disasters; however, this is the first known cluster occurring after a tornado. None of the infections were found in persons cleaning up debris; instead it is believed transmission occurred through penetrating injuries inflicted by contaminated objects (e.g. splinters from a woodpile). Health-care providers should consider environmental fungi as potential causes of necrotizing soft-tissue infections in patients injured during tornados and initiate early treatment for suspected infections.

Predisposing factors for mucormycosis include AIDS, diabetes, malignancies such as lymphomas, renal failure, organ transplant, long term corticosteroid and immunosuppressive therapy, cirrhosis energy malnutrition,[6][7] and Deferoxamine therapy. Despite this, however, there have been cases of mucormycosis reported with no apparent predisposing factors present.

Mucormycosis is extremely rare, and its incidence is difficult to calculate accurately. Further, since mucormycosis is not a reportable disease, the true incidence is unknown, but an estimated 500 cases occur in the United States annually.

ETIOLOGY AND PATHOPHYSIOLOGY

Risk factors

Immunocompromising conditions are the main risk factor for mucormycosis. Patients with uncontrolled diabetes mellitus, especially with ketoacidosis, are at high risk. Patients with cancer—especially those who are neutropenic and receiving broad-spectrum antibiotics—as well as individuals receiving immunosuppressive agents—including oral or intravenous steroids and tumor necrosis factor (TNF)–alpha blockers—are at risk. In addition, hematologic cancer patients with opportunistic herpetic infections (eg, cytomegalovirus) and graft versus host disease are at increased risk.

Extreme malnutrition is also linked to mucormycosis, especially the gastrointestinal (GI) form. Iron is a growth stimulant for Mucorales, and deferoxamine acts as a siderophore that delivers iron to the fungi. Older iron chelators such as deferoxaminetherapy and all causes of iron overload are additional risk factors for mucormycosis. Trauma and the use of contaminated medical supplies over wounds are associated with cutaneous mucormycosis. In addition, patients with burns and those who use intravenous drugs are at a higher risk.

Some patients with mucormycosis have no identifiable risk factors.[3, 4]

PATHOPHYSIOLOGY

Mucoraceae are ubiquitous fungi that are commonly found in soil and in decaying matter. Rhizopus can be found in moldy bread. Given the ubiquitous nature of these fungi, most humans are exposed to these organisms on a daily or weekly basis. Nonetheless, they rarely cause disease because of the low virulence of the organisms; instead, they mainly affect individuals with immunocompromising conditions. Immunocompromised hosts with poorly controlled diabetes mellitus (especially with ketoacidosis), who are receiving glucocorticosteroids, who have neutropenia in the setting of hematologic or solid malignancy, who have undergone transplantation, who have iron overload, and who have burns are at risk for disease.

The major route of infection is via inhalation of conidia; other routes include ingestion and traumatic inoculation (see the images below). Ingestion leads to GI disease and occurs primarily among malnourished patients, but it can also occur after ingesting nonnutritional substances (pica). Regarding cutaneous disease, nonsterile tape and contaminated wooden splints have caused wound infections.[5, 6] Such cases are associated with trauma/surgery, the presence of a preexisting wound or line, or both. Additionally, natural disasters (after hurricanes, tsunamis, or tornados) may be associated with wound infections due to mucormycosis and should be considered in the setting of a necrotic-appearing wound or poor response to antibiotic treatment.[7, 8, 9]

When spores are deposited in the nasal turbinates, rhinocerebral disease develops (see Rhinocerebral Mucormycosis); when spores are inhaled into the lungs, pulmonary disease develops; when ingested, GI disease ensues; and when the agents are introduced through abraded skin, cutaneous disease develops.

Mucoraceae are molds in the environment that become hyphal forms in tissues. Once the spores begin to grow, fungal hyphae invade blood vessels, producing tissue infarction, necrosis, and thrombosis. Neutrophils are the key host defense against these fungi; thus, individuals with neutropenia or neutrophil dysfunction (diabetes, steroid use) are at highest risk.[10] Few cases of mucormycosis have been reported in patients with acquired immunodeficiency syndrome (AIDS), suggesting that the host defense against this infection is not primarily mediated by cellular immunity.

PROGNOSIS

Rhinocerebral disease causes significant morbidity in patients who survive, because treatment usually requires extensive, and often disfiguring, facial surgery.

Surviving mucormycosis requires rapid diagnosis and aggressive coordinated medical and surgical therapy.

Mucormycosis carries a mortality rate of 50-85%. The mortality rate associated with rhino-cerebral disease is 50-70%. Pulmonary and gastrointestinal (GI) diseases carry an even higher mortality rate, because these forms are typically diagnosed late in the disease course.

CHAPTER FOUR

CONCLUSION

Mucormycosis is on the rise especially among patients with immunosuppressive conditions. There seems to be more cases seen at the end of summer and towards early autumn. Several studies have attempted to look at the seasonal variations of fungal pathogens in variou indoor and outdoor settings. Only two reports, both from the Middle East, have addressed the relationship of mucormycosis in human disease with climate conditions. In this paper we review, the relationship of indoor and outdoor fungal particulates to the weather conditions and the reported seasonal variation of human cases.

 

RECOMMENDATION

Patient survival from mucormycosis requires rapid diagnosis and aggressive coordinated medical and surgical therapy. To that effect, consultations with various specialists are critical.

An infectious diseases consultation is warranted for management of antifungal therapy and coordination of medical care.

Surgical specialties consultations depend on the location of disease, as follows:

  • Ear, nose, and throat consultation and neurosurgery consultation for rhinocerebral mucormycosis
  • Thoracic surgery consultation for pulmonary involvement
  • Gastrointestinal (GI) surgery consultation for GI involvement
  • Plastic surgery consultation for cutaneous involvement

In addition, endocrinologic consultation may be necessary for the management of unstable diabetes; hematologic/oncologic consultation may be needed for the management of issues related to hematology and solid tumors; and surgical intensive care unit (SICU) consultation is important for supportive care.

REFERENCES

[1] G. Lamaris, R. Ben-Ami, R. Lewis, G. Chamilos, G. Samonis and D. Kontoyiannis, “Increased virulence of Zygomycetes Organisms Following Exposure to Voriconazole: A Study Involving Fly and Murine Models of Zygomycosis,” The Journal of Infectious Diseases, Vol. 199, No. 9, 2009, pp. 1399-1406. doi:10.1086/597615
[2] M. Al-Ajam, A. R. Bizri, J. Mokhbat, J. Weedon and L. Lutwick, “Mucormycosis in the Eastern Mediterranean: A Seasonal Disease,” Epidemiology & Infection, Vol. 134, No. 2, 2006, pp. 341-346. doi:10.1017/S0950268805004930
[3] T. Shpitzer, N. Keller, M. Wolf, A. Goldschmied-Reouven, G. Bahar, I. Bahar, J. Kronenberg, R. Feinmesser and Y. Talmi, “ Seasonal Variations in Rhino-Cerebral Mucor Infection,” Annals of Otology, Rhinology and Laryngology, Vol. 114, No. 9, 2005, pp. 695-698.
[4] C. Bartzokas, “Relationship between the Metereological Conditions and the Air-Borne Fungal Flora of the Athens Metropolitan Area,” Mycopathologia, Vol. 57, No. 1, 1975, pp. 35-38. doi:10.1007/BF00431176
[5] M. Calvo, J. Guarro, G. Suarez and C. Ramírez, “Air-Borne Fungi in the Air of Barcelona (Spain). IV. Various Isolated Genera,” Mycopathologia, Vol. 71, No. 2, 1980, pp. 119-123. doi:10.1007/BF00440618
[6] B. Herrero, “Weekly Variation of Fungal Colonies in the Atmosphere of Palencia (Spain) Throughout the Year 1992,” Journal of Investigational Allergology and Clinical Immunology, Vol. 7, No. 6, 1997, pp. 611-618.