Pediatric Mucormycosis

In this article, pediatric mucormycosis will be reviewed, such as infection involving immunosuppressed children; this disease has also been observed in neonates (especially premature infants), patients with burns, and children with a history of incidental trauma.

Mucormycosis usually refers to fungal infections in immunosuppressed hosts caused by ubiquitous molds found in organic matter and soil. Such molds belong to the order Mucorales.[1, 2, 3] The infections they cause manifest in the rhinocerebral, pulmonary, cutaneous (see the image below), gastrointestinal (GI), disseminated, and central nervous systems.[4]

Mucormycosis is often life threatening. Therefore, prompt diagnosis and institution of antifungal therapy are vital, as is appropriate management of the underlying disease process.

See also Pediatric Mucormycosis and Rhinocerebral Mucormycosis.

The fungus of mucormycosis gains entry into the body through the nasopharynx. It can be inhaled into the lungs, or it can extend to the sinuses, orbit, and brain. The occurrence of mucormycosis depends on host immunity, but the mechanisms of increased susceptibility in certain hosts remain perplexing. Regardless of the anatomic site involved, characteristic histopathologic findings include angioinvasion with subsequent tissue infarction and necrosis leading to tissue destruction.[5]

The fungal pathogens that cause mucormycosis belong to the class Zygomycetes and the order Mucorales. Rhizopus species are the agents most commonly isolated in mucormycosis, followed by Rhizomucor species, Absidia corymbifera, Apophysomyces elegans, Cunninghamella bertholletiae, Mucor species, and Saksenaea vasiformis.[1, 2, 3]

Immunodeficiency

Risk factors for mucormycosis in adults and children include diabetes mellitus (especially with ketoacidosis), which is the underlying condition most commonly associated with this disease. This feature is probably due to diminished function of phagocytes at low pH.

Other individuals at risk include patients with malignancy, those with protein-calorie malnutrition, those with skin breakdown due to burns, those with trauma or who are undergoing surgery, those with acute and chronic renal disease, and those with hematologic disease who are receiving deferoxamine.

Patients with immunosuppression due to acquired immunodeficiency syndrome (AIDS), organ transplantation, neutropenia, or steroid therapy are also at risk.

Nosocomial infection

Hospital-acquired mucormycosis has been reported. In a review of 26 hospitalized, posttraumatic patients with mucormycosis, approximately 57% were females and two thirds had comorbidities (ie, diabetes mellitus, leukemia, immunosuppression); diabetes was noted in 6 patients.[6] In hospitalized patients with cannula, wound or occlusive dressings should be closely watched for erythema or necrosis.

Neonatal infection and prematurity

Neonates, especially those born prematurely, can be at risk. Unusual incidents of neonatal mucormycosis might have occurred when patients were exposed to contaminated surfaces, such as bandages, tongue depressors used as arm splints, or cardiac-monitor leads.[7]

In the United States, mucormycosis is most common in immunocompromised hosts, although cases in immunocompetent patients are also reported. Underlying diseases, such as diabetes mellitus and malignancy, are risk factors. Environmental spore exposure (from exposure to construction activity) has also led to clinical cases of mucormycosis. Other cases have been reported in patients with traumatic skin injury (eg, associated with the use of nonsterile adhesive tape or with use of tongue depressors as splints in neonates). Exposure to voriconazole, which is not active against mucormycosis, is noted to be a risk factor in patients with cancer.

No racial or sexual predilection is reported. However, most cases of mucormycosis occur in immunosuppressed adults. In a pooled review, Kline described 41 cases of rhinocerebral mucormycosis occurring in children and adolescents aged 2 months to 18 years.[8] About 49% of cases were found in patients with diabetes mellitus, and 15% of cases were found in those with leukemia. Four of the 41 children (10%) had no predisposing conditions.

Survival rates largely depend on early diagnosis and treatment of mucormycosis as well as resolution of the patient's underlying condition. If the disease progresses and if the underlying condition remains uncontrolled, death usually ensues. The overall mortality rate in adults is 50%, though survival rates higher than this have been reported.

In neonates, these invasive fungal infections can be rapidly fatal; the time from clinical symptoms to death is in the range of 6 to 42 days.

Because the disease is rare and because therapy is not standardized, no studies aid in predicting patient outcomes.

Symptoms of mucormycosis vary depending on the involved anatomic site. However, unexplained or persistent fever in a patient who has immunosuppression and who is receiving broad-spectrum antibiotics should alert the clinician to look for possible foci of mucormycosis.

Rhinocerebral disease

The most common signs and symptoms of rhinocerebral mucormycosis are altered mental status, fever, and pain and swelling over the involved site. Severe headache can also manifest. Most of these findings occur in patients with diabetic ketoacidosis.

A black eschar of the nasal mucosa or palate is usually a hallmark sign of rhinocerebral mucormycosis. It is a sign of deep infection and tissue destruction of the nasal mucosa. This finding on physical examination should prompt biopsy and empiric treatment.

CNS disease

Persistence of altered mental status after metabolic abnormalities are corrected, especially in patients with diabetic ketoacidosis, should alert the physician to consider mucormycosis involving the central nervous system (CNS).

Loss of extraocular muscular function, along with proptosis and cranial nerve dysfunction of cranial nerves V and VII, are signs of neurologic involvement in mucormycosis. Several other cranial nerves, such as cranial nerves I, III, and IV, can also be involved.

Pulmonary and GI disease

Fever, dyspnea, hemoptysis, and cough are observed in patients with pulmonary mucormycosis.

Abdominal pain can be a manifestation of gastrointestinal (GI) mucormycosis. GI mucormycosis is mostly encountered in premature neonates and in patients with malnutrition. Severe malnutrition is an independent risk factor.

Cutaneous disease

A black eschar on the skin of a patient who is immunocompromised should prompt skin biopsy, as seen in the following image. Progressive cellulitis of skin lesions with gangrene and necrosis is another concern in cutaneous mucormycosis.

Antemortem diagnosis of mucormycosis has improved, leading to improving patient survival.

Once mucormycosis is suspected, obtaining tissue for culture is vital (see Biopsy and Histologic Features). However, isolating fungus from infected tissue is usually difficult, and analysis of nasal and sputum swabs is rarely helpful.[9]

Specimens should be obtained from areas such as suggestive skin lesions, black eschars found in the nasopharynx, and nasal discharge that may appear like clotted blood. These specimens should be immediately sent to the microbiology laboratory for culturing.

Because fungi of the order Mucorales contaminate laboratory specimens, use caution when these organisms are isolated from bronchial washings, sinus samples, and sputum obtained from immunosuppressed hosts.

Although Rhizopus or Mucor species can be contaminants, the laboratory finding of these organisms in specimens from patients who are immunosuppressed or from patients with certain risk factors for mucormycosis should not be ignored.

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) are valuable in delineating extent of disease for most forms of mucormycosis.[10] These 2 imaging modalities are also helpful in planning surgical debridement when needed.

In rhinocerebral mucormycosis, opacification of the sinuses, bone destruction, and osteomyelitis may be noted. In some patients, images may reveal minimal changes even when extensive tissue destruction is present.

Biopsy of necrotic lesions from pulmonary, rhinocerebral, and mucocutaneous sites is appropriate for obtaining specimens for microscopy and cultures. Sensitivity is better with tissue staining than with culturing, but collecting tissue for studies is critical for diagnosis.

Routine stains, such as hematoxylin and eosin (H&E) stains, help in visualizing Mucor hyphae, whereas Grocott methenamine silver (GMS) stain and periodic acid-Schiff (PAS) stains help to demarcate fungal elements in tissue. However, GMS stains may not reveal chlamydospores of Mucor fungi.

Histologic findings

Direct microscopic findings of hyphal elements in tissue biopsy specimens are important for the diagnosis of mucormycosis.

Biopsy material can be examined with potassium hydroxide (KOH), H&E, and GMS stains. Another useful stain is cresyl violet, which colors Mucor fungi walls brick red while coloring other fungi purple or blue.

Upon microscopic examination, fungi of the Mucorales order are characterized by aseptate hyphae, which vary in width up to 50 µm. These hyphae are broad and branch from the main hyphal trunk; they are often angled 90°.[5] Identification of most of the Zygomycetes is accomplished by observing the morphology of the sporangia, such as presence or absence of the columellae and apophyses, arrangement and number of sporangiospores, and absence or presence of rhizoids.

Fungal hyphae of Mucor species can often be differentiated from other fungi, such as Aspergillus and Fusarium species. Hyphae of Mucor species are aseptate or pauciseptate, they are broad and thick (6-25 mm wide), they have nonparallel edges, and they possess irregularly shaped fungal elements with relatively infrequent acute-angle and nonrandom branching (see the following image).

Characteristic but not pathognomonic histologic findings include angioinvasion, with the Mucor fungi invading the walls of arteries, resulting in the necrosis and thrombosis of surrounding tissue, as can be seen in the first image below. Immunohistochemical methods of staining biopsy material are available in specialized laboratories. Perineuronal invasion can also occur (see the second image below).

Mucormycosis is often life threatening. A combination of a high index of suspicion with prompt diagnosis and medical and surgical care are vital in the management of mucormycosis.[11] Patients' survival rates also depend on resolution of their underlying condition. If mucormycosis progresses and if the underlying condition remains uncontrolled, death usually ensues.

Care of a pediatric patient with mucormycosis should involve several pediatric subspecialists, depending on the patient's underlying risk factors and the extent of disease. Therefore, if the child has an underlying malignancy, the following physicians should be involved in the child's care: oncologist, infectious disease specialist, surgeon (ear, nose, and throat [ENT] specialist and neurosurgeon, if the patient has rhinocerebral disease), and critical care specialists.

Underlying comorbidities such as hyperglycemia, acidosis in diabetic patients, nutritional problems, neutropenia, lymphopenia, and immunosuppression must be addressed.

The drug of choice for treating mucormycosis is amphotericin B, with a dosage of 1-1.5 mg/kg/d. Liposomal amphotericin B at dosages higher than these have also been used to treat disseminated disease.[12, 13] Some authors have suggested doses as high as 10-15 mg/kg. A term neonate who was diagnosed with facial mucormycosis after liver and small bowel transplantation survived after wide excision and 26 weeks of treatment with liposomal amphotericin B.[14]

Azoles (eg, fluconazole, itraconazole) are not helpful in the treatment of mucormycosis. Among relatively new triazoles, posaconazole is effective against mucormycosis. This agent has an oral formulation and undergoes liver metabolism. Posaconazole may be effective compared with other azoles against molds, including mucormycosis.[15, 16] Studies are being conducted to evaluate combination antifungal therapies.

Hyperbaric oxygen has been noted to reduce the morbidity and mortality when given in combination with medical and surgical therapy, with a 50% survival rate.[17]

Surgical debridement should be undertaken early in the course of the illness, especially in cases of rhinocerebral mucormycosis. Instilling amphotericin B into abscess cavities after debridement has been suggested. Repeat surgery may be necessary to effectively eliminate all necrotic tissue in patients who survive. Reconstructive surgery is inevitable for those who have disfigurement due to severe rhinocerebral mucormycosis.

Close observation of patients who were treated and who survived the acute mucormycosis infection is important, because chronic manifestation of mucormycosis or late sequelae is possible.

In patients with rhinocerebral mucormycosis, cerebral abscess formation, cavernous sinus thrombosis, and thromboembolism of the internal carotid artery should be suspected as complications.

Studies in adults have demonstrated some benefit with the use of high-efficiency particulate air (HEPA) filters and different chelating agents instead of deferoxamine to decrease the risk of mucormycosis.

No method to prevent mucormycosis is recognized.

The drug of choice for the treatment of mucormycosis is amphotericin B. Posaconazole has been rarely used in combination with amphotericin B as a salvage therapy in severe cases of mucormycosis in adults and children.

High doses of this drug are required, and nephrotoxicity may result. Lipid formulations of amphotericin B allow for very high doses to be administered while better protecting renal function. Whether lipid formulations of amphotericin B provide better therapeutic outcomes is not clear, and the high cost necessitates careful consideration of use.

Renal impairment and failed treatment with conventional amphotericin B are appropriate indications for the use of the lipid formulations. Lipid preparations of amphotericin B are used at 5 mg/kg/d. Some have doses of up to 15 mg/kg/d to treat mucormycosis.

Class Summary

High-dose liposomal amphotericin B has been used to treat disseminated disease. Azoles (eg, fluconazole, itraconazole) are not helpful in the treatment of mucormycosis.

Amphotericin B

Amphotericin B is produced by Streptomyces nodosus. The mechanism of action of this agent is the binding of sterols in fungal cytoplasmic membrane, resulting in membrane permeability that impairs survival of the fungus. This leads to loss of intracellular potassium. Amphotericin B is administered intravenously (IV) when used to treat mucormycosis.

Liposomal amphotericin B (AmBisome)

Liposomal amphotericin B is amphotericin B encapsulated in a bilayer of liposomes. This is the antifungal agent of second choice when renal toxicity develops or conventional amphotericin B therapy is failing. Nephrotoxicity and infusion-related toxicity are reduced compared with conventional amphotericin B.

Amphotericin B lipid complex (Abelcet)

Amphotericin B lipid complex is amphotericin B in phospholipid complexed form. This is the drug of third choice when conventional amphotericin B therapy is failing, but renal function is not impaired.