Oral complications associated with aspergillosis in patients with a hematologic malignancy Presentation and treatment

Mark S. Chambers, DMD, MS, a Will iam A. Lyzak, DMD, MS, b Jack W. Mart in, DDS, MS, c Judy S. Lyzak, MD, d and B61a B. Toth, DDS, MS, e Houston, Tex. and Chicago, Ill. DEPARTMENT OF DENTAL ONCOLOGY, THE UNIVERSITY OF TEXAS, M. D. ANDERSON CANCER CENTER AND UNIVERSITY OF CHICAGO

Opportunistic mycotic infections, such as aspergillosis, can produce morbid consequences with or without aggressive therapy in an immunocompromised patient. Treatment including amphotericin B and resection of the infected tissue must be considered early in the overall management of the patient. We describe two patients with acute myelogenous leukemia who underwent intense cytoreductive therapy with bone marrow transplantation and an associated fungal infection treated with an investigational form of amphotericin B. (ORAL SURG ORAL MED ORAL PATHOL ORAL RADIOL ENDOD 1995;79:559-63)

Blood diseases, including leukemia, frequently lead to abnormal clinical situations that can involve the oral tissues. These conditions could include opportunistic mycotic infections such as aspergillosis, which by its nature can destroy oral structures to produce morbid consequences.

In leukemia and bone marrow transplant patients with aspergillosis, early recognition and aggressive therapy is critical to achieve optimal therapeutic re- suits. 1-14 Unfortunately, the diagnosis of aspergillosis may be difficult because concomitant bacterial, viral, or other fungal infections may hinder prompt diagno- sis as may the associated compromised complex med- ical status of the marrow transplant patient.

Here we describe two patients with acute myelog- enous leukemia ( A M L ) and the disease/ t reatment- related oral infectious complications while each un- derwent intense chemotherapy or bone marrow trans- plant t reatment at M. D. Anderson Cancer Center, Houston, Tex.

CASE REPORTS Case 1

On November 13, 1992, a 30-year-old white female pre- sented to an emergency room of a local hospital with fever,

aMaxillofacial Prosthodontist/Dental Oncologist; Department of Dental Oncology, The University of Texas. bFormer Fellow, Maxillofacial Prosthodontics, The University of Texas. Currently, Assistant Professor, Department of Restorative Dentistry, University of Illinois, Chicago. cProfessor, Department of Dental Oncology, Maxillofacial Prosth- odontist, The University of Texas. dResident, Pathology, University of Chicago. eAssociate Professor, Department of Dental Oncology, Dental On- cologist (Oral Pathology), The University of Texas. Copyright �9 1995 by Mosby-Year Book, Inc. 1079-2104/95/$3.00 + 0 7/13/62864

chills, and sweating, which gave the initial clinical impres- sion of bronchial pneumonia. After admission to the hospi- tal and with the appropriate hematologic workup, her con- dition was diagnosed as AML.

After the diagnosis, she began a treatment of chemo- therapy consisting of idarubicin and cytosine-arabinosine (Ara-C) as well as prophylactic broad-spectrum antibiotics. High-dose consolidation chemotherapy was initiated in January 1993 along with hematologic supportive care. Be- fore her last cycle of chemotherapy, the patient developed sinus pains. A computed tomography (CT) scan of the paranasal sinuses revealed maxillary sinus opacities (Fig. 1). Culture and fluorescent microscopy of the nasal dis- charge revealed A. fumigatus infection. The sinusitis was treated with daily doses of amphotericin B on an outpatient basis.

At the completion of her last course of chemotherapy, she was referred to M. D. Anderson Cancer Center to be eval- uated by the Hematology/Oncology Service for a possible bone marrow transplant. During the pretreatment workup, a Dental Oncology consultation was obtained on April 12, 1993. The oral/dental examination revealed that the pa- tient's hygiene was excellent, her teeth were in good clini- cal repair without periodontal disease and with no soft tis- sue lesions. A panoramic radiograph revealed possible ab- normal maxillary sinus opacities.

With the patient's sister as an HLA compatible donor, an allogenic transplant was performed. During the recovery phase of the transplant, the patient remained afebrile in spite of neutropenia and several episodes of epistaxis, sto- matitis, and esophagitis.

Because of hematologic abnormalities, additional che- motherapy was started on May 1, 1993 along with an investigational amphotericin B colloidal dispersion (ABCD) as a prophylaxis because of her compromised status and the maxillary sinus abnormality. Several days after the start of this new chemotherapy cycle, a left facial swelling with pe- riorbital edema developed. In addition, an oroantral open- ing developed centrally on the hard palate (Fig. 2). A biopsy

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Fig. 1. Case l , CT scan reveals maxillary sinus opacities later confirmed as A. fumigatus infection.

Fig. 2. Oroantral opening developed centrally on hard palate (patient was referred to dental oncology for prosth- odontic care).

confirmed invasive fungal sinusitis. New diagnostic imaging films revealed significant extension of the sinusitis. On May 7, 1993, an emergency sinusectomy was performed in which the surgery essentially removed the contents of the right and left maxillary sinuses, the ethmoid bones, and a right me- dial maxillectomy. The contents of the sinuses and the sur- gical specimens were sent for pathologic study and appro- priate cultures. The cultures from the maxillary sinuses and the ethmoids were positive for Aspergillus. The patient continued on the ABCD regimen. The patient began to

show white blood cell count recovery on the eleventh day after the transplant along with a decrease in the left peri- orbital swelling. On posttransplant day 28, a bone marrow biopsy revealed no leukemia cells. The patient was dis- charged on June 3, 1993; she was given several posttrans- plant outpatient medications, among which was ABCD, as well as instructions on cleaning the nasal and maxillary de- fect. 15

Case 2 AM L was diagnosed in a 23-year-old white male in April

1991. He achieved complete remission after several cycles of chemotherapy. In November 1993, relapse occurred and the patient was admitted for reinduction chemotherapy consisting of idarubacin and Ara-C supported by granulo- cyte-colony stimulating factor. On day 13 of this treatment the patient had a fever, diarrhea, and a cough. Examination of his oral mucosa by the medical oncologist showed a small erythematous lesion on the hard palate. The patient was admitted and treated with multiple antibiotics and flucon- azole. Within 24 hours the patient's fever subsided and he was discharged after 5 days in the hospital on ciprofloxacin and fluconazole. Three days later, the patient again had a fever, sore throat, cough, and diarrhea. In addition, a 2-cm tender area was noted by the medical oncologist at the an- gle of the right mandible. The patient was readmitted and started on the same antibiotic regimen as before. A dental oncology consultation was then requested. The oral/dental evaluation revealed no oral cause for the "swollen jaw." Cultures ultimately grew out Pseudomonas fluroescenes,

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and the right jaw swelling resolved with appropriate anti- biotic therapy.

One month later (day 11 of chemotherapy course 2) the patient was admitted with fever, headache, and diarrhea. Examination of the oral mucosa by the medical team revealed leukoedema and erythema. The patient was started on a neutropenic antibiotic protocol. Despite antibiotic therapy, the patient's stomatitis continued with a painful area on the left maxillary palatal mucosa. He was dis- charged afebrile 4 days later with the appropriate outpa- tient antibiotics.

Four days later the patient was again readmitted with increasing discomfort, severe enough to prevent eating, and swelling in the left maxillary area. A second dental oncol- ogy consultation showed swelling and a violaceous discolor- ation of the left hard palate. The lesion extended across the gingival crest to the labial and buccal gingival tissue and the labial vestibule (Fig. 3). The patient had no feeling in the left cheek area. Primaxin and fluconazole were added to the previous antibiotic regimen.

A magnetic resonance image (MRI) demonstrated ex- tensive maxillary sinusitis. Punch biopsies of the hard pal- ate and left gingival/buccal mucosa demonstrated extensive necrosis and organisms morphologically consistent with Aspergillus species. ABCD therapy was initiated along with the recommendation for surgical debridement.

In addition to the MRI, a paranasal sinus CT scan showed extensive sinusitis involving the left maxillary antrum, left ethmoid air cells, and left sphenoid sinus (Fig. 4). Involvement of the right maxillary antrum could not be ruled out. Bony sclerosis of the lateral aspect of the left maxillary antrum was noted.

Over the next several days the infection showed clinical signs of improvement: demarcation of the involved area, in- growth of new epithelial tissue, and decrease in size of the eschar. On hospital day 23, the patient was discharged on an outpatient regimen of ABCD along with several other outpatient medications. Once the patient became medically stable, an infrastructural maxillectomy and buccal soft tis- sue resection was performed. Once healing was adequate, the patient was discharged with several outpatient medica- tions, among which was ABCD, as well as instructions on cleaning the maxillary defect. 15

DISCUSSION In the early stages of leukemia or its treatment, in-

fections are often bacterial in nature originating in such sites as skin, upper aerodigestive tract, perianal, and perineal regions. Fungal infections are particu- larly common in patients who have undergone multi- ple courses of chemotherapy with prolonged periods of neutropenia and antibiotic therapy. Although much less common than candidiasis, aspergillosis can be a major cause of infection-related morbidity in leukemia and bone marrow transplant patients. 16, 17 Prolonged granulocytopenia as well as acute and chronic graft-versus-host disease and its t reatment has been associated with such infection.1 As demon-

Fig. 3. Case 2, extensive violaceous discoloration that had developed centrally on the hard palate was replaced with tan necrotic tissue. Patient underwent left infrastructural max- illectomy and buccal resection.

strated here, the clinical and dental picture of head and neck infection in transplant patients can be com- plicated by nonspecific and varied signs and symp- toms. For example, sinusitis and epistaxis are very frequent problems immediately after transplantation or in patients with treatment-related sequelae. Mu- cositis as a result of transplant conditioning and viral infections can also interfere with the early recognition of oral involvement.

Aspergillus infection of the nose and paranasal si- nuses can take one of several forms. The fulminant and invasive forms are the most severe and aggressive types and cause gross morbid soft tissue and bony de- struction and death. Successful t reatment of as- pergillosis, especially in the compromised patient, re- quires prompt diagnosis and rapid institution of ther- apy. is One should consider the t reatment of choice in this patient population to be surgical excision with antifungal therapy using amphotericin B. Delay or nonaggressive therapy can result in the spread of in- fection with lethal consequences. Antifungal therapy or surgery alone can produce suboptimal results, whereas both can be a valuable adjunctive therapy for survival and limiting the destructive infectious pro- cess.

Amphotericin B is a lipophilic drug that is insolu- ble in an aqueous solution but is administered as a colloidal intravenous suspension with sodium deoxy- cholate as a dispersing agent. 19 The mechanism of action of amphotericin B is through its strong binding to sterols in lipid membranes of the microorganism. The drug-sterol complex produces pores in mem- branes through which ions efflux. 2~ Amphotericin B has a higher affinity coefficient for ergosterol-- the main sterol in fungal membranes - - than cholesterol--

562 Chambers et al. ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY May 1995

Fig. 4. Paranasal sinus CT scan shows extensive sinusitis that involves left maxillary, ethmoid, and sphe- noid sinuses.

the main sterol in mammalian cells. This provides some selectivity of the drug for fungal cells. However, there is some binding of amphotericin B to mamma- lian cells that can result in cellular toxicity. 19 Acute effects of this toxicity include fever, chills, vomiting, cardiotoxicity, and hypotension; whereas long-term adverse effects include hypokalemia, hypomag- nesemia, renal toxicity, and anemia. The relatively rapid and reliable appearance of these adverse drug effects results in a narrow therapeutic index, which continues to be a very significant dose-limiting fac- tor. 21

Because of the marked toxicity with conventional amphotericin B, extensive laboratory and clinical in- vestigation has led to reformulation of this efficacious antifungal agent. The highly lipophilic nature of am- photericin B makes it an ideal candidate for incorpo- ration into lipid membranes for liposomal delivery. This formulation accomplishes two goals: first, it dra- matically reduces the drug's toxicity by 10- to 20-fold; and second, it targets delivery of the drug to tissues rich in reticuloendothelial cells where the organism can reside, such as the lung, spleen, liver, and bone marrow.19, 21 Toxicity reduction and targeted delivery result in a significantly improved therapeutic index for liposomal amphotericin B. 19

The two cases of Aspergillis infection presented here that occurred during immunocompromised states were not corrected by prophylactic antifungal thera- py.l, 16 Given the difficulties in diagnosing invasive aspergillosis and the apparent frequency of severe or fatal disease in the compromised host, aggressive di- agnosis and management was prudent. The appear- ance of this infection may vary, and definitive diag- nostic procedures, such as a biopsy, should be per- formed unless contraindicated by the patient's medical status.

Although most patients initially have nasal lesions, the patient in case 2 first had an oral lesion. Of inter- est is how aspergillosis was diagnosed in this case. Several attempts to definitively identify this organism as Aspergillus species with cultures were unsuccess- ful. This case represents 10% of the false-negative culture results associated with aggressive aspergillo- sis. 12 The diagnosis was finally made by combining the results of tissue histopathologic testing with the radiographic sclerotic bony changes. The presence of sclerosis reflects the relative chronicity of this infec- tion and makes a diagnosis of a rapidly progressive infection like mucormyc0sis less likely. 5

Aspergillosis can involve nearly all major head and neck structures; thus, all suspected Aspergillus infec-

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tions should be vigorously identified and treated. 1 Si- nus disease often tends to be invasive and involve bone. This was true of both of our cases, as the infec- tions led to oroantral openings in the palate, necessi- tating rehabilitation with prosthetics.22, 23 Aspergillus invades the walls of both large and small blood ves- sels, producing thrombosis and hemorrhagic necrosis, which may lead in turn to fatal bleeding.

Early aggressive systemic antifungal chemother- apy with amphotericin B, combined with surgical re- section of the involved tissue is recommended; how- ever, surgery can be complicated by the patient's general status. Topical therapy, such as rinses and ir- rigation, along with systemic and aggressive support- ive therapy is beneficial in the treatment of oral and nasal fungal infections. 18-21

CONCLUSIONS Aspergillosis in immunocompromised patients can

appear differently and can be easily confused clini- cally with other types of infections. Clinicians must be able to recognize these infections early and aggres- sively manage and treat these patients. Such treat- ment would involve appropriate cultures, biopsy, and surgery along with systemic antifungal therapy. An- tifungal therapy consists of effective, though less toxic, amphotericin B colloidal dispersion in lipo- somal form.

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Reprint requests: Dr. Mark S. Chambers Department of Dental Oncology 09 University of Texas M. D. Anderson Cancer Center 1515 Holcombe Boulevard Houston, TX 77030