Mucormycosis

Mucormycosis Discussion and report of a case involving Andrew

Breiman,*

ALBERT

EINSTEIN

the maxillary sinus

Donald Sadowsky, ** and Joel Friedman,* ** Bronx, N. Y. COLLEGE

OF MEDICINE

Mucormycosis is a human fungal infection which occurs in two main forms: superficial and visceral. The visceral variety has been associated with a poor prognosis and usually presents with. etther pulmonary, gastrointestinal, or head and neck involvement. Mucprmycosis is frequently found in patients with uncontroiled or poorly’controlled diabetes. .This article reports a case of this potentially lethal disease in which satisfactory treatment and cure entailed both definitivesurgical intervention and a therapeutic regimen of amphotericin B.

S

ymptoms of chronic or acute sinusitis secondary to’the surgical removal of maxillary posterior teeth are frequently presented for evaluation either to rule out odontogenic etiology or to treat a possible oroantral communication.~ Although a relatively rare entity,. mucorrnycosis should be considered in the differential diagnosis of dentofacial pathosis involving the maxillary ‘sinus. Mucdrmycosis is a fungal disease in which normal saprophytic molds produce an acute and often rapidly fatal infection. Mucor itself is only one genus of the three organisms potentially responsible for the disease in man, the other two being Rhizopus and Abisidia.’ A histopathologic distinction among the’three organisms is of little or no clinical significance, since the pathology, pathogenesis, and symptoms attributable to all -fungi in the class Mucoracase are identical2 Mucormycosis of the head and neck (including the rhinocerebral variety) is often accompanied by a triad of symptoms: ,uncontrolled diabetes mellitus, periorbital infection, and meningoencephalitis. Although the disease is often, associated with poorly controlled diabetes mellitus (more than 70 percent of all cases), there are instances of mucormycosis occurring in patients with only. mild underlying diabetes who &ow neither hyperglycemia nor ketosia3 In addition to diabetes, other possible factors predisposing to this type of systemic fungal mfection include malignant lymphomas, leukemia, chemotherapy (especially. in -patients on *Clinical Instructor. **Director, Division ***Associate Clinical 0030-42200

11100375

of Dentistry. Professor. + 04$00.40/O

0

1981 The C. V. Mosby

Co.

antimetabolites) and chronic renal failure.’ An inference can be drawn that as a debilitating disease state decreases systemic resistance, the likelihood of mucormycotic infection is increased. Unfortunately, the specific mechanism by which the aforementioned factors decrease immune defenses and stimulate the usually nonpathogenic; ‘saprophytic fungi to become highly invasive is not known at present. The route of inoculation and transmission of the disease in the head and neck variety is probably via inhalation in the nasal cavity and subsequent extension into the paranasal sinuses, orbit, and cmnial cavity via vascular channels5 The direct invasion of vascular channels by hyphae is the mode by which the disease progresses. Thrombosis and hemorrhagic &hernia result in a marked polymorphonuclear inflammatory response in the involved tissues. A dark, bloody nasal discharge commonly occurs, with associated necrosis of the turbinates. ‘Other frequently occurring symptoms can include ptosis and proptosis, ophthalmoplegia, loss of vision, trigeminal anesthesia, and facial palsy.6 Mucormycosis involving the maxillary sinus may resemble a tumor or mass in the antrum on radiographic examination.’ Biopsy and microscopic evaluation of tissue are the most definitive diagnostic tools for mucormycosis of the maxillary sinus. Bacteriologic evidence is of some value in making the diagnosis. However, negative culture results often appear despite positive histologic findings.* Treatment of mucormycosis should begin with a complete work-up- and management of associated medical problems. Concurrently, surgical dtbridement in conjunction dth an extensive regimen of 375

376 Breiman, Sadowsky,

Fig.

and Friedman

1.

antibiotic therapy should be initiated. The drug of choice in the treatment of mucormycosis is amphotericin B, which has a well-established efficacy, both experimentally and clinically. Because of the nephrotoxic effects of the drug and the existence of satisfactory serum levels of amphotericin B 48 hours after administration, an alternate-day regimen of 0.8 to 1 mg per kilogram, with a total dosage of 2 Gm. during the course of therapy, is recommended.Y A close monitoring of blood urea nitrogen (BUN) and creatinine levels on a daily basis is required with the therapy temporarily discontinued if the BUN value exceeds 50 mg./lOO ml. and the creatinine level exceeds 3.0 mg./ 100 ml.‘” This point is the arbitrary dividing line for reversal of the nephrotoxic effects of amphotericin B. Amphotericin B is not an innocuous agent. The extensive list of idiosyncratic effects of amphotericin B therapy includes anaphylactoid shock, thrombocytopenia, hepatic failure, vertigo, generalized body pain, seizures, fever, anemia, and phlebitis.” Addition of 500 to 1,000 units of heparin to the intravenous infusion of the drug may alleviate or diminish the occurrence of phlebitis. Similarly, the use of antipyretics and steroids may help to minimize untoward side effects. CASEREPORT

On Sept. 25, 1979, a S-year-old Hispanic man presented to the dental clinic at this institution complaining of severe pain in the right maxilla accompanied by headaches and occasional nosebleeds. Dental examination revealed a tenderness to palpation in the right mucobuccal fold and surrounding hard tissue of the maxilla and alveolar ridge. Periapical radiographs showed no periapical pathosis in the two remaining teeth in the quadrant (upper right first and second molars). Further

Oral Surg. October, 198 1 radiographic studies, including panoramic and Water’s views, however, showed marked cloudiness and density in the right maxillary sinus (Fig. 1) without air fluid levels. The patient’s history revealed that, 1 year prior to presentation, a premolar had been extracted and that a root tip may have been retained. The patient, however, had no postoperative problems until 1 month prior to presentation. At this time, a tentative diagnosis of a chronic sinusitis secondary to either a foreign body (root tip) in the maxillary sinus or an oroantral communication was entertained. No evidence of an existing oroantral fistula could be found upon careful intraoral examination. The patient was started on ampicillin, 500 mg. by mouth four time daily, and told to return to the clinic in 3 days. When he returned the pain was worse and a purulent right nasal discharge was noted. At this time the patient was admitted to the hospital for treatment consisting of a Caldwell-Luc procedure, antral curettage and dkbridement, nasal antrostomy, and intravenous antibiotics. Upon admission, a review of systems and physical examination were within normal limits with the exception of the nasal discharge (there was no apparent nasal septal pathosis). Admission laboratory values included hemoglobin, 16.0 Gm. percent; hematocrit, 47.7 percent; white blood count, 12,100/mm.S; sodium, 134; potassium 4.0; chloride, 98; carbon dioxide 28; blood urea nitrogen, 18 mg./lOO ml.; and blood glucose, 5.5. The electrocardiogram, chest x-ray, and vital signs were all within normal limits. The patient was being followed on an outpatient clinic basis for hypertension and diabetes and was on the following medications: methyldopa, 250 mg. orally every 6 hours; hydrochlorothiazide, 100 mg. four times a day; KCL elixir, 2 tablespoons four times a day; NPH insulin, 24 units subcutaneously at 9 A.M. daily. On Oct. 1, 1979, the patient was taken to the operating room and placed under general anesthesia. A right Caldwell-Luc procedure, an antral curettage, and a nasal antrostomy with a 1/4inch gauze drain were performed. I’he patient tolerated the procedure well. Specimens from the maxillary sinus, which were mucoid in nature with a dark brown-black coloring, were sent for histologic and microbiologic evaluation. The postoperative course was unremarkable except for an elevation of blood glucose ranging from 168 to 430 over the three postoperative days, coupled with 3+ glucose in the urine. The patient was placed on urine fractions and, as per medical consultation, the NPH insulin was increased from 24 units to 40 units subcutaneously each morning. The patient was subsequently discharged in good condition 4 days postoperatively, was told to return to the oral surgery clinic in 6 days for follow-up, and was given an appointment to the medical clinic for further follow-up of his diabetes. Two days later a surprising and unexpected pathology report was received. The specimen was signed out as “respiratory mucosa with extensive acute and chronic inflammation with mucormycosis.” The sections showed respiratory mucosa with colonies of thick-walled broad hyphae consistent with mucormycosis (Fig. 2). It is note-

Mucormyucosis

Volume 52 Number 4

377

Fig. 2.

worthy that the culturesfor fungi from the antral specimen were consistentlynegative. Following the pathology report the patient was readmitted to the hospital on Oct. 6, 1979.The Infectious DiseaseServicesuggesteda treatment plan involving a 2 Cm. courseof Fungizone. Consultation with other services related no ocular or periorbital symptoms, no involvement of the nervesor turbinates,and, mostimportant, no neurologic involvement. Baseline SMA-6 and SMA-12 were drawn to begin monitoring BUN and creatinine in anticipation of a 6 to I-week course of Fungizone. The BUN level at this time was 29 mg./lOO ml., and the creatinine level was 1.3. The Fungizone therapy was commencedon Oct. 7, 1979,with a testdoseof 1 mg. administeredintravenously in 500ml. of D5W over a period of 1hour. There wereno apparent untoward effects with this initial dose. On subsequentdays the dosagewasgradually increaseduntil a maximumdoseof 50 mg. daily wasachievedon Oct. 15, 1979.Daily monitoring of BUN, creatinine, and platelets wascontinued throughout the therapy. After 10 days of therapy, laboratory values indicated a rise in the BUN level to 51 and a risein the creatininelevel to 3.0 (from a baseline of 29 and 1.3, respectively).Consultationswith the Infectious DiseaseService and with the Nephrology Service were obtained and at this point alternate-day,

rather than daily, administrationof Fungizonewasstarted with a 50 mg. dose.Three days later the creatinine level had dropped to 2.7, but the BUN level had risen to 55. Concernwasexpressedat this time regardingthe possibility or irreversible nephrotoxicity. The recommendation wasthat 50 mg. alternate-day dosagesbe continued for 3 dayslonger, to seeif kidney function stabilized, and that adequatehydration be maintainedto minimize the renal tubular concentrationof Fungizone.As expected,kidney function did indeed stabilize and on Nov. 6, 1979,or 1 month after therapy commenced,the patient had received a doseof 1,006mg. of Fungizonewith a BUN level of 38 and a creatinine level of 2.6. At this time, following consultationwith the Infectious Diseaseand Nephrology Services,daily administrationof 50 mg. of Fungizone was reinstituted with continued monitoring of kidney function. Therapy proceededdaily until on Nov. 29, 1979, 7 weeks after the initiation of treatment,a total doseof 2 Cm. wasachievedwith a BUN level of 46 and a creatininelevel of 3.0. Fungizonetherapy was discontinued,and severaldays later a repeat Caldwell-Luc procedure was performed with biopsy and culturing of sinus contents. Both culture and histologic results were negative for mucormycosis,and after a 2-month hospitalstay, the patient wasdischargedin good condition.

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Breiman, Sadowsky,

and Friedman

The patient was followed after discharge by the Medicine, Nephrology, and Oral Surgery Departments. Nine months later, the patient showed good reversal of the nephrotoxic effects with a creatinine level of 1.7 and a BUN level of 20. The patient is now asymptomatic and apparently cured. SUMMARY

As is often the case, early diagnosis of a disease process is crucial for the success of subsequent treatment. The dentist, as a clinician, often has the opportunity to make a diagnosis or proper referral during the incipient stages of a systemic disease. It must be stressed that, while rare, mucormycosis has been observed and reported with increasing frequency. The patient presented here obviously was fortunate in the limitation of mucormycosis to the antrum and maxilla. This, combined with an early diagnosis and appropriate drug therapy, enabled him to survive an often fatal mycotic infection. REFERENCES 1. Taylor C. G., et al.: Mucormycosis Involving the Maxilla, ORAL SURG. 27~806-820, 1969.

Oral Surg. October, 1981 2. Hoeprich,P. D. (editor):InfectiousDiseases, Philadelphia,

1977,Harper& Row,p. 962.

3. Pastore, P. N.: Mucormycosis of the Maxillary Sinusand Diabetes Mellitus: Report of a Case With Recovery, South. Med. J. 60:1164-l 167, 1967. 4. Meyer, R. D., and Armstrong, D.: Phycomycosis Complicating Leukemia and Lymphoma, Ann. Intern. Med. 77:871879, 1972. 5. Berger, C. J., et al.: Rhinocerebral Mucormycosis: Diagnosis and Treatment, ORAL SURG. 40127-33, 1975. 6. Ramon, Y., et al: Extension Maxiilary Sequestration Resulting From Rhinocerebral Mucormycosis, ORAL SWIG. 35:989991, 1977.

Faillo, P. S., et al.: Mucormycosis of the Paranasal Sinuses and Maxilla, ORAL SURG. 12~304-309, 1959. Andiole, V. T.: The Use of Amphotericin B in Man, J.A.M.A. 180~269-272, 1962. Battock, D. J., et al.: Alternate Day Amphotericin B Therapy in the Treatment of Rhinocerebral Mucormycosis, Ann. Intern Med. 68~122-136, 1968. 10. Bibschandler, D. D., and Bennett, J. E.: A Pharmacologic Guide to the Clinical Use of Amphotericin B, J. Infect. Dis. 120~427, 1969. 11. Butler, W. T.: Pharmacology, Toxicity and Therapeutic Usefulness of Amphotericin B, J.A.M.A. 195:371-375, 1966. Reprint

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to:

Dr. Donald Sadowsky Director, Division of Dentistry Bronx Municipal Hospital Center Pelham Parkway South and Eastchester Road Bronx, N. Y. 10461