oral surgery oral medicine oral pathology WirhKC~~O~S

on

endodontics anddental radiology

Volume

46, Number

6, December,

1978

oral surgery Editor: ROBERT B. SHIRA, D.D.S. School of Dental Medicine, Tufts University 1 Kneeland St. Boston, Massachusetts 02 I I I

Agranulocytosis associatedwith an infected mandibular fracture Owen Ross Beirne, D.M.D., Los Angeles, Calif.

Ph.D., and Donald L. Leake, D.M.D.,

DEPARTMENTS

AND

THE

UCLA

OF DENTISTRY SCHOOLS

OF DENTISTRY

SURGERY, AND

HARBOR

GENERAL

M.D.,

HOSPITAL

AND

MEDICINE

This report describes a case of agranulocytosis associated with an infected mandibular fracture. Because agranulocytosis is most frequently associated with drug sensitivity, drug therapy is usually stopped or changed when the disease is discovered. This case demonstrates the need to evaluate the causes of agranulocytosis before stopping or changing a patient’s medications.

A granulocytosis

is an acute disease in which there is a severe depression in the white blood cell count. In a fulminant case of agranulocytosis, oral, vaginal, and anal ulcers may be present. The oral cavity is the most frequent site of these lesions, which appear as necrotic ulcerations of the oral mucosa, tonsils, and pharynx. Less extreme agranulocytosis may appear slowly and be recognized during the investigation of frequent minor infections. The disease is rare, but it is the gravity of the condition, not its frequency, that accounts for its importance. Because of the dangerous sequelae of agranulocytosis, the clinician must be aware of the disorder. While drug sensitivity is the most common cause 0030.4220/78/120737+05$00.50/0

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Oral Surg. December. I978

of agranulocytosis, in some instances no causative agent can be identified. Since factors other than drug reactions are sometimes responsible, it is important to investigate carefully the probable origin of this condition before arbitrarily stopping necessary drug therapy. The case report that follows concerns a patient with agranulocytosis associated with an infected mandibular fracture. The agranulocytosis may have been the cause or the result of the infection. This case demonstrates the need to evaluate the potential causes of agranulocytosis in patients taking medications who develop concurrent infection. A careful search of the literature failed to disclose any similar cases. CASE REPORT

A 2 1-year-old Mexican-American man received multiple blows to the face during an assault. He lost consciousness for an unknown period of time, with resultant retrograde amnesia. Immediately following the assault, he was examined in the emergency room of another hospital, where he was told that he had mandibular fractures. He was referred to an oral surgeon for treatment but returned home after refusing care. While at home he developed generalized facial pain and was admitted to Harbor General Hospital approximately 12 hours after the assault. Radiographic examination confirmed bilateral fractures of the mandible, at the left angle and the right parasymphysis, and a basilar skull fracture. The medical history and a review of systems were unremarkable except for a questionable history of a seizure several months previously, for which he received no medical treatment. The neurologic examination and laboratory findings were normal except for a white blood cell count of 11,500 cells per milliliter. During the patient’s hospital stay, the neurologic findings remained normal except for a slight decrease in mental alertness. On the evening of the third hospital day, the patient had a grand ma1 seizure. Deep tendon reflexes showed hyperreflexia of the lower extremities with a positive Babinski sign. Diphenylhydantoin (Dilantin) was given immediately. A computer-assisted tomographic (CAT) emergency scan revealed bilateral frontal intracerebral hematomas with edema. Following the CAT scan, a cerebrovascular angiogram demonstrated bilateral frontal masses with a mild left-to-right shift without subdural or epidural hematomas. Conservative treatment with dexamethasone and diphenylhydantoin was instituted, and the patient’s mental status slowly improved. Because of the patient’s neurologic condition, general anesthesia had to be deferred and the mandibular fractures were reduced with intermaxillary fixation under local anesthesia on the seventh hospital day. An open reduction with removal of the third molar was considered the most appropriate treatment, but it was precluded by the patient’s neurologic status. Adequate reduction was achieved, with the impacted mandibular left third molar remaining in the line of fracture. The patient also received a IO-day course of intravenous penicillin (I ,OOO,OOO units every 6 hours). Fourteen days following the initial CAT scan, a repeat scan showed that the hematomas were resolving. The patient was discharged after 21 days, taking diphenylhydantoin, 300 mg. every day, and vitamins. On discharge, the laboratory findings were normal (hematocrit, 37.4 percent; white blood cell count, 8,100 cells per milliliter). The patient failed to keep his follow-up appointments until 2 weeks after discharge from the hospital, when he returned to the oral surgery clinic. Three days before, he had developed a painful left submandibular swelling. Examination revealed a febrile patient (101.6” F. orally) with 2,200 white blood cells per milliliter, a hematoct-it value of 39.0 percent, and a purulent exudate draining intraorally from the mandibular left third molar. The patient was admitted to the hospital, intravenous penicillin (2,000,OOO units every 6 hours) was begun, and the mandibular left third molar was extracted. Duplicate blood cultures taken from each arm before initiation of antibiotic treatment were negative for bacteria. Cultures of the purulent exudate revealed a mixed infection, including anaerobic gram-positive cocci, gram-negative coccobacilli, aerobic Klebsiella, a-group D streptococci, Alculigenes dentifricium, and staphylococci.

A repeat whitebloodcellcount was 2,400 cells permilliliter. Twelve hours after admission, the whitebloodcellcountwas3,700cellspermilliliter, with2 percent eosinophils, 5 percent bands, 9 percent neutrophils, Sl percent lymphocytes, and33 percent monocytes. Thepatient hadanabsolute neutrophilic agranulocytosis and normal levels of the other types of white blood cells. The white blood cell count continued to increase, and 8 days after admission it was 6,900 cells per milliliter (2 percent basophils, 1 percent eosinophils, 7 percent bands, 61 percent neutrophils, 26 percent lymphocytes, and 3 percent monocytes). The patient was afebrile on the second hospital day. The swelling resolved, and on the eighth hospital day he was discharged on oral penicillin and diphenylhydantoin. On follow-up visits, there was no evidence of submandibular infection. Two weeks after discharge, the patient developed pericoronitis around the mandibular right third molar, which was extracted and healed normally. The fracture sites healed without malunion or osteomyelitis. DISCUSSION Neutrophilic granulocytes function to protect the host against bacterial infections.’ Bacterial infections occur more frequently in patients with agranulocytosis than in normal patients. l* 2 The chance of becoming infected is dependent on the severity and duration of the agranulocytosis.‘, z Cell counts of less than 500 cells per milliliter may be associated with overwhelming infections. Cell counts of greater than 500 cells per milliliter indicate a mild or moderate risk of infection. If the depressed cell count is of several weeks’ duration, there is a greater chance of infection than in agranulocytosis that lasts only a few days. The total blood granulocyte pool is divided into the circulating and marginal pools which normally are equal in size.3 The circulating pool is measured by the peripheral blood cell count. The marginal pool is the group of cells adhering to the vessel walls. Because the peripheral blood cell count measures only the circulating pool, agranulocytosis can develop in two ways. 3 A decreased peripheral blood cell count can be caused by a decrease in the total blood granulocyte pool (absolute agranulocytosis) or a shift of cells from the circulating pool to the marginal pool without a decrease in the total blood pool (pseudoagranulocytosis) Absolute agranulocytosis is created by a decreased production or an increased loss of granulocytes. Decreased production is usually due to bone marrow hypoplasia.3 Drugs, chemicals, ionizing radiation, infection, vitamin deficiency, and tumor replacement of the marrow space cause a decreased production of bone-marrow-derived cells. ‘* ‘, 4 Increased loss has been divided into immunologic and nonimmunologic etiologic groups.13 4 Agranulocytosis in patients with systemic lupus erythematosus, infectious mononucleosis, or drug reactions is probably caused by an allergic reaction.4 Nonimmunologic causes of agranulocytosis have been implicated in severe systemic infections and enlarged spleen syndrome. 4 Patients with agranulocytosis do not always manifest the usual symptoms associated with an infection.’ These patients are usually febrile but are unable to elicit a purulent inflammatory response, making it difficult to determine the source of infection. Antibiotic treatment is usually initiated on the basis of a presumptive diagnosis until the site of infection can be discovered and a culture taken. The differential distribution of the patient’s white blood cell count 12 hours after admission is consistent with the lymphocytosis and monocytosis seen in mononucleosis or leukemia. A differential cell distribution, however, indicates the relative number of cell

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Fig. 1. Absolute values of various white blood cell types during the patient’s second hospitalization. Leukocytic granulocytopenia slowly improved while levels of all other cell types remained normal. Absolute cell numbers were calculated using the total white blood cell counts and differential distributions.

increase in a particular cell type or a decrease in other cell types. Calculation of the absolute cell numbers for this patient shows a neutrophilic granulocytopenia with normal levels for the other cells. Fig. 1 demonstrates the steady increase in neutrophilic granulocytes during the patient’s hospitalization, with little change in the other cells. This abnormal differential distribution emphasizes the importance of evaluating the absolute cell number as well as the relative distribution of cells. The agranulocytosis seen in this patient could be due to a variety of factors. Ten cases of agranulocytosis caused by diphenylhydantoin taken in the dosage given this patient have been reported. 5-7 The actual mechanism for this response is unknown, but when diphenylhydantoin is discontinued the agranulocytosis resolves. This patient’s agranulocytosis resolved even though he continued to take 300 mg. of diphenylhydantoin a day. Some reports have implied that an overdose of diphenylhydantoin might cause agranulocytosis.5 While this patient could have taken an overdose of the drug as an outpatient, he lacked the gastrointestinal symptoms usually associated with a diphenylhydantoin overdose. In addition to diphenylhydantoin, the patient had a 9-day course of dexamethasone during his first hospitalization. Steroids decrease the effectiveness of granulocytes and are usually associated with granulocytosis rather than agranulocytosis.* The patient had received no steroids for 3 weeks before his second hospitalization, and it is therefore unlikely that the steroids influenced his susceptibility to infection. Because the agranulocytosis resolved while the patient continued to take medications, it was probably not drug induced. It is important to consider whether the agranulocytosis or the infection came first. Several diseases, including tuberculosis and viral infections, may cause agranulocytosis.4 There is no evidence of any underlying systemic disease in this patient’s episode of agranulocytosis. However, the patient did have an infected

Volume 46 Number 6 mandibular fracture.Because earlystages of infectionin manhavebeendifficultto study, animal models have beenusedto show the initial responseof granulocytesto infection. In one study,g the bone marrow of a dog was unable to keep pace with the egress of granulocytes and the animal becameagranulocytotic. This resolved in 24 hours without treatment as the dog’s clinical symptoms improved. Our patient showed a similar response;the initial agranulocytosis resolved as his clinical symptoms improved. The fact that the agranulocytosis resolved without discontinuation of the patient’s medications indicates that the mandibular infection may have initially overwhelmed the bone marrow. The purulent infection offers further evidence that the infection came first, because patients who develop an infection after agranulocytosis are usually unable to manifest a purulent response.If the patient’s neurologic condition had not precluded an open reduction with removal of the third molar, this infection might not have occurred. Becausethe patient continued diphenylhydantoin therapy for his seizure disorder, the agranulocytosis was probably not drug related. While the exact cause of the agranulocytosis is unknown, it was probably due to egress of granulocytes into the site of infection at a greater rate than the bone marrow could produce cells. SUMMARY

When agranulocytosis is associatedwith an infection, it is essential to correct the granulocyte abnormality to effect the rapid recovery of the patient. Because agranulocytosis is often related to a drug reaction, medications are often arbitrarily stoppedin an attempt to reverse the condition. This case report demonstratesthe importance of considering the infection itself as a causeof agranulocytosisand indicates that necessary medical treatment need not be discontinued in the presenceof agranulocytosis. REFERENCES I. Trowbridge, A. A.: Neutropenia, Postgrad. Med. 61: 208-213, 1977. 2. Levine, A. S., Graw, R. G., and Young, R. C.: Management of Infections in Patients With Leukemia and Lymphoma: Current Concepts and Experimental Approaches, Semin. Hematol. 9: 141-179, 1972. 3. Boggs, D. R.: The Kinetics of Neutrophilic Leukocytes in Health and in Disease, Semin. Hematol. 4: 359-386, 1967. 4. Wintrobe, M. M., Lee, G. R., Daggs, D. R., Bithell, T. C., Athens, J. W., and Foerster, J.: Clinical Hematology, ed. 7, Philadelphia, 1974, Lea & Febiger, pp. 1268-1282. 5. Sparberg, M.: Diagnostically Confusing Complications of Diphenylhydantoin Therapy, Ann. Intern. Med. 59: 914-930, 1963. 6. Isan, M., Mehlman, D. J., Green, R. S., and Bell, W. R.: Dilantin, Agranulocytosis, and Phagocytic Marrow Histocytes, Ann. Intern. Med. 84: 710-711, 1976. I. Slavin, R. G., and Broun, Jr., G. 0.: Agranulocytosis After Diphenylhydantoin and Chlorothiazide Therapy, Arch. Intern. Med. 108~ 940944, 1961. 8. Athens, J. W., Haab, 0. P., Raab, S. O., Mauer, A. M., Ashenbrucker, H., Cartwright, G. E., and Wintrobe, M. M.: Leukokinetic Studies. IV. The Total Blood, Circulating and Marginal Granulocyte Pools and the Granulocyte Turnover Rate in Normal Subjects, J. Clin. Invest. 40: 989-995, 1961. 9. Marsh, J. C., Boggs, D. R., Cartwright, G. E., and Wintrobe, M. M.: Neutrophil Kinetics in Acute Infection, J. Clin. Invest. 46: 1943-1953, 1967. Reprint requests to: Dr. 0. Ross Beime Division of Oral Surgery Harbor General Hospital 1000 W. Carson St. Torrance, Calif. 90509

Agranulocytosis associated with an infected mandibular fracture.

oral surgery oral medicine oral pathology WirhKC~~O~S on endodontics anddental radiology Volume 46, Number 6, December, 1978 oral surgery Edito...
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