Cyclic neutropenia

GORDON S. WALBROEHL, M.D., and P. GEORGE JOHN, M.D. Wright State University School of Medicine, Dayton, Ohio

Neutropenia is an uncommon but potentially serious complication of drug therapy. Many drugs, especially antibiotics, can produce this untoward effect. Typically, drug-induced neutropenia occurs in a patient receiving a semisynthetic penicillin for two weeks or more. The cause is believed to be either a hypersensitivity reaction or a toxic dose-related suppression of white blood cell precursors. Most patients improve after discontinuation of the drug.

Antibiotic-associated neutropenia is an uncommon but potentially serious complication. It is likely to occur in a patient undergoing prolonged treatment for a serious infection, often a staphylococcal infection. The reported incidence of antibiotic-associated neutropenia ranges from 0.13 percent to 8 percent. [1] The onset can be fairly sudden, and the patient may appear to be doing well clinically. Periodic monitoring of the complete blood count in patients at high risk of drug-induced neutropenia can help physicians prevent this complication.

Illustrative Case

A 12-year-old boy was admitted to the hospital with a one-day history of pain and swelling of the right knee. His temperature was 39.4*C (103*F) orally. Physical examination revealed a red, tender right knee with palpable effusion and enlarged inguinal nodes. The remainder of the physical examination was normal.

The peripheral white blood cell count on admission was 12,100 per [mm.sup.3] (12.1 X [10.sup.9] per L), with 8 percent (0.08) band neutrophils, 75 percent (0.75) segmented neutrophils, 15 percent (0.15) lymphocytes and 3 percent (0.03) monocytes. Cultures of fluid from the knee revealed both group A streptococcus and Staphylococcus aureus.

Treatment was initiated with nafcillin, 750 mg intravenously every four hours. The patient steadily improved with this regimen. After one week of antibiotic therapy, culture of the joint fluid showed no bacteria. White blood cell counts during the next 12 days remained in the normal range (4,600 to 6,100 per [mm.sup.3] [4.6 to 6.1 X [10.sup.9] per L]).

On the 20th day of hospitalization, the patient's white blood cell count was markedly depressed to 2,700 per [mm.sup.3] (2.7 x [10.sup.9] per L), with 29 percent (0.29) polymorphonuclear cells, 4 percent (0.04) band neutrophils, 16 percent (0.16) eosinophils, 1 percent (0.01) basophils, 40 percent (0.40) lymphocytes and 10 percent (0.10) monocytes. This suppression was thought to be the result of prolonged nafcillin therapy.

Nafcillin was discontinued, and the patient was given clindamycin, 300 mg intravenously every four hours. Daily blood cell counts over the next four days demonstrated a rise in the white blood cell count to 3,700 per [mm.sup.3] (3.7 x [10.sup.9] per L), with 23 percent (0.23) polymorphonuclear cells, 1 percent (0.01) band neutrophils, 17 percent (0.17) eosinophils, 2 percent (0.2) basophils, 42 percent (0.42) lymphocytes, 12 percent (0.12) monocytes and 5 percent (0.05) atypical lymphocytes. Clindamycin was continued for a total of nine days. At the time of discharge (the 29th hospital day), the patient was clinically well, with a white blood cell count of 3,600 per [mm.sup.3] (3.6 x [10.sup.9] per L) and an absolute granulocyte count of 1,200 per [mm.sup.3] (1.2 x [10.sup.9] per L).

The patient was followed on an outpatient basis with periodic complete blood cell counts. At three weeks after discharge, the white blood cell count was at its lowest point: 2,800 per [mm.sup.3] (2.8 x [10.sup.9] per L), with 13 percent (0.13) segmented neutrophils and 2 percent (0.02) band neutrophils. Bone marrow aspiration showed a myeloid shift and mild lymphocytosis. A peripheral count at three months after discharge showed a white blood cell value of 3,500 per [mm.sup.3] (3.5 x [10.sup.9] per L), with 23 percent (0.23) segmented neutrophils and 9 percent (0.09) band neutrophils. At four months after discharge, the white blood cell count was 5,600 per [mm.sup.3] (5.6 X [10.sup.9] per L), with 40 percent (0.40) segmented neutrophils and 5 percent (0.05) band neutrophils. The patient was subsequently lost to follow-up.

In summary, this patient developed neutropenia after a two-week course of a beta-lactam antibiotic. With discontinuation of the offending agent, the neutrophil count gradually returned to normal. Bone marrow aspiration showed no major pathologic changes.

Etiology

The peripheral neutrophil count represents about 5 percent of the total body concentration; the majority of neutrophils reside in the bone marrow. [2] Neutrophils circulate freely for about six to 12 hours, then move into the extravascular space, where they survive for two to five days. [3]

Neutropenia in adults is defined as an absolute neutrophil count below 1,800 per [mm.sup.3] (1.8 x [10.sup.9] per L). [4] With absolute neutrophil counts below 1,000 per [mm.sup.3] (1.0 X [10.sup.9] per L), susceptibility to infection is increased. The risk of infection is significantly increased when the neutrophil count falls to 500 per [mm.sup.3] (0.5 x [10.sup.9] per L) or lower. [2] Several etiologies have been proposed, including cyclic neutropenia, chronic benign neutropenia, "pseudoneutropenia" and drug-induced neutropenia. [3]

Cyclic neutropenia is a recurring disorder in which neutrophil counts may fall below 1,000 per [mm.sup.3] (1.0 X [10.sup.9] per L) with or without symptoms. The condition may have a genetic basis in some patients. Cyclic neutropenia is probably caused by a regulatory defect in stem cells. The disorder is seldom life-threatening. [5]

Chronic benign neutropenia, which occurs primarily in blacks and Yemenite Jews, is usually detected in infancy. The prognosis is good, despite the presence of an apparent defect in neutrophil production and release from the bone marrow. Other childhood neutropenias associated with congenital defects (e.g., Fanconi's syndrome, dyskeratosis congenita) usually result in death or a lifelong increased risk of infection.

Pseudoneutropenia is the result of redistribution of neutrophils from the circulating pool to the marginal pool. The condition may occur in starvation states. There is no serious risk of infection, and treatment of the apparent neutropenia is not necessary.6

Drug-induced neutropenia is the most common type of neutropenia. It may be caused by drugs frequently associated with neutropenia, such as cancer agents, or drugs that affect only certain individuals, such as antibiotics. The mechanism is not well understood. Some authors have demonstrated the presence of complementfixing antibodies that react with the patient's granulocytes in the presence of the drug. [7] Other researchers have demonstrated dose-dependent inhibition of granulopoiesis in vitro .8 Still others postulate that certain drugs have a direct toxic effect on neutrophil precursors. [1,9] To date, no theory predominates. Some authors believe that a combination of toxic and immune factors are involved. [7] Perhaps the best explanation may be the existence of two separate processes--one immunebased, the other dose-related. [1]

Clinical Presentation

The patient in the illustrative case represents a fairly typical presentation of antibiotic-induced neutropenia. Semisynthetic penicillins seem to be the most frequent offenders reported in the literature, followed by cephalosporins ( Table 1 ). Other antibiotics, such as vancomycin (Vancocin) and sulfonamides (either alone or in combination with trimethoprim), are less frequently involved. 3 The length of time an antibiotic is administered before neutropenia develops can vary from as short as two days [1] to as long as 36 days. [10] The mean duration reported in other series ranges from 10 to 27 days. [8]

Most cases of antibiotic-induced neutropenia involve parenteral administration of the offending drug. However, neutropenia following both initial and secondary use of oral antibiotics has been reported. [11] Not all patients who have an episode of drug-related neutropenia experience a recurrence on subsequent exposure to related compounds. [12]

Drug-induced neutropenia has been reported to last from two to seven days. Retrospective studies have not shown a direct correlation between length of treatment or amount of drug given and duration of neutropenia or severity of white cell count depression? However, a prospective study of treatment with benzylpenicillin (Pre-Pen/MDM) showed that patients with lower pretreatment neutrophil counts were more likely to develop clinically significant neutropenia. [13] The investigators postulated that 12 g per day of a beta-lactam antibiotic for more than two weeks represents a threshold for the development of neutropenia.

Diagnosis

The diagnosis of drug-induced neutropenia is based primarily on the laboratory findings and on a high index of suspicion. Signs may include fever (68 percent of patients), rash (41 percent of patients) and eosinophilia (32 percent of patients). [8] Periodic monitoring of the complete blood cell count is probably the best and most economical way to follow a patient who is at high risk of drug-induced neutropenia (i.e., a patient receiving prolonged therapy with a parenteral antibiotic).

Bone marrow evaluation may become necessary if the patient does not respond to discontinuation of the offending agent. If a patient with suspected antibiotic-caused neutropenia fails to improve after drug discontinuation, the physician should consider a different etiology, such as hematologic malignancy or another blood dyscrasia.

The presence of hypocellular marrow suggests the existence of a production defect. Normal or increased cellularity suggests the presence of distribution or cellular survival problems. Production defects suggest the need to look for causes such as leukemia, infection (e.g., tuberculosis, human immunodeficiency virus infection) or vitamin deficiency. Hypercellular marrow suggests the possibility of autoimmune disease or pseudoneutropenia, among others.

Treatment

An absolute neutrophil count of less than 1,000 per [mm.sup.3] (1.0 x [10.sup.9] per L) is an indication to change to a different antibiotic. [14] This leads to resolution in most cases. A review of the literature revealed no fatalities in patients with an intact immune system who were being treated for soft tissue or musculoskeletal infections. Patients with immunodeficiency states may not fare as well. In addition, zidovudine (Retrovir) can cause neutropenia. When combined with vancomycin, zidovudine led to a marked decrease in absolute neutrophil counts in one series of patients; however, the neutropenia resolved in all patients after discontinuation of vancomycin or zidovudine. [15]

The patients most at risk of drug-induced neutropenia are those with absolute neutrophil counts below 500 per [mm.sup.3] (0.5 X [10.sup.9] per L). Most frequently, these are cancer patients. Broad-spectrum antibiotic therapy is usually started if the patient is febrile. Suggested antibiotics include third-generation cephalosporins or carbapenems. Patients who are already receiving antibiotics pose a more difficult problem. In such cases, the best course is probably to perform another culture and start treatment with a different antibiotic. If the patient becomes afebrile and the neutrophil count rises above 500 per [mm.sup.3] (0.5 X [10.sup.9] per L) on two consecutive days, the antibiotic can be stopped. If not, the antibiotic should be continued, and the addition of an antifungal agent should be considered. [16]

Various agents have been tried in an attempt to stimulate the bone marrow. Steroids and lithium are two examples; however, both have numerous side effects, and the response is unpredictable.3 Granulocyte-macrophage colony-stimulating factor can stimulate neutrophil production. Early trials of recombinant isolates of filgrastin (Neupogen), a granulocyte colony-stimulating factor, in patients undergoing chemotherapy and in patients with acquired immunodeficiency syndrome have shown some promise, but further study is necessary. [17]

Granulocyte transfusions have also been used in cancer patients with neutropenia who have not responded to more conservative measures. However, the high cost of' these transfusions ($14,000 to $50,000 per year) limits their use of such treatment to patients with overwhelming sepsis who have not responded to other measures.

The authors thank S. Bruce Binder, M.D., for reviewing this manuscript.

REFERENCES

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11. Kancir LM, Tuazon CU, Cardella TA, Sheagren JN. Adverse reactions to methicillin and nafcillin during treatment of serious Staphylococcus aureus infections. Arch Intern Med 1978;138:909-11.

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15. Kitchen LW, Clark RA, Hanna BJ, Pollock B, Valainis GT. Vancomycin and neutropenia in AZT-treated AIDS patients with staphylococcal infections [Letter]. J Acquir Immune Defic Syndr 1990;3:925-6.

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17. Weisbart RH, Gasson JC, Golde DW. Colony-stimulating factors and host defense. Ann Intern Med 1989;110:297-303.

18. Menitove JE, Abrams RA. Granulocyte transfusions in neutropenic patients. Crit Rev Oncol Hematol 1987; 7:89-113.

The Authors

GORDON S. WALBROEHL, M.D. is associate professor and director of the thirdyear clerkship at Wright State University School of Medicine, Dayton, Ohio. A graduate of the University of Medicine and Dentistry of New Jersey, New Jersey College of Medicine, Newark, Dr. Walbroehl completed an internship at the Medical Center of Delaware, Wilmington, and a family practice residency at Malcolm Grow U.S. Air Force Medical Center, Andrews Air Force Base, Md.

P. GEORGE JOHN, M.D. is associate professor in family practice and assistant professor in pediatrics at Wright State University School of Medicine. He graduated from the University of Kerala Medical School in India and trained in pediatrics and medicine at Mercy Hospital and Medical Center in Chicago.

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