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CASE REPORT
Case of Agranulocytosis and Perianal Abscess Developed due to Propylthiouracil and Resistant to G-CSF Treatment Yusuf Aydın, MD,* Sedat Caner, MD,† Dilek Berker, MD,* Ihsan Ustun, MD,* Baris Yılmaz, MD,† Tuncay Delibasi, MD,* Esin Beyan Unlu, MD,† and Serdar Guler, MD*
Abstract: A 53-year-old female patient with Graves disease developed severe agranulocytosis and perirectal infection on the 50th day of propylthiouracil (PTU) therapy. After cessation of PTU, broad spectrum antibiotic regimens plus recombinant human granulocyte colony stimulating factor (G-CSF) were instituted, but C-GSF did not elevate the granulocyte count after 14 days of treatment. We added corticosteroid (CS) treatment because of the lack of response to G-CSF. The second day of CS treatment a response was seen in granulocyte count. We concluded that if there is no response to G-CSF in PTU-induced agranulocytosis in severe cases, CS treatment should be added and accepted as a part of standard therapy for this serious complication of PTU. Key Words: perianal abscess, propylthiouracil, agranulocytosis (The Endocrinologist 2009;19: 000 – 000)
P
ropylthiouracil (PTU) and methimazole are thioureylene drugs commonly used in the management of hyperthyroidism, especially that due to Graves disease. During the treatment period many side effects of these drugs can be serious. The most common of these are skin eruptions and rashes, liver dysfunction, arthralgia, and agranulocytosis.1 Many drugs other than PTU can cause agranulocytosis (eg, cimetidine, dipyrone, sulfasalazine, methyldopa, spironolactone, penicillin, indomethacin, sulfamethoxazole with trimethoprim, and gentamicin).2 Agranulocytosis is rarely seen, but it is the most common life-threatening complication of PTU.3 We report a very severe case of agranulocytosis and its treatment.
CASE F1
A 53-year-old woman was admitted to the emergency with swelling in the perianal and gluteal regions (Fig. 1). She had fever, fatigue, pain, and rash. Physical examination revealed a fever of 39°C, and increased pulse rate of 120 per minute. Complete blood count showed a white blood cell of 3000/mm3, neutrophils of 0/mm3, thrombocyte of 186,000/mm3, and a hemoglobin of 10 mg/dL. Other laboratory parameters were in the normal range. The patient was hospitalized with the diagnosis of neutropenic fever and perianal abscess. Medical history was significant for initiation of PTU medication, 900 mg/d, 50 days before for thyrotoxicosis. The laboratory findings at the time of initial diagnosis of thyrotoxicosis showed a white cell count of 7400/mm3, a neutrophils count of 4960/mm3, a hemoglobin count of 11 mg/dL, and 255,000/mm3 platelets. Accordingly, we made the diagnosis of a perianal soft tissue infection superimposed upon agranulocytosis and neutropenia related to PTU treatment.
From the Departments of *Endocrinology and Metabolism, and †Internal Medicine, Ankara Numune Education and Research Hospital, Ankara, Turkey. Reprints: Yusuf Aydın, MD, Pınarbası Mh Afacan Sk No:6/9 Keçio¨ren /Ankara, Turkey. E-mail:
[email protected]. Copyright © 2009 by Lippincott Williams & Wilkins ISSN: 1051-2144/09/1901-0001 DOI: 10.1097/TEN.0b013e3181958fda
The Endocrinologist • Volume 19, Number 1, February 2009
CLINICAL COURSE After cultures were obtained from blood, urine, and the infection site, IV imipenem at the dose of 500 mg, 4 times a day was prescribed. Bone marrow biopsy, thyroid function tests, anti-TPO, anti thyroglobulin, thyroid receptor antibody, ANA, anti-DNA, brucella, CMV, HSV type I-I, rubella, toxoplasma antibodies, and estimations of B12, folic acid and ferritin were measured (Table 1). Subcutaneous granulocyte colony stimulating factor (G-CSF) at the dose of 48 million units per day was started. Abscesses in perianal and gluteal regions were not drained because of the lack of fluctuation. Fever continued and the lesions did not improve despite imipenem treatment of 72 hours. All cultures were repeated, and vancomycin 2 g/d and amicacin 1 gr/d, intravenously, were added to imipenem treatment. Thyroid function tests showed TSH: 0.01 IU/mL (0.35–4.9), FT4: 1.73 pg/mL (0.7–1.4), total FT4: 3.04 ng/mL (0.7–1.4), anti-TPO:290 IU/mL (0–34, anti-Tg:183 IU/mL 关0–83兴 and TSH receptor antibody 52 IU/L 关0–9兴). The bone marrow aspiration and biopsy showed a focal nonparatrabecular, slightly hypocellular bone marrow demonstrating reactive lymphotic aggregates. Collagen fibrosis was not determined and blastic infiltration was not observed (Fig. 2). When the fever and abscesses were intractable to triple antibiotic therapy for 72 hours, cultures were repeated, and metronidazole 500 mg, intravenously, 4 times a day was added. Thyroid ultrasound (revealed a very heterogeneous thyroid gland with no nodules. Thyroid scintigraphy showed diffuse hyperplasia. The 24-hour uptake was found to be 32%. At the 72nd hour of the 4-drug antibiotic regimen, the fever continued but a marked improvement was seen in perineal lesions. Amphotericin B, 1 mg/kg a day, was added to the antibiotic regimen. On the 14th day of G-CSF treatment, no improvement was seen in neutrophil values. White cell count was 800/mm3 and after second biopsy of bone marrow, methyl prednisolone at the dose of 1 mg/kg/day was added to the regimen. On the third day of this regimen, white cells rose to 2100/mm3 and neutrophils rose to 200/mm3. On the fourth day, the white cells increased to 4500/mm3 and neutrophils to 2100/mm3. The fever lapsed and rapid improvement was seen in the perineal lesions. G-CSF was stopped on its 18th day (4th day of combined treatment with corticosteroid 关CS兴). Treatment was maintained with oral CS and white cell and neutrophil counts continued to rise. Antibiotic and antifungal treatment was stopped and CS dose was tapered. The second bone marrow biopsy showed granulocyte maturation arrest and reactive hyper cellular bone marrow with some aplasia. The cause of the thyrotoxicosis was diagnosed as Graves Disease and radioactive iodine treatment was planned.
DISCUSSION The median time reported for the appearance of neutrophil dyscrasia (agranulocytosis and neutropenia) is 30 days after the initiation of treatment. The range is 7 to 875 days.3 Neutrophil dyscrasia is more frequently fatal in patients over 65 years of age. It is seen more often with PTU than with carbimazole or methimazole.3 The complication may or may not be dose related.4 PTU-induced agranulocytosis is an idiosyncratic reaction of rapid and unpredictable onset. Fever and sore throat are the earliest symptoms of agranulocytosis. Patients who develop either of these symptoms should be closely monitored with white blood cell and granulocyte count 1
T1
F2
balt6/zuz-ten/zuz-ten/zuz00109/zuz2480-09z xppws Sⴝ1 12/9/08 7:33 Art: TEN200303 The Endocrinologist • Volume 19, Number 1, February 2009
Aydın et al
FIGURE 1. Perirectal abcess and perinal cellulitis. TABLE 1. Immunologic and Microbiologic Investigations Ordered for the Differential Diagnosis of Neutropenia Results ANA Anti-DNA Vitamin B12 Folik asit Ferritin CMV IgM CMV IgG EBV IgM EBV IgG Toxoplasma IgM Toxoplasma IgG HSV type 1–2 IgM HSV type 1–2 IgG Brucella Ag test Salmonella Ag test
Negative Negative 212 pg/mL (normal levels: 160–900) 4 ng/mL (normal levels: 2, 5–6) 250 ng/mL (normal levels: 18–204) Negative Positive Negative Positive Negative Positive Negative Positive Negative Negative
examinations.4 The major complaints of agranulocytosis are high fever (100%), chills (91%), and sore throat (73%).5 Anorectal and perirectal infections are common during chemotherapy for malignant disease and remain a major contributing cause of death. Early recognition and therapy for this potentially fatal infection will become increasingly important.6,7 During the treatment of perirectal or anorectal infections, abscess drainage should be done if possible. As far as we know, this is the first report in literature of a severe perirectal infection due to PTU-induced agranulocytosis. Bone marrow examinations during PTU-induced agranulocytosis commonly show maturation arrest of the granulocytic cell line.8,9 The causes of agranulocytosis due to PTU are not known. Treatment of PTU-induced agranulocytosis is difficult, time-consuming, and expensive. First-line treatment is cessation of PTU and broad spectrum antibiotics. In addition, recombinant human G-CSF should be prescribed.13 Human G-CSF is effective in the treatment of antithyroid drug-induced, mild to moderate granulocytopenia. Early studies suggest that in severe agranulocytic cases G-CSF is not effective.9 If there is response to human G-CSF in the early days of treatment, the drug treatment should be continued.14 Although treatment of PTU-induced agranulocytosis with CS is controversial,4 a response to CS can be seen as in our case.
2
FIGURE 2. The bone marrow aspiration and biopsy. Focal nonparatrabecular, slightly hypocellular bone marrow demonstrating reactive lymphois aggregate, reticulin or collagen fibrosis, and blastic infiltration were not determined (⫻400). REFERENCES
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