Case Reports © 1991S. K arger A G , Basel 0001-5792/91/0862-0095 S 2.75/0
Acta Haematol 1991;86:95-98
Human Recombinant Granulocyte Colony-Stimulating Factor for the Treatment of Autoimmune Neutropenia Kazuhiro Takahashi, Shuichi Taniguchi, Koichi Akashi, Kazuma Fujimoto, TunefumiSibuya, Hiromi Ishibashi, Mine Harada, Yoshiyuki Niho First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Key Words. Autoimmune neutropenia • Granulocyte colony-stimulating factor
Introduction
Recently recombinant human granulocyte colonystimulating factor (rhG-CSF) has become available for clinical use [1, 2], Clinical studies indicate that rhG-CSF is effective in accelerating granulocyte re covery from substantial granulocytopenia caused by intensive chemotherapy with or without bone marrow transplantation [3, 4], rhG-CSF is also useful for the management of idiopathic neutropenia [5] or cyclic neutropenia [6]. We report here a case of severe au toimmune neutropenia treated successfully with rhGCSF. Case Report A 57-year-old male was admitted to a community hospital be cause of high-grade fever in October 1988. He was diagnosed as having liver cirrhosis and hepatocellular carcinoma, in addition to severe neutropenia. Fever subsided after antibiotic therapy. How
ever, neutropenia persisted despite the administration of pred nisolone 30 mg/day for 30 days and he was referred to us for the evaluation of neutropenia in November 1988. On admission, he had high-grade fever. Physical examination revealed a thick white coating of the oral mucosa and tongue and mild hepatomegaly. Anemia, superficial lymphadenopathy and splenomegaly were not evident. Breathing sounds were normal without crackles. Complete peripheral blood counts disclosed WBC of 1,700/pl with 88% lymphocytes, 11% monocytes and 1% band-form neutrophils, Hb concentration was 13.4 g/dl and plate let count 2.8 x 104/pl. A bone marrow aspirate showed normocellularity with a nucleated cell count of 16.1 x 104/|xl with differentials as follows: myeloblasts 0.4%, promyelocytes 6.4%, myelocytes 18.0%, metamyelocytes 15.2%, band-form neutrophils 6.0%, and segmented neutrophils 2.0% (fig. la). The examination of the cell components of colony-forming unit (CFU)-G colonies revealed that the patient’s CFU-G in the bone marrow could maturate to segmented-form neutrophils in vitro as same as the normal con trol. The number of CFU-GM colonies in the patient’s bone mar row were 187±11 per 1 x 105 bone marrow mononuclear cells, which was increased compared to the normal control (table 1). The se rum G-CSF level measured by radioimmunoassay was less than 0.1 ng/ml. The serum C-reactive protein (CRP) concentration was elevated to as high as 7.2 mg/dl. Platelet-associated IgG was 97.4
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/6/2018 1:11:09 AM
Abstract. We have recently treated a case of autoimmune neutropenia in a 57-year-old male. Because neu tropenia persisted despite the administration of prednisolone for 30 days, daily subcutaneous injection of hu man recombinant granulocyte colony-stimulating factor (rhG-CSF) at a dosage of 100 pg was started. Neutro phil count increased gradually and reached a plateau of 5,000/pl by day 25 after administration of rhG-CSF. This observation suggests that rhG-CSF is effective for the treatment of autoimmune neutropenia.
96
Takahashi/Taniguchi/Akashi/Fujimoto/Sibuya/Ishibashi/Harada/Niho
Tabic 1. Clonal assay for bone marrow cells on admission and cell components of CFU-G colonies a Clonal assay for bone marrow cells on admission CFU-GM: 187 ± 11 (control 147 ±9) Burst forming unit (BFU-E): 97±8 (control 103± 11)/1 x 105 bone marrow mononuclear cells b Cell components of CFU-G colonies
Fig. 1. Bone marrow aspirate on admission (a) and on day 23 (b). Note few segmented neutrophils in a but increased number in b.
Colony No.
Mbl
ProM
Myelo
Meta
Rod
Seg
Patient
1 2 3
2.5 0 0
5.0 2.1 4.4
10.0 25.5 28.9
20.0 34.0 22.2
27.5 14.9 22.2
32.5 23.4 22.2
Control
1 2 3
0 0 5.0
7.2 2.5 5.0
15.9 25.1 22.5
29.0 33.0 32.5
15.9 21.0 17.5
31.9 17.3 22.5
Mbl = Myeloblast; ProM = promyelocyte; Myelo = myelocyte; Meta = metamyelocyte; Rod = rod-shaped neutrophils; Seg = segmented neutrophils.
ng/107 cells (normal range 9.0-25.0). Immunological studies were negative for direct Coombs test, antinuclear antibody and antiDNA antibody. Chest X-ray showed a ring-shaped shadow sug gesting cavity formation (3 x 3 cm) in the right upper lobe (fig. 2a). A sputum culture was negative for bacteria, tubercle bacilli and fungus. Abdominal sonographic studies disclosed a pattern of liver cirrhosis with a hypoechoic mass lesion in the anterio-superior segment of the right lobe. Since prednisolone was not effective for the improvement of persistent neutropenia, a daily subcutaneous injection of rhG-CSF at a dosage of 100 pg was started on November 8,1988. A rapid in
crease of the granulocyte count was not observed shortly after the administration of rhG-CSF (fig. 3). However, it began to increase gradually 1 week after rhG- CSF administration, exceeding 500/pl by day 10 after the administration of rhG-CSF and reaching a pla teau of 5,000/pl by day 25 (fig. 4). A bone marrow aspirate on day 23 showed hypercellularity with a nucleated cell count of 21.6 x 104/pl with differentials as follow: myeloblasts 0.8%, promye locytes 5.6%, myelocytes 11.2%, metamyelocytes 24.8%, band-form neutrophils 25.6% and segmented neutrophils 13.2% (fig. 1h). The serum level of uric acid rose from 4.9 mg/dl up to 8.0 mg/dl on day 28. Both numbers of red blood cells and platelets remained un-
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Fig. 2. Chest X-ray film on admission (a) and after 1 month (b). Note a ring-shaped shadow with infiltration in the right upper field in a disappeared in b.
97
rhG-CSF for Autoimmune Neutropenia
affected. When rhG-CSF was stopped after 6 weeks’ administra tion, neutrophil counts fell to the previous level within a week. A cavity shadow in the right upper lung disappeared (fig. 2b) and CRP levels returned to normal (0.5 mg/dl) about 1 month af ter the start of rhG-CSF. For the treatment of hepatocellular car cinoma, adriamycin and mitomycin C were given through the he patic artery by the Seldinger method on day 36 without inducing any infection. No adverse effects of rhG-CSF were seen and an antibody against rhG-CSF was not detected by radioimmunoassay. Diagnosis of autoimmune neutropenia was made based on the detection of neutrophil-bound immunoglobulins on neutrophils by direct and indirect immunofluorescence tests when neutrophils in creased in response to rhG-CSF. For the immunofluorescence test, a pure granulocyte population was isolated from the patient’s peripheral blood using the Ficoll-Hypaquc method and washed twice with phosphate-buffered saline. The neutrophil suspension was incubated with FITC-labeled anti-human Ig rabbit IgG for 30 min for the direct test. For the indirect test, the neutrophil sus pension was incubated with the patient’s sera for 30 min and fur ther incubated with FITC-labeled anti-human Ig rabbit IgG for 30 min.
G-CSF 100
pl
t rhG-CSF 100 ng s.c.
Time, rt
Fig. 3. Effect of rhG-CSF in the first 24 h following the sub cutaneous administration of rhG-CSF.
s.c.
Discussion
This report demonstrates effectiveness of rhG-CSF in the treatment of autoimmune neutropenia. Au toimmune neutropenia is characterized by severe neutropenia with cell-bound neutrophil antibodies or circulating antibodies against neutrophils [7]. The presence of autoimmune neutropenia in this patient was confirmed by positivity for cell-bound neutrophil antibodies using direct and indirect immunofluores cence test. There are some reports describing the
effectiveness of corticosteroid [7] or intravenous high-dose gammaglobulin [8] administration for some patients with autoimmune neutropenia. However, the use of rhG-CSF in the treatment of autoimmune neu tropenia has not yet been reported. Our case appeared to be a severe form of cortico steroid-resistant autoimmune neutropenia because there were a few neutrophils in the peripheral blood despite the long-term prednisolone therapy. Although causative micro-organisms were not identified from sputum culture, high-grade fever and a ring-shaped
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/6/2018 1:11:09 AM
Fig. 4. Clinical course. NCC = Nucleated cell count; Pit = platelet count; Scg = seg mented neutrophil.
shadow with lung infiltrates suggested the presence of an infection such as pulmonary tuberculosis, pulmo nary abscess or fungal infection. The cause of this pul monary infection was thought to be severe neutrope nia and long prednisolone administration. Therefore, we started rhG-CSF administration along with the an timicrobial agents in order to elevate the neutrophil level. In association with the recovery of neutrophils to the normal level, the pulmonary shadow disap peared and the CRP level returned to normal. In ad dition, we were able to give anticancer drugs for the treatment of hepatocelullar carcinoma without induc ing any infection. Although the neutrophil counts fell rapidly after stopping rhG-CSF, we are still giving an ticancer drugs to hepatocelullar carcinoma at inter vals of 4 months using rhG-CSF. These results indi cate that rhG-CSF is effective in controlling autoim mune neutropenia even though the effect is transient. rhG-CSF stimulates myeloid progenitor cells to proliferate and differentiate [2] and releases neutro phils from a marrow reserve and a peripheral margin al pool. In this patient, after the administration of rhG-CSF, bone marrow showed myeloid hyperplasia without the maturation to rod-shaped or segmented neutrophils. This suggests that absorption of anti-neutrophil antibodies with increased neutrophils is a pos sible mechanism for the correction of autoimmune neutropenia by rhG-CSF. An elevated level of scrum uric acid after the administration of rhG-CSF indi cates the increased destruction of neutrophils which absorbed anti-neutrophil antibodies. The lack of a rapid increase of neutrophils on the first day suggest ed marked decreases of marrow reserves and a mar ginal pool of mature neutrophils in autoimmune neu tropenia. We conclude that rhG-CSF is useful for the treat ment of autoimmune neutropenia, particularly when associated with life-threatening infection or prophy laxis of infection.
Takahashi/Taniguchi/Akashi/Fujitnoto/Sibuya/Ishibashi/Harada/Niho
References 1 Zscbo KM. Cohen AM, Murdock DC. Boone TC, Inoue H, Chazin VR, Hines D. Souza LM: Recombinant granulocyte colony stimulating factor: Molecular and biological character ization. Immunobiology 1986;172:175-184. 2 Souza LM, Boone TC, Gabrilove J, Lai PH, Zsebo KM, Mur dock DC. Chazin VR, Bruszewski J, Lu H. Chen KK, Barcndt J, Platzer E, Moor MAS. Mertelsmann R, Welte K: Recombi nant human granulocyte colony stimulating factor: Effects on normal and leukemic myeloid cells. Science 1986;232:61-64. 3 Kodo H, Tajika K, Takahashi S, Ozawa K, Asano S, Takaku F: Acceleration of neutrophilic granulocyte recovery after bone marrow transplantation by administration of recombinant human granulocyte colony stimulating factor. Lancet 1988;ii: 38-39. 4 Morstyn G, Campbell L, Souza LM, Alton NK, Keech J, Green M, Sherdan W, Metcalf D: Effect of granulocyte colony stim ulating factor on neutropenia induced by cytotoxic chemother apy. Lancet 1988; i:667— 671. 5 Jakubowski AA, Souza LM, Kelly F, Fain K, Budman D, Clark son B, Bonilla MA, Moore MAS, Gabrilove J: Effect of human granulocyte colony stimulating factor in a patient with idio pathic neutropenia. N Engl J Med 1989;320:38-42. 6 Hammond WP. Price TH. Souza LM. Dale DC: Treatment of cyclic neutropenia with granulocyte colony stimulating factor. N Engl J Med 1989;320:1306-1311. 7 Boxer LA, Greenberg MS, Boxer GI, Stossel TP: Autoimmune neutropenia. N Engl J Med 1975;293:748-753. 8 Pollack S, Rundlc CC, Smithwick EM. Barandun S, Good RA: High dose intravenous gammaglobulin for autoimmune neu tropenia. N Engl J Med 1982;307:253.
Received: October 5, 1990 Accepted: January 11, 1991 Dr. Kazuhiro Takahashi First Department of Internal Medicine Faculty of Medicine Kyushu University Maidashi 3-1-1 Higashi-ku Fukuoka 812 (Japan)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/6/2018 1:11:09 AM
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Acta Haematol 1991;86:95-98
Human Recombinant Granulocyte Colony-Stimulating Factor for the Treatment of Autoimmune Neutropenia Kazuhiro Takahashi, Shuichi Taniguchi, Koichi Akashi, Kazuma Fujimoto, TunefumiSibuya, Hiromi Ishibashi, Mine Harada, Yoshiyuki Niho First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Key Words. Autoimmune neutropenia • Granulocyte colony-stimulating factor
Introduction
Recently recombinant human granulocyte colonystimulating factor (rhG-CSF) has become available for clinical use [1, 2], Clinical studies indicate that rhG-CSF is effective in accelerating granulocyte re covery from substantial granulocytopenia caused by intensive chemotherapy with or without bone marrow transplantation [3, 4], rhG-CSF is also useful for the management of idiopathic neutropenia [5] or cyclic neutropenia [6]. We report here a case of severe au toimmune neutropenia treated successfully with rhGCSF. Case Report A 57-year-old male was admitted to a community hospital be cause of high-grade fever in October 1988. He was diagnosed as having liver cirrhosis and hepatocellular carcinoma, in addition to severe neutropenia. Fever subsided after antibiotic therapy. How
ever, neutropenia persisted despite the administration of pred nisolone 30 mg/day for 30 days and he was referred to us for the evaluation of neutropenia in November 1988. On admission, he had high-grade fever. Physical examination revealed a thick white coating of the oral mucosa and tongue and mild hepatomegaly. Anemia, superficial lymphadenopathy and splenomegaly were not evident. Breathing sounds were normal without crackles. Complete peripheral blood counts disclosed WBC of 1,700/pl with 88% lymphocytes, 11% monocytes and 1% band-form neutrophils, Hb concentration was 13.4 g/dl and plate let count 2.8 x 104/pl. A bone marrow aspirate showed normocellularity with a nucleated cell count of 16.1 x 104/|xl with differentials as follows: myeloblasts 0.4%, promyelocytes 6.4%, myelocytes 18.0%, metamyelocytes 15.2%, band-form neutrophils 6.0%, and segmented neutrophils 2.0% (fig. la). The examination of the cell components of colony-forming unit (CFU)-G colonies revealed that the patient’s CFU-G in the bone marrow could maturate to segmented-form neutrophils in vitro as same as the normal con trol. The number of CFU-GM colonies in the patient’s bone mar row were 187±11 per 1 x 105 bone marrow mononuclear cells, which was increased compared to the normal control (table 1). The se rum G-CSF level measured by radioimmunoassay was less than 0.1 ng/ml. The serum C-reactive protein (CRP) concentration was elevated to as high as 7.2 mg/dl. Platelet-associated IgG was 97.4
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/6/2018 1:11:09 AM
Abstract. We have recently treated a case of autoimmune neutropenia in a 57-year-old male. Because neu tropenia persisted despite the administration of prednisolone for 30 days, daily subcutaneous injection of hu man recombinant granulocyte colony-stimulating factor (rhG-CSF) at a dosage of 100 pg was started. Neutro phil count increased gradually and reached a plateau of 5,000/pl by day 25 after administration of rhG-CSF. This observation suggests that rhG-CSF is effective for the treatment of autoimmune neutropenia.
96
Takahashi/Taniguchi/Akashi/Fujimoto/Sibuya/Ishibashi/Harada/Niho
Tabic 1. Clonal assay for bone marrow cells on admission and cell components of CFU-G colonies a Clonal assay for bone marrow cells on admission CFU-GM: 187 ± 11 (control 147 ±9) Burst forming unit (BFU-E): 97±8 (control 103± 11)/1 x 105 bone marrow mononuclear cells b Cell components of CFU-G colonies
Fig. 1. Bone marrow aspirate on admission (a) and on day 23 (b). Note few segmented neutrophils in a but increased number in b.
Colony No.
Mbl
ProM
Myelo
Meta
Rod
Seg
Patient
1 2 3
2.5 0 0
5.0 2.1 4.4
10.0 25.5 28.9
20.0 34.0 22.2
27.5 14.9 22.2
32.5 23.4 22.2
Control
1 2 3
0 0 5.0
7.2 2.5 5.0
15.9 25.1 22.5
29.0 33.0 32.5
15.9 21.0 17.5
31.9 17.3 22.5
Mbl = Myeloblast; ProM = promyelocyte; Myelo = myelocyte; Meta = metamyelocyte; Rod = rod-shaped neutrophils; Seg = segmented neutrophils.
ng/107 cells (normal range 9.0-25.0). Immunological studies were negative for direct Coombs test, antinuclear antibody and antiDNA antibody. Chest X-ray showed a ring-shaped shadow sug gesting cavity formation (3 x 3 cm) in the right upper lobe (fig. 2a). A sputum culture was negative for bacteria, tubercle bacilli and fungus. Abdominal sonographic studies disclosed a pattern of liver cirrhosis with a hypoechoic mass lesion in the anterio-superior segment of the right lobe. Since prednisolone was not effective for the improvement of persistent neutropenia, a daily subcutaneous injection of rhG-CSF at a dosage of 100 pg was started on November 8,1988. A rapid in
crease of the granulocyte count was not observed shortly after the administration of rhG-CSF (fig. 3). However, it began to increase gradually 1 week after rhG- CSF administration, exceeding 500/pl by day 10 after the administration of rhG-CSF and reaching a pla teau of 5,000/pl by day 25 (fig. 4). A bone marrow aspirate on day 23 showed hypercellularity with a nucleated cell count of 21.6 x 104/pl with differentials as follow: myeloblasts 0.8%, promye locytes 5.6%, myelocytes 11.2%, metamyelocytes 24.8%, band-form neutrophils 25.6% and segmented neutrophils 13.2% (fig. 1h). The serum level of uric acid rose from 4.9 mg/dl up to 8.0 mg/dl on day 28. Both numbers of red blood cells and platelets remained un-
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/6/2018 1:11:09 AM
Fig. 2. Chest X-ray film on admission (a) and after 1 month (b). Note a ring-shaped shadow with infiltration in the right upper field in a disappeared in b.
97
rhG-CSF for Autoimmune Neutropenia
affected. When rhG-CSF was stopped after 6 weeks’ administra tion, neutrophil counts fell to the previous level within a week. A cavity shadow in the right upper lung disappeared (fig. 2b) and CRP levels returned to normal (0.5 mg/dl) about 1 month af ter the start of rhG-CSF. For the treatment of hepatocellular car cinoma, adriamycin and mitomycin C were given through the he patic artery by the Seldinger method on day 36 without inducing any infection. No adverse effects of rhG-CSF were seen and an antibody against rhG-CSF was not detected by radioimmunoassay. Diagnosis of autoimmune neutropenia was made based on the detection of neutrophil-bound immunoglobulins on neutrophils by direct and indirect immunofluorescence tests when neutrophils in creased in response to rhG-CSF. For the immunofluorescence test, a pure granulocyte population was isolated from the patient’s peripheral blood using the Ficoll-Hypaquc method and washed twice with phosphate-buffered saline. The neutrophil suspension was incubated with FITC-labeled anti-human Ig rabbit IgG for 30 min for the direct test. For the indirect test, the neutrophil sus pension was incubated with the patient’s sera for 30 min and fur ther incubated with FITC-labeled anti-human Ig rabbit IgG for 30 min.
G-CSF 100
pl
t rhG-CSF 100 ng s.c.
Time, rt
Fig. 3. Effect of rhG-CSF in the first 24 h following the sub cutaneous administration of rhG-CSF.
s.c.
Discussion
This report demonstrates effectiveness of rhG-CSF in the treatment of autoimmune neutropenia. Au toimmune neutropenia is characterized by severe neutropenia with cell-bound neutrophil antibodies or circulating antibodies against neutrophils [7]. The presence of autoimmune neutropenia in this patient was confirmed by positivity for cell-bound neutrophil antibodies using direct and indirect immunofluores cence test. There are some reports describing the
effectiveness of corticosteroid [7] or intravenous high-dose gammaglobulin [8] administration for some patients with autoimmune neutropenia. However, the use of rhG-CSF in the treatment of autoimmune neu tropenia has not yet been reported. Our case appeared to be a severe form of cortico steroid-resistant autoimmune neutropenia because there were a few neutrophils in the peripheral blood despite the long-term prednisolone therapy. Although causative micro-organisms were not identified from sputum culture, high-grade fever and a ring-shaped
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/6/2018 1:11:09 AM
Fig. 4. Clinical course. NCC = Nucleated cell count; Pit = platelet count; Scg = seg mented neutrophil.
shadow with lung infiltrates suggested the presence of an infection such as pulmonary tuberculosis, pulmo nary abscess or fungal infection. The cause of this pul monary infection was thought to be severe neutrope nia and long prednisolone administration. Therefore, we started rhG-CSF administration along with the an timicrobial agents in order to elevate the neutrophil level. In association with the recovery of neutrophils to the normal level, the pulmonary shadow disap peared and the CRP level returned to normal. In ad dition, we were able to give anticancer drugs for the treatment of hepatocelullar carcinoma without induc ing any infection. Although the neutrophil counts fell rapidly after stopping rhG-CSF, we are still giving an ticancer drugs to hepatocelullar carcinoma at inter vals of 4 months using rhG-CSF. These results indi cate that rhG-CSF is effective in controlling autoim mune neutropenia even though the effect is transient. rhG-CSF stimulates myeloid progenitor cells to proliferate and differentiate [2] and releases neutro phils from a marrow reserve and a peripheral margin al pool. In this patient, after the administration of rhG-CSF, bone marrow showed myeloid hyperplasia without the maturation to rod-shaped or segmented neutrophils. This suggests that absorption of anti-neutrophil antibodies with increased neutrophils is a pos sible mechanism for the correction of autoimmune neutropenia by rhG-CSF. An elevated level of scrum uric acid after the administration of rhG-CSF indi cates the increased destruction of neutrophils which absorbed anti-neutrophil antibodies. The lack of a rapid increase of neutrophils on the first day suggest ed marked decreases of marrow reserves and a mar ginal pool of mature neutrophils in autoimmune neu tropenia. We conclude that rhG-CSF is useful for the treat ment of autoimmune neutropenia, particularly when associated with life-threatening infection or prophy laxis of infection.
Takahashi/Taniguchi/Akashi/Fujitnoto/Sibuya/Ishibashi/Harada/Niho
References 1 Zscbo KM. Cohen AM, Murdock DC. Boone TC, Inoue H, Chazin VR, Hines D. Souza LM: Recombinant granulocyte colony stimulating factor: Molecular and biological character ization. Immunobiology 1986;172:175-184. 2 Souza LM, Boone TC, Gabrilove J, Lai PH, Zsebo KM, Mur dock DC. Chazin VR, Bruszewski J, Lu H. Chen KK, Barcndt J, Platzer E, Moor MAS. Mertelsmann R, Welte K: Recombi nant human granulocyte colony stimulating factor: Effects on normal and leukemic myeloid cells. Science 1986;232:61-64. 3 Kodo H, Tajika K, Takahashi S, Ozawa K, Asano S, Takaku F: Acceleration of neutrophilic granulocyte recovery after bone marrow transplantation by administration of recombinant human granulocyte colony stimulating factor. Lancet 1988;ii: 38-39. 4 Morstyn G, Campbell L, Souza LM, Alton NK, Keech J, Green M, Sherdan W, Metcalf D: Effect of granulocyte colony stim ulating factor on neutropenia induced by cytotoxic chemother apy. Lancet 1988; i:667— 671. 5 Jakubowski AA, Souza LM, Kelly F, Fain K, Budman D, Clark son B, Bonilla MA, Moore MAS, Gabrilove J: Effect of human granulocyte colony stimulating factor in a patient with idio pathic neutropenia. N Engl J Med 1989;320:38-42. 6 Hammond WP. Price TH. Souza LM. Dale DC: Treatment of cyclic neutropenia with granulocyte colony stimulating factor. N Engl J Med 1989;320:1306-1311. 7 Boxer LA, Greenberg MS, Boxer GI, Stossel TP: Autoimmune neutropenia. N Engl J Med 1975;293:748-753. 8 Pollack S, Rundlc CC, Smithwick EM. Barandun S, Good RA: High dose intravenous gammaglobulin for autoimmune neu tropenia. N Engl J Med 1982;307:253.
Received: October 5, 1990 Accepted: January 11, 1991 Dr. Kazuhiro Takahashi First Department of Internal Medicine Faculty of Medicine Kyushu University Maidashi 3-1-1 Higashi-ku Fukuoka 812 (Japan)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/6/2018 1:11:09 AM
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