Autoimmune neutropenia accompanied by Tolosa-Hunt syndrome

A 47-year-old woman presented with severe neutropenia accompanied by diplopia and orbital pain. Her bone marrow was normal except for the absence of segmented neutrophils. Because the administration of granulocyte colony-stimulating factor (G-CSF) at a dose of 1 microgram/kg/day was not sufficiently effective and neutropenia developed, the patient was admitted to our hospital. Physical examination revealed painful ophthalmoplegia and hypoalgesia in the first region of trigeminal nerve, suggestive of Tolosa-Hunt syndrome. Severe neutropenia was observed in both peripheral blood and bone marrow, together with mild anemia and thrombocytopenia. The life span of red cells and platelets was shortened. High PAIgG levels, a positive Coombs test, and a positive test for anti-NA1 antibody suggested that blood cells were being destroyed by an autoimmune mechanism. Corticosteroid hormone therapy preceded by the administration of G-CSF at 5 micrograms/kg/day was effective for both neutropenia and in improving the patient's neurological findings.     

Granulocyte transfusion in the G-CSF era

Granulocyte transfusions have been used since the 1960s with varying degrees of clinical success in the treatment of infection in patients with neutropenia or inherited granulocyte disorders. A number of studies have indicated that efficacy may well be associated with the dose of granulocytes delivered. Collection of granulocytes using modern apheresis machines and corticosteroid administration yields approximately 20 to approximately 30 x 10(9) neutrophils, unlikely to be adequate for treating an established infection. The administration of G-CSF to healthy donors has resulted in average granulocyte yields up to 8 x 10(10) cells. Normal or near normal blood neutrophil counts are often attained when these concentrates are transfused to neutropenic recipients, and these levels are sustained for up to 24 h. G-CSF-primed granulocytes appear to be functionally normal by both in vitro and in vivo measurements. Adverse effects experienced by recipients are similar to those seen with traditional doses of granulocytes. G-CSF administration to donors is well tolerated. Controlled clinical trials are needed to determine the therapeutic efficacy of G-CSF-primed granulocyte transfusions.     

Leukocyte integrin activation mediates transient neutropenia after G-CSF administration

After administration of granulocyte colony-stimulating factor (G-CSF), there is a marked, albeit transient, drop in circulating neutrophils. To determine the role of leukocyte integrins in this disappearance, a dog having canine leukocyte adhesion deficiency (CLAD) or CLAD dogs who had undergone gene correction either by matched littermate allogeneic transplant or autologous gene therapy were evaluated. Shortly after G-CSF administration, a dramatic, yet transient, neutropenia was observed in the control littermates. This neutropenia was not as marked in the CLAD dogs. In all instances, it was CD18(+) neutrophils that preferentially egressed from the circulation. The association of CD18 with this rapid loss suggested leukocyte integrin activation after G-CSF administration. To determine the activation status of the integrin, a monoclonal antibody recognizing the activated α-subunit cation binding domain (mAb24) was used to evaluate human leukocytes after G-CSF administration. Mirroring the dramatic decrease in circulating neutrophil numbers, there was a dramatic and specific increase in the activation of the α-subunit after G-CSF expression on polymorphonuclear leukocytes. This activation, like the drop in neutrophil count, was transient. These results demonstrate that the leukocyte integrin on circulating neutrophils is transiently activated after G-CSF administration and mediates the transient neutropenia observed after G-CSF administration.     

G-CSF in Peg-IFN induced neutropenia in liver transplanted patients with HCV recurrence

AIM: To evaluate the efficacy of granulocyte colony stimulating factors (G-CSF) in liver transplanted patients with hepatitis C (HCV) recurrence and Pegylated-IFN α-2b induced neutropenia, and to evaluate the impact of G-CSF administration on virological response.METHODS: Sixty-eight patients undergoing antiviral treatment for post-liver transplantation (OLT) HCV recurrence were enrolled.All patients developing neutropenia received G-CSF.RESULTS: Twenty three (34%) received G-CSF.Mean neutrophil count at the onset of neutropenia was 700/mmc (range 400-750/mmc); after 1 mo of G-CSF it increased to 1210/mmc (range 300-5590/mmc) ( P < 0.0001).Three patients did not respond to G-CSF.Treatment duration was similar in neutropenic and non-neutropenic patients.No differences in the rate of discontinuation, infections or virological response were observed between the two groups.G-CSF was protective for the onset of de novo autoimmune hepatitis ( P < 0.003).CONCLUSION: G-CSF administration is effective in the case of Peg-IFN induced neutropenia increasing neutrophil count, prolonging treatment and leading to sustained virological response (SVR) rates comparable to non-neutropenic patients.It prevents the occurrence of de novo autoimmune hepatitis.     

Granulocyte colony-stimulating factor dosing in pegylated interferon alpha-induced neutropenia and its impact on outcome of anti-HCV therapy

Many patients with chronic hepatitis C (HCV) infection undergoing treatment with pegylated interferon-alpha (PEG-IFN-alpha) and ribavirin develop neutropenia requiring dose reduction or granulocyte colony-stimulating factor (G-CSF) supplement. We analysed the database of patients who completed treatment for chronic HCV infection between 2003 and 2006. Patients with absolute neutrophil counts below 1000 cells/microL were initiated on G-CSF (G-CSF group) while a matching group of patients who received anti-HCV treatment without developing neutropenia were used as a control group (non-G-CSF group). Patients on the G-CSF arm were divided into two subgroups based on the timing of G-CSF administration relative to PEG-IFN-alpha administration. Of the 163 patients with HCV infection, 30 patients received G-CSF, most of who were maintained on 300 microg of G-CSF once a week. Administration of G-CSF 2 days before or after each dose of PEG-IFN-alpha did not make a significant difference in the neutrophil counts. In the G-CSF arm, 23 of 30 patients (77%) had undetectable end-of-treatment viral response which was comparable with 27 of 30 in the control group (90%; P = 0.17). There was no statistically significant difference in the sustained viral response between the two groups (61%vs 76%, P = 0.18). In most patients PEG-IFN-alpha induced neutropenia improved with a once-a-week dose of G-CSF with a comparable virological outcome. Timing of G-CSF administration did not make any significant impact on the patient's neutrophil counts but was better tolerated when given 2 days apart from PEG-IFN-alpha.     

Granulocyte transfusion in the G-CSF era

Granulocyte transfusions have been used since the 1960s with varying degrees of clinical success in the treatment of infection in patients with neutropenia or inherited granulocyte disorders. A number of studies have indicated that efficacy may well be associated with the dose of granulocytes delivered. Collection of granulocytes using modern apheresis machines and corticosteroid administration yields approximately 20～30×10⁹ neutrophils, unlikely to be adequate for treating an established infection. The administration of G-CSF to healthy donors has resulted in average granulocyte yields up to 8×10¹⁰ cells. Normal or near normal blood neutrophil counts are often attained when these concentrates are transfused to neutropenic recipients, and these levels are sustained for up to 24 h. G-CSF-primed granulocytes appear to be functionally normal by both in vitro and in vivo measurements. Adverse effects experienced by recipients are similar to those seen with traditional doses of granulocytes. G-CSF administration to donors is well tolerated. Controlled clinical trials are needed to determine the therapeutic efficacy of G-CSF-primed granulocyte transfusions.     

G-CSF enhanced granulocyte production in a child with severe neutropenia in the setting of fatal virus-associated hemophagocytic syndrome.

A 14-year-old boy with fatal varicella zoster virus-associated hemophagocytic syndrome (VAHS) was treated with recombinant human granulocyte colony-stimulating factor (G-CSF) based on the finding that the patient had severe neutropenia and possible bacterial superinfection. Support for the G-CSF therapy in VAHS is provided by the recent reports that G-CSF is relatively specific for the granulocyte lineage; it would not activate mature monocyte/macrophage/histiocyte lineage in VAHS, where the most striking morphologic feature is histiocytic hyperplasia with hemophagocytosis. He responded well to G-CSF with an elevation of neutrophil counts. There were no effects on other blood cells. The result indicates that G-CSF is useful to increase granulocyte production in severe neutropenia, even in the setting of fatal VAHS.     

Efficacy of delayed administration of post-chemotherapy granulocyte colony-stimulating factor: evidence from murine studies of bone marrow cell kinetics

The optimal schedule of post-chemotherapy granulocyte colony-stimulating factor (G-CSF) administration has not been determined. G-CSF is customarily started 24 hours after chemotherapy; however, clinical data demonstrated that delaying G-CSF until 5 days after completion of chemotherapy has not resulted in a longer duration of neutropenia. Here, we examined the optimal timing of post-chemotherapy G-CSF administration in a mouse model, to show that delayed administration does not postpone the appearance of mature granulocytes in the peripheral blood. We also investigated the mechanism of decreased efficacy of the early G-CSF application after chemotherapy by characterizing the changes in bone marrow cellular composition. To our knowledge, we demonstrate for the first time, that early after chemotherapy, the bone marrow is predominantly composed of mature residual granulocytes and very few progenitors and precursors, on which G-CSF would act to generate granulocytes. The point when immature progenitors reappear does not occur in murine bone marrow until 48 hours after a single dose of cyclophosphamide. Our results indicate that the bone marrow cellular composition early after discontinuation of chemotherapy is not optimal for G-CSF action on acceleration of myeloid recovery. Given the high cost of G-CSF prophylaxis, its delayed administration may potentially result in substantial economic benefits.     

Spontaneous remission of granulocyte colony-stimulating factor-associated leukemia in a child with severe congenital neutropenia

Leukemia is observed with increased frequency in patients with severe congenital neutropenia (SCN). In the past decade, recombinant human granulocyte colony-stimulating factor (rh G-CSF) has prolonged the survival of patients with SCN increasingly reported to have leukemias. In this communication acute myelogenous leukemia (AML) associated with a mutation of the G-CSF receptor (G-CSF-R) developed in a patient with SCN maintained on long-term G-CSF therapy. The blast count in the blood and bone marrow fell to undetectable levels twice on withholding G-CSF and without chemotherapy administration, but the mutant G-CSF-R was detectable during this period. The patient subsequently underwent successful allogeneic bone marrow transplantation. After transplantation, the patient's neutrophil elastase (ELA-2) mutation and G-CSF-R mutation became undetectable by polymerase chain reaction. This report provides novel insights on leukemia developing in congenital neutropenia.     

Granulocyte colony-stimulating factor (G-CSF) treatment in a neutropenic leukemia patient with diffuse interstitial pulmonary infiltrates

Summary Adult respiratory distress syndrome (ARDS) in patients suffering from acute leukemia usually occurs during chemotherapy-induced neutropenia. In addition, intensified chemotherapy with high-dose cytosine arabinoside and mediastinal irradiation may contribute to the development of ARDS. This complication is usually refractory to conservative treatement with antibiotics, steroids, and mechanical ventilation. In this report, we describe a 25-year-old patient with acute lymphoblastic leukemia who developed ARDS during the phase of chemotherapy-induced neutropenia. Subcutaneous administration of granulocyte colony-stimulating factor (G-CSF) at doses of 300–600 g/day led to a prompt increase of peripheral granulocyte counts. With resolution of neutropenia, respiratory function gradually improved, and mechanical ventilatory support was stopped after 2 weeks. From this observation we surmise that the application of G-CSF may be an effective therapeutic approach for preventing the fatal outcome of ARDS in leukemia patients with bone marrow aplasia.     

Abnormal responses of myeloid progenitor cells to recombinant human colony-stimulating factors in congenital neutropenia.

The effects of recombinant human interleukin-3 (IL-3) and recombinant human granulocyte colony-stimulating factor (G-CSF) on the growth of myeloid progenitor cells (CFU-C) in semisolid agar culture were studied in two patients with Kostmann-type congenital neutropenia. CFU-C growth in bone marrow cells from patients was significantly reduced in response to various concentrations of either IL-3 or G-CSF alone, compared with that from normal subjects. There was no inhibitory effect of bone marrow cells from patients on normal CFU-C formation supported by IL-3 or G-CSF. However, the simultaneous stimulation with IL-3 and G-CSF induced the increase of CFU-C formation in patients with congenital neutropenia. Furthermore, CFU-C growth in both patients was supported when bone marrow cells were preincubated with IL-3 in liquid culture followed by the stimulation with G-CSF in semisolid agar culture. In contrast, that was not supported by the preincubation with G-CSF and the subsequent stimulation with IL-3. This evidence suggests that the hematopoietic progenitor cells in patients with congenital neutropenia have the potential for developing CFU-C in the combined stimulation with IL-3 and G-CSF, and that this growth may be dependent on the priming of IL-3 followed by the stimulation with G-CSF. The level of mature neutrophils in peripheral blood was not fully restored to normal levels by the daily administration of G-CSF in doses of 100 to 200 micrograms/m2 of body surface area for 20 to 25 days in both patients. These observations raise the possibility that the combination of IL-3 and G-CSF might have a potential role for the increase of neutrophil counts in patients with congenital neutropenia.     

Granulocyte colony stimulating factor in neutropenic patients with infective endocarditis

A well known complication in the treatment of infectious endocarditis is development of neutropenia caused by treatment with antibiotics in high concentrations over long periods. Neutropenia often necessitates discontinuation of antibiotic treatment. Three patients with infectious endocarditis who developed neutropenia are reported. The patients were treated with granulocyte colony stimulating factor (G-CSF), a haematopoietic growth factor that stimulates neutrophils. G-CSF induced an immediate increase in white blood cell count, primarily neutrophils. G-CSF may be effective in ameliorating neutropenia in patients who receive antibiotics for treatment of infectious endocarditis.

Keywords: granulocyte colony stimulating factor;  neutropenia;  endocarditis     

Severe neutropenia in T-large granular lymphocyte leukemia corrected by intensive immunosuppression

 Optimum treatment of severe neutropenia, a major factor for morbidity and mortality in T-large granular lymphocyte (LGL) leukemia, is undefined. We observed a rapid improvement of the neutrophil count in a patient with T-LGL leukemia and severe neutropenia after the combined administration of anti-lymphocyte-globulin (ALG), cyclosporin A, prednisone, and granulocyte colony-stimulating factor (G-CSF). Although G-CSF treatment was terminated after 7 days, the neutrophil count has persisted above 1.0×10⁹/l for up to 6 months now. Oral methotrexate is given continuously as treatment for T-LGL leukemia. The response to this immunosuppressive regimen suggests a T-cell-mediated mechanism as the underlying cause for neutropenia in T-LGL leukemia. Received: 26 January 1996 / Accepted: 3 May 1996     

Role of granulocyte colony-stimulating factor as adjunct therapy for septicemia in children with acute leukemia

The granulocyte colony-stimulating factor (G-CSF) has been shown to accelerate recovery from severe neutropenia and to decrease the incidence of documented infections after intensive chemotherapy in cancer patients. However, the routine prophylactic use of G-CSF is expensive. This study was conducted to determine the role of G-CSF as adjunct therapy for septicemia following neutropenia caused by chemotherapy in children with acute leukemia. Fifty consecutive episodes of septicemia were studied involving 34 episodes of Gram-negative, 7 episodes of Gram-positive, 5 episodes of polymicrobial bacterial septicemia, one episode of fungemia, and 3 episodes of disseminated fungal infection. In the first 25 episodes, G-CSF was not used (group A). For the next 16 episodes, G-CSF 200 μg per square meter per day subcutaneously was given immediately after the septicemia was documented until the absolute neutrophil count was maintained at more than 1,500 per cubic millimeter (group B). Thereafter, G-CSF at the same dose as that of group B was prophylactically used in all the children who received high-dose cytosine arablnc-side-containing regimens. Nine episodes of septicemia occurred (group C). The incidences of mortality per episode of septicemia in groups A, B, and C were 12.0% (3/25), 12.5% (2/16) and 0% (0/9), respectively. Statistically, there was no difference between the three groups overall and in pair-wise comparisons (all P > 0.5). The durations of G-CSF administration in group B ranged from 6 to 26 days with a median of 12 days and the durations of G-CSF administration in group C ranged from 10 to 23 days with a median of 19 days. With or without G-CSF, there may be no significant difference in the mortality of septicemia following neutropenia caused by chemotherapy in children with acute leukemia.     

Granulocyte colony-stimulating factor (G-CSF) production and G-CSF receptor structure in patients with congenital neutropenia

Congenital neutropenia (Kostmann's syndrome [KS]) is an autosomal recessive syndrome that is characterized by profound neutropenia, resulting in major clinical infections and death. Since the neutropenia and symptoms in KS improve in response to exogenous administration of granulocyte colony-stimulating factor (G-CSF), we studied bone marrow cytokine (G-CSF, granulocyte-macrophage CSF [GM-CSF], and interleukin- 6) production under both basal and stimulated conditions. No differences in G-CSF, GM-CSF, or IL-6 gene expression were found in bone marrow stromal cells between normal controls and KS patients, and all three cytokines were detected by enzyme-linked immunosorbent assay (ELISA) in medium conditioned by bone marrow stromal cells from normal donors and patients with KS. Each KS patient tested had detectable, functional G-CSF in their own serum before exogenous G-CSF administration. Since G-CSF production appeared normal in KS patients, we then asked whether we could detect structural defects in the signaling portion of G-CSF receptor genes. Polymerase chain reaction (PCR) amplification of the G-CSF receptor transmembrane region alone, and of the transmembrane plus cytosolic portions of the receptor, yielded the size products predicted from the sequences of the normal G- CSF receptor. Single-strand conformational polymorphism (SSCP) analysis of G-CSF receptor PCR products demonstrated no variance in structural conformation between KS patients and normal subjects. These results demonstrate that bone marrow stromal cells in patients with KS secrete normal concentrations of functional G-CSF and suggest that the neutropenia in KS patients is caused by an inability of neutrophilic progenitor and precursor cells to respond to normal, physiologic levels of G-CSF. Such a defect, clinically responsive to pharmacologic doses of G-CSF, might be caused by defects in the post-G-CSF receptor signal transduction pathway.     

A case of an SLE patient with febrile neutropenia who experienced exacerbation of cutaneous manifestations after the administration of G-CSF

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease. Although hematological anomalies are commonly found in SLE, severe polymorphonuclear leukocyte depletion is rare. Most episodes of severe granulocytopenia in SLE patients tend to occur as part of drug toxicity-induced medullar hypoplasia, and recombinant human (rh) granulocyte colony-stimulating factor (G-CSF) has been shown to be effective for treating neutropenia associated with SLE. However, flares of some autoimmune diseases, including flares in six SLE patients, have been reported after G-CSF therapy. This report presents the case of a patient with SLE who experienced exacerbation of skin symptoms after G-CSF therapy. There is sufficient evidence to suggest that G-CSF can exacerbate inflammatory disease. Furthermore, the possibility that several factors other than rhG-CSF may affect the disease activity of SLE should be considered when SLE patients with neutropenia require the administration of rhG-CSF. Therefore rhG-CSF should be used with considerable caution in neutropenic patients with SLE.     

Oral ulcers and necrotizing gingivitis in relation to HIV-associated neutropenia: a review and an illustrative case

An unusual case of necrotizing gingivitis and neutropenic oral ulcers in an HIV-seropositive patient is presented. In spite of a very low CD4(+) T cell count and severe neutropenia, the necrotizing gingivitis responded favorably to standard periodontal treatment, and the oral ulcers healed after administration of granulocyte colony-stimulating factor (G-CSF). Nonspecific oral ulcers in HIV-seropositive subjects with neutropenia should be regarded as neutropenic ulcers. The term nonspecific ulcers should be restricted to those ulcers with nonspecific histopathological features in patients without neutropenia or a nutritional deficiency such as iron, folic acid, and vitamin B.     

Myelodysplasia and acute myeloid leukaemia in cases of aplastic anaemia and congenital neutropenia following G-CSF administration

Summary. Myelodysplasia and acute myeloid leukaemia (MDS/AML) developed in three cases of severe aplastic anaemia (SAA) and one case of congenital neutropenia (CN, Kostmann's disease) who received recombinant human granulocyte colony-stimulating factor (G-CSF) are reported. In these four MDS/AML cases, age at diagnosis of SAA/CN was 0–13 years, the cumulative dose of G-CSF was 98 μg/kg to 10 mg/kg over 1–57 months, and the interval from initiation of G-CSF to MDS/AML was 25, 23, 31 and 57 months, respectively. These results suggest a link between SAA/CN and MDS/AML in relation to G-CSF administration; however, large studies are necessary to determine if such a risk is significant in patients with SAA/CN who are treated with G-CSF.     

Concomitant granulocyte colony-stimulating factor and induction chemoradiotherapy in adult acute lymphoblastic leukemia: a randomized phase III trial

This prospective multicenter study examined whether simultaneous administration of granulocyte colony-stimulating factor (G-CSF; Filgrastim) and induction chemotherapy for adult acute lymphoblastic leukemia (ALL) could prevent treatment-related neutropenia, infections, and resulting treatment delays. Seventy-six patients were randomly assigned to receive either G-CSF (n = 37) or no growth factor (n = 39) in conjunction with a uniform chemotherapy consisting of cyclophosphamide, cytarabine, mercaptopurine, intrathecal methotrexate, and cranial irradiation. The median duration of neutropenia (absolute neutrophil count < 1 x 10(9)/L) during chemotherapy was 8 days in patients receiving C-CSF, compared with 12.5 days in the control group (P < .002). A similar reduction from 11.5 to 7 days was observed in patients with T-ALL receiving additional mediastinal irradiation (P = .13). Infections occurred in 43% and 56% of patients in the G-CSF and control arm, respectively (P = .25); the incidence of nonviral infections was reduced by 50%, from 32 episodes in the control arm to 16 episodes in the G-CSF arm. Prolonged interruptions of chemotherapy administration were less frequent, with delays of 2 weeks or more occurring in only 24% of patients receiving G-CSF as opposed to 46% in the control arm (P = .01). Accordingly, chemotherapy was completed significantly earlier with the use of G-CSF (39 v 44 days, P = .008). With a median follow-up of 20 months, the probability of disease-free survival was 0.45 in the G-CSF group and 0.43 in the control group (P = .34). In conclusion, adult ALL patients appear to benefit by the simultaneous administration of G-CSF with induction chemotherapy because of a significant reduction in the duration of neutropenia, a trend to fewer infections, and a more rapid completion of chemotherapy.     

Myeloid progenitor cell growth characteristics and effect of G-CSF in a patient with congenital cyclic neutropenia.

A 17-year-old male with congenital cyclic neutropenia was treated with recombinant human granulocyte colony stimulating factor (G-CSF) administered subcutaneously at 1 to 2 micrograms/kg per day. The peak and nadir counts of neutrophils and the peak counts of monocytes were significantly elevated, and the period of cycling decreased from 3 to 2 weeks. Bone marrow culture studies revealed the following abnormalities in granulocytic progenitor cells (CFU-G): a decrease in the concentrations of G-cluster forming cells, stimulated by a maximal dose of G-CSF, and a tendency of abnormally low responsive growth of the CFU-G to lower concentrations of G-CSF and GM-CSF. Our findings suggest that administration of G-CSF at relatively low doses overcomes or compensates for these abnormalities, though not completely, as fluctuation in the neutrophil counts persisted.