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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the City of Hope/Samaritan Bone Marrow Transplant
Program, Good Samaritan Regional Medical Center, Phoenix, AZ; the
Division of Immunologic and Infectious Diseases and the Division of
Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA;
the Division of Hematology, The Hospital for Sick Children, Toronto,
Ontario, Canada; and the Division of Pediatrics, Duke University
Medical Center, Durham, NC.
The purpose of this study was to evaluate the efficacy and
toxicity of recombinant human granulocyte colony-stimulating factor (rhG-CSF) therapy in patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease (GSD) type 1b. Thirteen patients with neutropenia and/or neutrophil dysfunction secondary to GSD type 1b were treated with rhG-CSF. The effects of
therapy on neutrophil numbers and in vitro neutrophil function and on
bone marrow cellularity and morphology were studied. The clinical
status of the patients and the occurrence of adverse events associated
with rhG-CSF use were monitored. Use of rhG-CSF therapy was associated
with a significant increase in circulating neutrophil numbers
(P < .01) and an improvement in neutrophil function as
assessed in vitro. In addition, rhG-CSF therapy produced a significant
increase in marrow cellularity and an increase in myeloid:erythroid
(M:E) ratio, indicating stimulation of granulopoeisis. No adverse
effects on marrow function were noted; in particular, no myelodysplasia
or marrow exhaustion was seen. Use of rhG-CSF therapy was
associated with objective and subjective improvements in
infection-related morbidity. The therapy was well tolerated, although
all patients developed splenomegaly, and 5 patients developed mild hypersplenism that did not require any specific treatment. rhG-CSF
therapy is efficacious in the management of neutropenia and neutrophil
dysfunction associated with GSD type 1b. Patients on this therapy need
to be monitored for hypersplenism. Continued follow-up will be
necessary to confirm long-term safety; however, no significant
short-term toxicity was noted.
(Blood. 2001;97:376-382) Glycogen storage disease (GSD) type 1b results from
a deficiency of the glucose-6-phosphate translocase enzyme. This enzyme transports glucose-6-phosphate into the lumen of the endoplasmic reticulum, where it is hydrolyzed by glucose-6-phosphatase into glucose
and inorganic phosphate.1 Absence of the translocase, therefore, results in an inability to liberate glucose from
glucose-6-phosphate that may be derived from either glycogenolysis or
gluconeogenesis. Consequently, patients with GSD type 1b are dependent
on dietary carbohydrate to maintain euglycemia and are susceptible to
fasting hypoglycemia and lactic acidosis. Hypoglycemia may cause coma and seizures; however, neurological damage is uncommon because the
brain is protected by its ability to metabolize lactic acid. Other
features of GSD type 1b include hepatomegaly, anemia, poor linear
growth, and delayed pubertal development.2 Anemia is of
uncertain etiology, but it is likely to be multifactorial. Contributing
factors could include chronic or recurrent infection; inflammatory
bowel disease; and nutritional deficiencies of iron, vitamin B12, or
folic acid. Poor growth and delayed development seem to be caused by an
excess of counter-regulatory hormones, such as cortisol, that are
secreted during chronic hypoglycemia.
In addition to the above features, patients with GSD type 1b frequently
have neutropenia and/or neutrophil dysfunction and are consequently
susceptible to recurrent infections. Infections most commonly involve
the skin, perirectal area, ears, and urinary tract; however, severe or
life-threatening infections, such as sepsis, pneumonia, and meningitis,
may also occur. The most frequently isolated organisms include
Staphlococcus aureus, group A streptococci, Streptococcus pneumoniae, Escherichia coli, and
the Pseudomonas species.3 The etiology of
neutropenia and neutrophil dysfunction are not known; however, bone
marrow aspirates performed on some GSD type 1b patients with
neutropenia have revealed hypocellularity with a myelocyte:erythrocyte
(M:E) ratio of less than 3:1 and maturation arrest beyond the
myelocytic stage.3 These findings suggest that at least in
a proportion of the patients, impaired granulopoiesis may underlie the
observed neutropenia. Defects in neutrophil chemotaxis and
intracellular bacterial killing have also been reported in patients
with GSD type 1b and probably contribute to the observed infection
risk.4-7 Defective intracellular bacterial killing is
associated with diminished respiratory burst activity following
phagocytosis.8 These and other neutrophil function defects
may be related in part to impaired calcium mobilization and diminished
calcium stores, which result in impaired signaling in phagocytic
cells.9,10
Recombinant human granulocyte colony-stimulating factor (rhG-CSF)
has in vitro activity which is identical to that of highly purified
human G-CSF.11 This activity includes support of growth of
bone marrow-derived colony-forming unit granulocyte-macrophage (CFU-GM) in methylcellulose culture; enhanced neutrophil-mediated, antibody-dependent cellular cytotoxicity; and induction of the expression of chemotactic receptors on mature granulocytes. These observed activities suggest that rhG-CSF therapy may be beneficial for
patients with GSD type 1b and neutropenia and/or neutrophil dysfunction. Clinically, administration of rhG-CSF has been associated with improved neutrophil numbers and a reduction in the severity and
frequency of infection in patients with chronic severe neutropenia from
a variety of causes.12 Although there are case reports of
G-CSF or GM-CSF use in patients with GSD type 1b,10,13,14 cytokine therapy has not been adequately studied in this group of patients.
Because the etiology of the neutropenia and neutrophil dysfunction in
patients with GSD type 1b is unknown and because cytokine therapy can
be associated with both acute and late side effects, it is imperative
to document that such therapy is beneficial before recommending routine
use of cytokines in these patients. This is, to the best of our
knowledge, the first time that cytokine therapy has been evaluated
systematically in a relatively large group of patients with this disorder.
The study, which was conducted in 3 stages, had a total duration
of 3 years. During stage I (historical data period), careful history
and review of clinical records were performed. Patients with a
confirmed diagnosis of GSD type 1b were eligible for enrollment if they
had a history of recurring infection and (1) severe neutropenia (defined as an absolute neutrophil count
[ANC] < 0.5 × 109 cells/L on at least 3 occasions
for a minimum of one month) and/or (2) documented neutrophil
dysfunction (as defined by any in vitro assay performed at each
patient's local institution). Several of our patients had received
treatment with G-CSF or GM-CSF prior to commencement of the trial.
These patients were eligible for enrollment provided that historical
data were available to confirm the presence of recurring infection and
severe neutropenia and/or neutrophil dysfunction before the use of
cytokine therapy.
During stage II (dose-equilibration period), patients were given
an initial subcutaneous dose of 2.5 µg/kg/d rhG-CSF. If the mean ANC in the subsequent 2-week period was less than
1.0 × 109 cells/L, the dose was escalated to 5 µg/kg/d
for the next 2 weeks. Subsequent dose escalations to 10, 20, and 30 µg/kg were permitted after 2 weeks of therapy at the previous dose
level if the mean ANC remained at less than 1.0 × 109
cells/L. After reaching the highest dose level (30 µg/kg), therapy could be continued for up to 6 weeks in patients with an ANC remaining at less than 0.5 × 109 cells/L. Patients were considered
treatment failures if after 6 weeks of therapy at the highest dose
level, the ANC failed to increase more than 0.5 × 109
cells/L; rhG-CSF was then discontinued.
During stage III (maintenance period), patients received rhG-CSF at the
lowest dose required to maintain a neutrophil count of more than
1.0 × 109 cells/L. During stage III, dose adjustments
were permitted for patients who experienced a decline in their
ANC < 1.0 × 109 cells/L for 3 consecutive readings or
who experienced an increase in their ANC > 10.0 × 109
cells/L for 3 consecutive readings. Doses were escalated according to
the schedule outlined in the dose-equilibration period for patients
with a low ANC, and doses were decreased by 1 µg/kg per dose every
second week for patients with an elevated ANC.
Bone marrow aspirates were performed prior to study entry, at 3 months
after start of treatment, at one year after start of treatment, and
annually thereafter. Bone marrow aspirates were assessed for
cellularity, morphology, M:E ratio, and postmitotic:mitotic ratio. The postmitotic:mitotic ratio, computed as
neutrophils + bands + metamyelocytes / myelocytes + promyelocytes + blasts, is reduced in patients with maturation arrest. This is therefore a useful test of the effect of therapy on
granulopoeisis.15 Marrow aspirates were sent for
chromosome analysis at the same time points.
Neutrophil and monocyte function was assessed in vitro by measuring the
production of oxygen radicals (superoxide anion
[O2 During the study patients were monitored for infection, antibiotic use,
and hospitalization. In addition, patients were evaluated for the
presence of oral ulcers, gingivitis, periodontal disease, otitis media,
and skin infections. A complete physical examination, including
assessment of liver and spleen size, was performed at each clinic
visit. Patients were asked to maintain a diary to assess compliance and
subjective response to therapy. The Research Ethics Board or
Institutional Review Board of each of the participating institutions
approved this study. Informed consent was obtained from all patients or
their parents.
Statistical analysis
Data concerning neutrophil and monocyte function were considered
in aggregate. Correction of respiratory burst activity to normal levels
(ie, 100% of control) was considered to be a CR. An improvement of
more than 50% over baseline was considered to be a PR, whereas an
improvement of less than 50% was considered NR. Data concerning
antibiotic use and infection were obtained by history and were not
necessarily complete; therefore it was not possible to quantify
antibiotic use or to quantify the frequency or severity of infection in
the prestudy and on-study periods. Consequently, statistical analysis
of the effect of therapy on infection was not possible. To
estimate clinical efficacy, we used patients who had a history of at
least one hospital admission for intravenous (IV) antibiotic therapy to
treat suspected or documented infection within the 12-month period
prior to the start of any cytokine therapy. These patients were
considered to have had an objective clinical response (OCR) if they
were not hospitalized for treatment of suspected or documented
infection during the 3-year study period. The patients were considered
to have had no clinical response (NCR) if at least one hospital
admission for treatment of suspected or documented infection occurred
during the study period. In addition, patients were asked to
subjectively rate the frequency and severity of oral ulceration,
gingivitis, and oral antibiotic usage for non-life-threatening
infections. Patients were considered to have had a response if their
subjective evaluation indicated an improvement in these symptoms.
Patient population
rhG-CSF dosage The mean starting rhG-CSF dose was 2.7 µg/kg/d, and the mean steady-state dose was 5.2 µg/kg/d, with a dose range of 3-7.5 µg/kg/d.Neutrophil responses ANC data are shown in Table 2. Twelve patients were evaluable for neutrophil responses. Eleven (92%) of these 12 patients had a CR as defined previously, and one patient (8%) had a PR. For the whole group, the mean pretherapy ANC = 0.46 × 109 cells/L, and the mean ANC during the maintenance phase was 2.43 × 109 cells/L (P < .01).
We have previously demonstrated markedly reduced oxygen radical
production in response to a variety of different stimuli in both
neutrophils and monocytes from GSD type 1b
patients.8-10,13,16 Neutrophils and monocytes were
isolated from 11 of our patients at various times through the course of
rhG-CSF therapy, and O2
Changes in bone marrow morphology Bone marrow aspirates were evaluated for morphology, cellularity, differential counts, postmitotic:mitotic ratio, and M:E ratio. We reviewed paired pretherapy and maintenance therapy bone marrow aspirates that were available for 9 patients. Results for these 9 patients are shown in Table 4. The cellularity was normal in 2 patients and increased in 7 of these 9 patients prior to therapy. Three patients showed maturation arrest in the granulocyte series at the band, metamyelocyte, or myelocyte stage and a marked paucity of mature forms during pretherapy, and 6 patients showed normal granulopoiesis with all stages of maturation during pretherapy. During maintenance therapy all 9 patients had normal granulopoiesis with all stages of maturation. Prior to therapy the segmented neutrophils expressed as a percentage of the bone marrow differential count was a mean of 16% (range, 3% to 44%). This increased to 25% (range, 11% to 35%) during the maintenance phase of therapy.
The mean pretherapy post-mitotic:mitotic ratio for our patients was 2.7:1 (range, 0.6:1 to 7:1). The post-mitotic:mitotic ratio did not change significantly during the maintenance phase of therapy (mean, 2:1; range, 0.7:1 to 5.5:1). The mean pretherapy M:E ratio for our patients was slightly elevated at 4.3:1 compared with the normal value of 3:1.17 For each patient the M:E ratio increased during rhG-CSF therapy, and for the whole group the mean M:E ratio increased to 6.5:1. None of the patients showed changes consistent with a diagnosis of myelodysplasia or developed cytogenetic abnormalities in the marrow during therapy. Effects of rhG-CSF on infection-related morbidity Infection-related morbidity is summarized in Table 5. Of the 11 patients who had at least one hospitalization for IV antibiotics prior to study enrollment, 8 patients were not hospitalized during the study, and the objective CR rate was 73%. Two of the 3 patients with NCR had one hospital admission each for IV antibiotic therapy. One of these patients (UPN 25), who had a history of meningitis with brain abscess and recurrent pneumonia requiring frequent hospitalization prior to rhG-CSF therapy, was admitted on only one occasion, for treatment of suspected pneumonia, while on therapy. A second patient (UPN 35) was admitted for treatment of periodontal abscess, which occurred at a time when his neutrophil count had dropped to less than 0.5 × 109 cells/L during the maintenance phase of therapy. The remaining patient (UPN 31) had frequent hospitalizations for fever, which were usually associated with neutropenia. The neutropenia promptly resolved in hospital with supervised administration of rhG-CSF, which called this patient's compliance with therapy into question.
Eleven patients had a history of recurrent oral ulceration and/or gingivitis prior to rhG-CSF therapy. The 2 patients without a positive history were both 8 months of age at study entry. All patients with a positive history reported an improvement in the duration and frequency of oral ulceration, and 3 patients had a complete resolution, with no oral ulceration occurring during the study. All 13 patients had a history of recurrent oral antibiotic use for treatment of superficial infections, and all patients subjectively reported a decrease in the incidence and frequency of oral antibiotic usage. One patient (UPN 23), who had been diagnosed with Crohn's disease prior to therapy, experienced a resolution of symptoms. This is consistent with previous case reports.18 Toxicity Adverse events experienced by the patients in this trial are summarized in Table 6. None of the patients experienced injection site reactions such as redness or swelling. Three patients had transient systemic symptoms including headache, muscle aches, nausea, and bone pain, all of which were mild and resolved with continued therapy. Although none of the patients had splenomegaly prior to therapy, all patients developed splenomegaly while on therapy, usually within 3 months of beginning therapy.
Splenomegaly was dramatic, with spleen tips palpable up to 13 cm below the costal margin (range, 3-13 cm). We defined hypersplenism as thrombocytopenia (platelet count less than 150 × 109 cells/L) present on at least 2 consecutive complete blood counts at least one month apart, in association with splenomegaly. Five patients developed hypersplenism by these criteria. Thrombocytopenia was mild, with the lowest recorded platelet counts ranging between 74 and 114 × 109 cells/L. Platelet counts tended to fluctuate during the course of therapy. One patient (UPN 31) had a splenectomy to treat chronic anemia that was presumed to be hemolytic in nature. This patient's lowest recorded platelet count was 85 × 109 cells/L, and this was recorded 16 months prior to splenectomy. At the time of splenectomy, the platelet count was normal at 225 × 109 cells/L. This patient's spleen showed sinusoidal hyperplasia with large numbers of neutrophils including some immature forms, but the spleen showed no other abnormality. These findings were interpreted as consistent with trapping of neutrophils in the spleen. The anemia did not resolve following splenectomy and was subsequently diagnosed as being secondary to vitamin B12 deficiency. No other patient required therapy to manage thrombocytopenia, and no patient had a bleeding complication. Eleven (85%) of 13 patients experienced a marked left shift in circulating neutrophils at some point during the course of therapy. Three patients (23%) developed what could be described as a leukoerythroblastic response, with blast cells being detected in the circulation. In all 3 patients the leukoerythroblastic response was transient. In one patient, rhG-CSF was temporarily discontinued and then resumed at a lower dose following resolution of the leukoerythroblastic response. One patient (UPN 22), who was 8 months old at the time of enrollment, was noted to have macrocephaly, with a head circumference just above the 97th percentile for age. Computed tomography and magnetic resonance image scanning of this patient's head revealed that widening of the diploic spaces, presumably due to myeloid hyperplasia, was the cause for this mild macrocephaly. This patient's maximum and steady-state rhG-CSF dose was 5 µg/kg/d, and no dosage adjustments were made because the macrocephaly was considered to be trivial. Hemoglobin and hematocrit values for our patients are presented in
Table 7. We defined anemia as either a
hemoglobin or hematocrit below the age- and sex-appropriate reference
range on at least 2 consecutive complete blood counts at least one
month apart. By these criteria, 9 of our patients were anemic at some
point during the study; however, 8 of these 9 patients were already anemic prior to study enrollment. For the whole group, the hemoglobin at study entry ranged from 77-130 g/L (mean, 105 g/L), and the lowest
recorded hemoglobin during the study ranged from 66 to 113 g/L (mean,
86 g/L). Although these differences did not appear to be significant,
we cannot exclude the possibility that the splenomegaly may have
exacerbated the anemia in some of the patients. As was the case with
thrombocytopenia, the anemia tended to fluctuate during the course of
therapy. As mentioned previously, patient UPN 31 underwent splenectomy
in part to treat anemia; however, the anemia persisted after the
splenectomy.
Twelve (92%) of the 13 patients completed the study. One patient (UPN 23) withdrew after nearly 3 years because he was concerned about the risk of myelodysplasia and hypersplenism. The remaining 12 patients all chose to remain on the drug following completion of the study.
GSD type 1b is associated with both neutropenia and neutrophil
dysfunction, which predispose patients to recurrent and sometimes severe or life-threatening infection. Use of rhG-CSF can stimulate marrow granulopoiesis and increase neutrophil production, but in
addition it can enhance neutrophil function both in vivo and in vitro.
In this study we prospectively evaluated the efficacy and toxicity of
rhG-CSF therapy in patients with GSD type 1b. Our results show that
patients with GSD type 1b and neutropenia or neutrophil dysfunction
experience significant increases in ANC and improvement in in vitro
neutrophil function, as assessed by O2 The increased ANC results, in part, from increased marrow granulopoiesis, as indicated by an increase in marrow cellularity, M:E ratio, and mature granulocyte percentage noted on marrow differential counts following initiation of therapy. Interestingly, the cellularity and M:E ratios were already normal or perhaps mildly elevated in the majority of our patients prior to therapy, and the post-mitotic:mitotic ratio did not indicate a maturation arrest. These findings are in contrast to previous reports5 and seem to suggest that in some patients with GSD type 1b, the neutropenia may not result from an underproduction by the bone marrow, but rather the neutropenia may result from a failure to release mature granulocytes into the blood stream or from failure to mobilize marginating granulocyte pools. rhG-CSF may increase ANC in these patients by affecting neutrophil trafficking. The use of rhG-CSF therapy significantly enhanced phagocytic cell
production of O2 Our study did not follow a prospective, randomized placebo-controlled design. In addition, we were not able to quantify the frequency or severity of infection or antibiotic use, and so comments on the clinical utility of rhG-CSF therapy for these patients need to be made with some caution. The majority of our patients did, however, experience both objective and subjective improvement in infection-related morbidity. In particular, the frequency of hospital admission for IV antibiotic therapy to treat suspected or documented infection declined significantly. In fact, only 2 patients had documented invasive bacterial infection while on the study. Both of these patients were neutropenic at the time of infection, which suggests that compliance with therapy and careful monitoring to maintain an ANC > 1.0 × 109 cells/L may be critical to obtain optimum effectiveness. To be sure, many of the pretherapy admissions for IV antibiotics were possibly precautionary because of fever in the presence of neutropenia or known neutrophil dysfunction; however, the freedom from hospitalization following therapy still represents a significant improvement in status for these patients. In addition, all patients reported subjective improvements in frequency and severity of oral ulceration, gingivitis, superficial infection, and oral antibiotic usage. These data strongly suggest that rhG-CSF is clinically efficacious in reducing the incidence and severity of infection in patients with GSD type 1b. Such an improvement would not be unexpected based on the observed effects of therapy on neutrophil numbers and function, and would be consistent with results from previous case reports16,17 in which the use of G-CSF or GM-CSF was associated with improvement in neutropenia and clinical status in patients with GSD type 1b. The dose of rhG-CSF required by our patients was low (range, 3-7.5 µg/kg/d), and the medication was well-tolerated. There were no identified adverse effects of therapy on marrow function. In particular, myelodysplasia or marrow exhaustion was not encountered; however, it should be noted that this study comprised a small group of patients and a relatively short follow-up. Three patients who showed maturation arrest in granulopoiesis with a relative paucity of mature granulocytic forms experienced correction to normal morphology while on therapy. Mild to moderate anemia was seen frequently in our patients, both prior to and after initiation of rhG-CSF. This is consistent with previous reports. For example, in a series of 5 adult patients with GSD type 1b, none of whom were receiving cytokine therapy, all 5 patients were anemic.2 Although hemoglobin and hematocrit values were not provided for the GSD type 1b patients, in the same report, such data were provided for 32 adult patients with GSD type 1a; 26 (81%) of these 32 patients were anemic. For men the hemoglobin concentrations ranged from 64-144 g/L (average, 115 g/L), and hematocrits ranged from 22.2% to 43.3% (average, 35.1%). For women the hemoglobin concentrations ranged from 80-129 g/L (average, 108 g/L), and the hematocrits ranged from 27.4% to 39.8% (average, 32.8%). These values are similar to values observed in our patients prior to and during the study. Although we cannot be certain that hypersplenism did not contribute to the anemia, a direct effect of rhG-CSF seems unlikely. The Severe Chronic Neutropenia Registry has data on over 700 patients who have received G-CSF for up to 12 years, and G-CSF therapy has not been noted to adversely affect hemoglobin levels (M. H. Freedman, director of the Severe Chronic Neutropenia Registry, oral communication, March 2000). The splenomegaly we have observed is of some concern. This side effect of rhG-CSF therapy seems to be peculiar to patients with GSD type 1b, and its etiology is unclear. One of our patients underwent splenectomy, and histological evaluation of the spleen showed only sinusoidal hyperplasia with trapping of neutrophils. Thrombocytopenia associated with splenomegaly has been mild, not associated with any bleeding diathesis, and has generally tended to wax and wane during the course of therapy; therefore, unless thrombocytopenia was severe and persistent, we would not recommend splenectomy or dosage adjustment in those patients with splenomegaly. None of our patients developed Sweet syndrome or complications other than those mentioned previously.27 In conclusion, our data confirm the short-term safety and efficacy of rhG-CSF therapy for GSD type 1b patients. However, continued monitoring and long-term follow-up will be required to ensure that this therapy has no significant late effects.
Supported by a research grant (no. 930145) from Amgen Corporation, Thousand Oaks, CA.
Submitted June 8, 2000; accepted September 6, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Stanley Calderwood, City of Hope National Medical Center, Department of Pediatrics, 1500 E Duarte Rd, Duarte, CA 91010; e-mail: scalderwood{at}coh.org.
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 T. W. Kuijpers, N. A. Maianski, A. T. J. Tool, G. P. A. Smit, J. P. Rake, D. Roos, and G. Visser Apoptotic neutrophils in the circulation of patients with glycogen storage disease type 1b (GSD1b) Blood, June 15, 2003; 101(12): 5021 - 5024. [Abstract] [Full Text] [PDF]
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R. Leuzzi, G. Banhegyi, T. Kardon, P. Marcolongo, P.-L. Capecchi, H.-J. Burger, A. Benedetti, and R. Fulceri Inhibition of microsomal glucose-6-phosphate transport in human neutrophils results in apoptosis: a potential explanation for neutrophil dysfunction in glycogen storage disease type 1b Blood, March 15, 2003; 101(6): 2381 - 2387. [Abstract] [Full Text] [PDF]
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| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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Abstract
Introduction
] generation) in response to phorbol
myristate acetate (PMA) and the chemotactic peptide
f-methionine-leucine-phenylalanine (fMLF). We measured
O2