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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2719-2724
Successful Treatment of Invasive Aspergillosis in Chronic
Granulomatous Disease by Bone Marrow Transplantation, Granulocyte
Colony-Stimulating Factor-Mobilized Granulocytes, and Liposomal
Amphotericin-B
By
Hülya Ozsahin,
Maya von Planta,
Irene Müller,
Hans C. Steinert,
David Nadal,
Roger Lauener,
Peter Tuchschmid ,
Ulrich
V. Willi,
Mahmut Ozsahin,
Nigel E.A. Crompton, and
Reinhard A. Seger
From the Divisions of Immunology/Hematology and Radiology, University
Children's Hospital of Zurich; the Division of Nuclear Medicine, the
University Hospital of Zurich, Zurich, Switzerland; and the Department
of Life Sciences, Paul Scherrer Institute, Villigen, Switzerland.
 |
ABSTRACT |
X-linked chronic granulomatous disease (X-CGD) is a primary
immunodeficiency with complete absence or malfunction of the
nicotinamide adenine dinucleotide phosphate (NADPH)
oxidase in the phagocytic cells. Life-threatening infections especially
with aspergillus are common despite optimal antimicrobial therapy. Bone
marrow transplantation (BMT) is contraindicated during invasive
aspergillosis in any disease setting. We report an 8-year-old patient
with CGD who underwent HLA-genoidentical BMT during invasive multifocal aspergillus nidulans infection, nonresponsive to treatment with amphotericin-B and  -interferon. During the first 10 days post-BMT, the patient received granulocyte colony-stimulating factor
(G-CSF)-mobilized, 25 Gy irradiated granulocytes from healthy
volunteers plus G-CSF beginning on day 3 to prolong the viability of
the transfused granulocytes. This was confirmed in vitro by apoptosis
assays and in vivo by finding nitroblue tetrazolium
(NBT)-positive granulocytes in peripheral blood 12 and 36 hours after the transfusions. Clinical and biological signs of
infection began to disappear on day 7 post-BMT. Positron emission
tomography with F18-fluorodeoxyglucose (FDG-PET) and computed
tomography (CT) scans at 3 months post-BMT showed complete
disappearance of infectious foci. At 2 years post-BMT, the patient is
well with full immune reconstitution and no sign of aspergillus
infection. Our results show that HLA-identical BMT may be successful
during invasive, noncontrollable aspergillus infection, provided that
supportive therapy is optimal.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
CHRONIC GRANULOMATOUS disease (CGD) is a
primary immunodeficiency resulting from complete absence or malfunction
of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in
the phagocytic cells, eg, neutrophils, monocytes, macrophages, and
eosinophils. Deficiency of this oxidase causes a marked reduction or
complete extinction of the phagocyte respiratory burst resulting in
defective microbial killing. As a consequence, the patient is
susceptible to recurrent bacterial and fungal infections. The major
clinical manifestations are pyoderma, pneumonia, gastrointestinal
involvement, lymphadenitis, liver abscess, and osteomyelitis. Although
the prognosis of CGD has markedly improved due to increased awareness of the disease with prompt and aggressive treatment of the infections, lifelong antibiotic prophylaxis and -interferon therapy, patients are still susceptible to life-threatening infections especially from
pathogens like Aspergillus spp.1-4 Based on the
observation that granulocyte colonies derived from progenitor cells of
CGD patients demonstrate defective oxidative metabolism, bone marrow transplantation (BMT) has been used in a dozen patients since 1976 with
varying results.5-12 Generally speaking, BMT from a histocompatible donor resulted mostly in the cure of the disease, provided that the patient was transplanted early, in an infection-free interval. Invasive aspergillosis is a universal contraindication for
BMT for fear of overwhelming aspergillus sepsis and death during
aplasia.13 We now present a case with CGD transplanted from
his histocompatible sister during invasive aspergillus infection, noncontrolled by conventional treatment, and wish to challenge this
view.
| |
MATERIALS AND METHODS |
Patient.
An 8-year-old boy with X-linked CGD (G828 A mutation in exon
VIII resulting in a premature translation stop at amino acid position
272 and complete gp91-phox deficiency) was hospitalized because of
pneumonitis. The patient had been under cotrimoxazole prophylaxis since
the diagnosis at 8 months of age, and additionally under itraconazole
prophylaxis since 3 years of age. No serious infections occurred until
the age of 7 years when he developed a lingula pneumonitis after having
stopped itraconazole for 4 weeks. After 5 months of unsuccessful
treatment with various antibiotics, cultures taken from bronchoalveolar
lavage showed growth of Aspergillus nidulans (A
nidulans). The patient was treated for another 5 months with
conventional amphotericin-B and -interferon, without improvement. Lingulectomy was performed with subsequent reisolation of A
nidulans from excised lung tissue and pleural swabs. All
isolates were susceptible to amphotericin-B and itraconazole, as
determined by broth dilution method (MIC = 0.25 mg/L for conventional
amphotericin, 0.25 mg/L for itraconazole, 1 to 2 mg/L for liposomal
amphotericin B; AmBisome; Nexstar, San Dimas, CA). A second infectious
agent, Actinomyces viscosus (A viscosus), was also
repeatedly isolated from the previous bronchoalveolar lavage as well as
from that performed during lingulectomy. These isolates were all
susceptible to ciprofloxacin (MIC = 3 mg/L). The patient was
administered liposomal amphotericin B (8 mg/kg/d) together with
-interferon after surgery. He was treated with ciprofloxacin (20 mg/kg/d) since the first isolation of A viscosus. Two months
after lingulectomy and while under this treatment, the patient
developed persistent fever, tachydyspnoea, and severe lumbar pain.
Whole-body positron emission tomography (PET) using
F18-fluorodeoxyglucose (FDG) demonstrated five hypermetabolic foci
(Fig 1). Four of these were pulmonary consolidations, one directly extending to the adjacent chest wall with
osteolytic changes of the sixth rib leading to fistula formation into
the skin. The fifth focus was a psoas abscess causing the excruciating
pain and showed A nidulans on computed tomography (CT)-guided
needle puncture. All PET lesions were seen in the corresponding CT
images. There was no epidural extension as shown by CT and PET. These
findings demonstrated that the conservative treatment had been
unsuccessful. We elected to perform an emergency BMT from the
HLA-genoidentical sister of the patient.
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| Fig 1.
(A and B) Coronal emission FDG-PET scan before BMT. PET
shows multiple inflammatory lesions in the lungs and an inflammatory
focus in the upper left psoas with an intense FDG uptake. Physiologic
high FDG uptake is seen in the brain, kidneys, and bladder. (C, D, and
E) Axial transmission corrected FDG-PET image and corresponding CT
images. Both PET and CT show inflammatory lesions in the left lung
invading a rib and in the left psoas. (F) Coronal emission FDG-PET scan
3 months after BMT. Hypermetabolic lesions have disappeared.
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Bone marrow transplantation.
The parents were extensively informed and gave their full consent for
BMT. The patient was transplanted from his 5-year-old HLA-genotypically
identical sister, a heterozygous carrier for CGD. Conditioning regimen
consisted of busulfan with a total dose of 16 mg/kg body weight (days
 9 to 6), and cyclophosphamide with a total dose of 200 mg/kg body weight (days 5 to 1). Gut decontamination was
performed by oral vancomycin, polymyxin B, ciprofloxacin, and
amphotericin B. Graft-versus-host disease (GVHD) prophylaxis consisted
of cyclosporin-A only. Erythrocyte-depleted bone marrow was transfused
with a total of 4 × 108 nucleated cells/kg
recipient body weight. The patient was placed in a laminar air flow
unit. To prevent further dissemination of aspergillus infection during
aplasia and until full cellular immune reconstitution, liposomal
amphotericin B was administered at 8 mg/kg/d.
Granulocyte transfusions.
During aplasia, G-CSF (granulocyte-colony stimulating factor; Neupogen,
Roche-Pharma AG, Switzerland) -mobilized, irradiated granulocytes from
healthy donors were transfused. Because G-CSF significantly increases
the quantity of granulocytes by threefold to 10-fold compared with
historical controls with steroid-mobilized granulocyte
collections,14,15 each donor was administered G-CSF at 5 µg/kg subcutaneously (SC) the night before granulocyte
collection. Leukapheresis was performed on the CS-3000 Plus Blood Cell
Separator (Baxter, Deerfield, IL). For each collection, 5 to 7 L of
acid citrate dextrose formula-A (ACD-A) anticoagulated
blood were processed by continuous-flow centrifugation at a flow-rate
of 50 mL/min. Red blood cells were sedimented by hydroxyethyl starch
(Plasmasteril 6%, Fresenius, Bad Homburg, Germany; 1:13
vol/vol). The final product was tested for complete blood count
and was irradiated with 25 Gy. Informed consent for G-CSF mobilization
was obtained from the three donors, two of whom were family
members with normal functioning NADPH oxidase. G-CSF was well
tolerated by the donors.
G-CSF administration to the patient.
In vitro tests have shown that neutrophils, when incubated with G-CSF,
can be protected from the premature onset of apoptosis triggered by
isolation procedure and irradiation.16-18 Based on these in
vitro studies, beginning on day 3 posttransplant, we administered the
patient G-CSF (10 µg/kg/d, 30-minute intravenous infusion) in
combination with granulocyte transfusions.
Granulocyte function tests.
The oxidative metabolism of the transfused granulocytes was tested in
the blood samples taken from the patient at 12 and 36 hours, as well as
in the sputum samples collected at 12, 36, and 60 hours after the end
of granulocyte transfusions. The metabolic function of cells maturing
from the transplanted bone marrow was tested by NBT, superoxide
formation, as well as cytochrome-b spectrum, and immunofluorescence.
NBT reduction.
This was performed as previously reported19 with
106 polymorphonuclear cells (PMN) in a final
volume of 1 mL. Phorbol myristate acetate (PMA; 200 ng/mL final
concentration) and opsonized zymosan particles (OPZ; 150 µg/mL final
concentration), respectively, were used for stimulation.
Superoxide formation.
This was measured at 37°C as the superoxide-dismutase (SOD)
sensitive reduction of cytochrome c. The assay was performed with 106 neutrophils in 1 mL Hanks' Balanced Salt Solution with
0.5% human serum albumin, 10 mmol/L glucose, and 85 µmol/L
cytochrome c. Stimulation of O2
formation was performed with both PMA (100 ng/mL) and
N-formyl-methionyl-leucyl-phenylalanine (fMLP; 1 µmol/L),
respectively. Absorbance changes were recorded in a single-beam
Hewlett-Packard 8452 A diode array spectrophotometer (Basel,
Switzerland).20
Optical heme (Cytochrome-b558) spectrum.
Cytochrome-b558 was extracted from frozen cell pellets (30 × 106 PMN) in 500 µL solubilization buffer (20 mmol/L HEPES, 4 mmol/L MgCl2, 2 mmol/L phenylmethylsulfonyl
fluoride, 2% Triton X-100). Nuclei and nondissolved cell components
were removed by centrifugation at 5,400g for 5 minutes. To
eliminate contaminating hemoglobin, 450 µL of the supernatant was
incubated on ice for 15 minutes with 50 µL of haptoglobin coupled to
sepharose 4B. The haptoglobin-sepharose was sedimented in an Eppendorf
centrifuge, and the cytochrome-b content of the extract was measured by
determination of the reduced-minus-oxidized spectrum on a single-beam
Hewlett-Packard 8452 A diode array spectrophotometer. For calculations,
an extinction coefficient of 106 mmol/L/cm for the Soret
band was used. This technique is described in detail
elsewhere.21 Fluorescence-activated cell sorting (FACS) analysis of the cytochrome-b558 small subunit was performed
as previously reported.22
Granulocyte apoptosis assay.
Granulocytes obtained from one leukapheresis product and granulocytes
obtained from fresh blood samples from healthy volunteer donors were
investigated. Granulocytes from fresh blood were separated from the
lymphocyte fraction following density centrifugation with Lymphoprep
(Mycomed, Oslo, Norway). The samples were first incubated with or
without G-CSF for 24 hours (1:10 dilution RPMI with 20% fetal bovine
serum, G-CSF: Neupogen [Roche-Pharma AG]; 2 µg/mL final
concentration),16,23 then irradiated at 0 or 25 Gy, and,
afterwards, examined at 0, 24, and 48 hours postirradiation for
apoptosis, as previously reported.23 Briefly, the cells were centrifuged and suspended in 4 mL lysing solution (Becton Dickinson, Basel, Switzerland) for 10 minutes, centrifuged, and washed
with 4 mL phosphate-buffered saline (PBS) and centrifuged and suspended
in 200 µL FACSflow (Becton Dickinson) plus 5 µL of a 1 mg/mL
propidium iodide plus 50 µL of a 1 mg/mL RNase (Serva, Mannheim,
Germany). Flow cytometry was performed with a Becton Dickinson FACScan
flow cytometer. A total of 10,000 cells per sample was analyzed.
Analysis of cell size versus intracellular granularity permitted
initial granulocyte selection. Subsequent selection of this population
and analysis of cellular DNA content (based on propidium iodide
fluorescence) versus cell size permitted final granulocyte
identification and discrimination between viable cells having a normal
intracellular DNA content and apoptotic cells with an approximately
fivefold lower DNA content. Apoptotic cells with reduced DNA content
displayed terminal deoxynucleotidyl transferase-mediated deoxyuridine
triphosphate nick end labeling (TUNEL) and Annexin-V
staining and typical chromatin morphology.24,25 Twelve
hours before leukapheresis, G-CSF was administered to the donor at a
dose of 5 µg/kg body weight. The leukapheresis product was
subsequently irradiated (25 Gy), incubated without further additive,
and apoptosis was assessed at the time intervals indicated.
| |
RESULTS |
Granulocyte counts and functions.
The patient received four granulocyte transfusions on days 1, 4, 8, and
11 post-BMT. The mean granulocyte yield per leukapheresis was 30.8 × 109 (range, 15.2 × 109 to 55.2 × 109). Flow cytometric analysis of granulocytes of
the leukapheresis product confirmed previous findings demonstrating
protection against PMN apoptosis in the presence of G-CSF
(Fig 2). Twelve hours after the first granulocyte transfusion, 740 PMN/µL with a 97% NBT
positivity were detected. Sputum contained many NBT-positive cells.
Twelve and 36 hours after the second transfusion, blood samples
contained 97% NBT positivity in 650 and 89% NBT positivity in 270 PMN/µL, respectively. Sputum collections at the same time points also showed NBT positive PMN. Sixteen hours after the third granulocyte transfusion, there were 800 PMN/µL in the blood. On day 11, before the fourth (last) granulocyte transfusion (60 hours after the third
one), the patient had 715 granulocytes, of which 58% were NBT-positive. On day 12 (16 hours after the last granulocyte
transfusion), there were 1,500 PMN/µL with a 69% NBT positivity.
Thereafter, PMN were always above 1,000/µL, with an average of 58%
NBT-positive cells. Based on these findings, we concluded that
engraftment had taken place on day 11 post-BMT, with about half of the
PMN functioning normally, as observed in the heterozygous donor
(Table 1).
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| Fig 2.
Protective effect of G-CSF on apoptosis in irradiated
fresh blood and leukapheresis granulocytes. Granulocytes were isolated
from fresh blood, G-CSF (2 µg/mL) was immediately added to the
medium. After 24 hours, the granulocytes were irradiated (or not) and
subsequently assessed for apoptosis at the time intervals indicated.
Apoptotic cells were identified as the population of granulocytes
displaying typical reduced DNA content and reduced cell size. Percent
vital cells means the percentage of all granulocytes showing no
apoptosis in this test. The granulocytes can be divided into two
populations. There is a significant (P < .05) increase in
viability at 48 hours compared with 24 hours.
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Clinical course and correction of the underlying disease following
BMT.
The clinical course was surprisingly good with healing of
the fistula over the rib and normalization of C reactive protein (CRP)
on day 11 post-BMT (Fig 3).
Cough disappeared after the third week. Fever persisted during the
earlier weeks probably because of infection and afterwards, possibly
due to GVHD. Starting on day 49, the patient developed grade III liver
and grade I skin GVHD. In addition to cyclosporine-A, he was
administered anti-interleukin-2 (IL-2) monoclonal antibodies (MoAb)
(BB-10, BT 563, Leucotac; Biotest, Othmarsingen, Switzerland) at 0.4 mg/kg/d intravenously (IV).26 Steroids were excluded from
the GVHD treatment because of their deleterious effects on PMN
functions.27,28 The anti-IL-2 MoAb was administered daily
until day 95 and every other day until day 109. Significant regression
of the infiltration in CT and disappearance of the active inflammatory
sites in PET were observed 3 months post-BMT (Fig 1). The cellular
immune recovery was full at 4 months. Liposomal amphotericin-B was then
replaced by oral itraconazole at 10 mg/kg/d. The patient was discharged
at 5 months after BMT. At the time of preparation of this report, the
patient, 2 years post-BMT, is doing well with no sign of infection or
GVHD. He was substituted with IV immunoglobulins monthly until 12 months post-BMT. The karyotype analysis done on the mononuclear cells from peripheral blood showed 100% donor chimerism. The granulocyte function studies also demonstrate that they are of donor origin (Table
1 and Fig 4).
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| Fig 3.
Clinical course during the first 3 weeks post-BMT. CRP, C
reactive protein; G-CSF, granulocyte-colony stimulating factor; BMT,
bone marrow transplantation.
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| Fig 4.
FACS analysis of cytochrome b558 on
granulocyte membrane. (A) Control: normal granulocytes expressing
cytochrome b558. (B) Patient's granulocytes before BMT
negative for cytochrome b558. (C) Patient's sister
(heterozygous carrier and bone marrow donor) presenting two distinct
granulocyte populations, negative and positive for cytochrome
b558. (D) Patient after BMT with two granulocyte
populations negative and positive for cytochrome b558.
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DISCUSSION |
Despite adequate antifungal prophylaxis, invasive aspergillosis is now
by far the most common cause of death, accounting for about one third
to one half of the mortality in CGD.1-4 Other invasive
infections, multiple liver abscesses, and inflammatory sequelae arising
despite control of infection are the other most common causes of death.
Widespread granuloma formation in vital organs results not only in
antral gastric or urethral stenosis, but more importantly, in
granulomatous colitis, liver fibrosis, and cirrhosis, as well as lung
fibrosis and cor pulmonale.
Despite itraconazole29 and -interferon
prophylaxis,30,31 which reduce the number of aspergillus
infections; a CGD patient, at present, runs the risk of contracting
aspergillosis several times in his life. In the case of invasive
aspergillosis, the conventional treatment consists of high dose
amphotericin-B, surgery, and granulocyte transfusions. Despite
amphotericin, usually given for months because of the risk of
resurgence of persisting microorganisms, mortality still remains around
30%2-4 due to progression and dissemination into various
organ systems such as bones, vertebral bodies with subsequent spinal
paralysis, heart, and the liver. Another important unfavorable
prognostic aspect is that the disease is now entering a phase not so
much characterized by overt infections, but by chronic inflammation resulting in functional impairment of vital organs and severe disability. The patients surviving multiple aspergillus-pneumonias develop almost inevitably restrictive lung disease with lung fibrosis and cor pulmonale. At the moment, there are no means to change this
course.
We have shown for the first time that HLA-genoidentical BMT is an
alternative to conventional treatment in otherwise noncontrollable aspergillus infections, provided the aplasia period after BMT is
efficiently supported with liposomal amphotericin-B and granulocyte transfusions. Liposomal amphotericin-B is taken up quite well by the
macrophages as shown in visceral Leishmaniasis, which can now be cured
by a single course of liposomal, but not by conventional amphotericin-B.32,33 On the other hand, G-CSF
administration to both donor and recipient made the passage through the
aplasia period with only four transfusions of preactivated, long-living granulocytes possible. The apparent increase in viability probably reflects a decrease in the apoptotic fraction. At 24 hours, incubation of isolated granulocytes in the absence of G-CSF, a high fraction of
apoptotic cells was observed. This was not observed in the presence of
G-CSF or at 48 hours. It represents an early wave of excess apoptosis,
which has passed by 48 hours, and can be protected against using G-CSF.
Because we treated granulocyte donors and recipient with G-CSF at the
same time, the respective contributions of each intervention have to be
separately evaluated in a future study. To our knowledge, this is the
only study combining the in vitro assessment of apoptosis and clinical
data of G-CSF-mobilized granulocyte transfusions in an allogeneic BMT
setting. Recent studies, performed exclusively in clinical setting,
support our view that G-CSF-mobilized donor neutrophils are
functionnal and survive longer despite being irradiated in allogeneic
BMT recipients.34,35
The FDG-PET scanning, a sensitive imaging modality to evaluate tissue
glucose utilization, was used to monitor the extent and the activity of
aspergillus infection. Besides malignant tumors, inflammatory disorders
show a high FDG uptake because of their increased glucose metabolism.
In FDG-PET scanning 3 months post-BMT, a normal glucose metabolism was
seen in all known lesions in accordance with the clinical course. This
observation shows that invasive, multifocal aspergillosis should not
generally be considered a contraindication for BMT, because even in
CGD, as shown by our case, preexisting invasive multifocal aspergillus
infection can be controlled during aplasia after BMT and until cellular
immune reconstitution. Although the survival of CGD patients under
conventional therapy has improved remarkably, up to early adulthood,
quality of life is relatively poor despite life-long antimicrobial
prophylaxis. We conclude that HLA-genoidentical BMT should be
considered in patients with CGD not responding to conventional therapy
before irreversible changes have occurred.
| |
FOOTNOTES |
Deceased May 3, 1998.
Submitted October 27, 1997;
accepted June 8, 1998.
Address reprint requests to Reinhard A. Seger, MD, University
Children's Hospital, Division of Immunology/Hematology, Steinwiesstr. 75, CH-8032 Zurich, Switzerland.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We thank Dr H.P. Hossle for mutation analysis and C. Erny for
granulocyte tests, the nursing and paramedical staff of the BMT unit
for taking meticulous care of the patient and his family, and Prof U. Stauffer and his team for excellent surgical skills.
| |
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Abstract
Introduction
Abstract