Respiratory status deterioration during G-CSF-induced neutropenia recovery

Abstract

Exacerbation of prior pulmonary involvement may occur during neutropenia recovery. Granulocyte colony-stimulating factor (G-CSF)-related pulmonary toxicity has been documented in cancer patients, and experimental models suggest a role for G-CSF in acute lung injury during neutropenia recovery. We reviewed 20 cases of noncardiac acute respiratory failure during G-CSF-induced neutropenia recovery. Half the patients had received hematopoietic stem cell transplants. All patients experienced pulmonary infiltrates during neutropenia followed by respiratory status deterioration coinciding with neutropenia recovery. Neutropenia duration was 10 (4-22) days, and time between respiratory symptoms and the first day with more than 1000 leukocytes/mm3 was 1 (-0.5 to 2) day. Of the 20 patients, 16 received invasive or noninvasive mechanical ventilation, including 14 patients with acute respiratory distress syndrome (ARDS). Five patients died, with refractory ARDS. In patients with pulmonary infiltrates during neutropenia, G-CSF-induced neutropenia recovery carries a risk of respiratory status deterioration with acute lung injury or ARDS. Clinicians must maintain a high index of suspicion for this diagnosis, which requires eliminating another cause of acute respiratory failure, G-CSF discontinuation and ICU transfer for early supportive management including diagnostic confirmation and noninvasive mechanical ventilation.

Full text

Respiratory status deterioration during G-CSF-induced neutropenia
recovery
L Karlin, M Darmon, G Thie
´ry, M Ciroldi, S de Miranda, A Lefebvre, B Schlemmer and E
´Azoulay
Medical Intensive Care Unit, Saint-Louis Teaching Hospital and Paris 7 University, Assistance Publique, Ho
ˆpitaux de Paris,
Paris, France
Summary:
Exacerbation of prior pulmonary involvement may occur
during neutropenia recovery. Granulocyte colony-stimu-
lating factor (G-CSF)-related pulmonary toxicity has
been documented in cancer patients, and experimental
models suggest a role for G-CSF in acute lung injury
during neutropenia recovery. We reviewed 20 cases of
noncardiac acute respiratory failure during G-CSF-
induced neutropenia recovery. Half the patients had
received hematopoietic stem cell transplants. All patients
experienced pulmonary infiltrates during neutropenia
followed by respiratory status deterioration coinciding
with neutropenia recovery. Neutropenia duration was 10
(4–22) days, and time between respiratory symptoms and
the first day with more than 1000 leukocytes/mm
3
was 1
(0.5 to 2) day. Of the 20 patients, 16 received invasive or
noninvasive mechanical ventilation, including 14 patients
with acute respiratory distress syndrome (ARDS). Five
patients died, with refractory ARDS. In patients with
pulmonary infiltrates during neutropenia, G-CSF-induced
neutropenia recovery carries a risk of respiratory status
deterioration with acute lung injury or ARDS. Clinicians
must maintain a high index of suspicion for this diagnosis,
which requires eliminating another cause of acute
respiratory failure, G-CSF discontinuation and ICU
transfer for early supportive management including
diagnostic confirmation and noninvasive mechanical
ventilation.
Bone Marrow Transplantation (2005) 36, 245–250.
doi:10.1038/sj.bmt.1705037; published online 6 June 2005
Keywords: ARDS; mechanical ventilation; intensive care;
prognosis; cancer; hematological malignancies
Acute respiratory failure is a major cause of morbidity in
cancer patients. About 20% of patients with solid tumors
or hematological malignancies present with a respiratory
complication,
1
and pulmonary disease occurs in about half
the patients with neutropenia or bone marrow transplant-
ation. Acute respiratory failure is the main reason for ICU
admission in cancer patients;
1–4
the mortality rate ranges
from 50 to 80%, and a need for mechanical ventilation is
the main predictor of death.
5
However, recent advances
including strategies for early diagnosis, noninvasive
mechanical ventilation, and better knowledge of clinical
patterns such as leukemic pulmonary infiltration have
translated into improved outcomes.
6–9
In cancer patients, neutropenia recovery may be asso-
ciated with a deterioration in oxygenation and exacerbation
of pre-existing pulmonary disease.
10
In a previous study, we
found that the main risk factor for acute respiratory distress
syndrome (ARDS) during neutropenia recovery was the
occurrence of pneumonia during the neutropenic period.
11
Human granulocyte colony-stimulating factor (G-CSF)
is the most important regulatory cytokine capable of
stimulating neutrophil production from committed hema-
topoietic progenitor cells, both in vitro and in vivo.
12,13
G-CSF is widely used in cancer patients to reduce the
duration of chemotherapy-induced neutropenia, most
notably after peripheral blood stem cell transplantation
and lymphoma treatments. In this last case, G-CSF allows
closer spacing of chemotherapy courses, thereby substan-
tially improving the prognosis.
14,15
Although G-CSF is
generally safe and well tolerated, there have been several
reports of acute respiratory failure during G-CSF-induced
neutropenia recovery.
16,17
G-CSF is believed to enhance
cytokine production and to activate the oxidative burst
within circulating or resident alveolar neutrophils and
macrophages.
11,18
Because early diagnosis and treatment
are key determinants of survival in cancer patients with
acute respiratory failure related to neutropenia recovery, a
careful and close clinical monitoring of respiratory
symptoms (respiratory rate, heart rate, and oxygen satura-
tion) must be proposed in this condition. To help clinicians
bear in mind the increased risk of acute respiratory failure
during G-CSF-induced neutropenia recovery in cancer
patients, we describe 20 cases seen in our intensive care
unit (ICU) over a 22-month period.
Patients and methods
All patients with respiratory status deterioration during
G-CSF-induced neutropenia recovery
11
requiring admission
Received 26 November 2004; accepted 4 April 2005; published online
6 June 2005
Correspondence: Dr E
´Azoulay, Service de Re
´animation Me
´dicale,
Hoˆ pital Saint-Louis, 1 Avenue Claude VELLEFAUX, 75010 Paris,
France; E-mail: elie.azoulay@sls.ap-hop-paris.fr
Bone Marrow Transplantation (2005) 36, 245–250
&2005 Nature Publishing Group All rights reserved 0268-3369/05 $30.00
www.nature.com/bmt

to the medical ICU of the Saint-Louis Teaching Hospital,
Paris, France, between June 1, 2002 and April 1, 2004, were
prospectively included. For each patient, the following were
recorded: (a) demographics; characteristics of the cancer;
7
(b) reason for ICU admission; (c) Simplified Acute
Physiology Score (SAPS II) and Logistic Organ Dysfunc-
tion score (LOD);
19,20
(d) characteristics of respiratory
involvement, including chest radiograph changes, type of
respiratory support needed, daily values of PaO
2
/FIO
2
,
and presence of ARDS;
21
(e) duration of neutropenia, of
G-CSF administration, time from neutropenia recovery to
respiratory symptoms; and ICU-mortality.
All patients underwent a thorough evaluation to rule out
pulmonary infection. When the clinical status allowed,
bronchoscopy was performed, as previously described.
5
Bronchoalveolar lavage (BAL) specimens were sent to
laboratories for microbiological studies (bacteria, myco-
bacteria, viruses, parasites, and fungi) and cytological
studies. Microbiologically documented pneumonia was
defined as a protected distal sample culture showing
410
3
colony-forming units/ml or a BAL fluid culture
showing 410
4
colony-forming units/ml for bacterial
pneumonia, or a positive nonquantitative screen for
Aspergillus fumigatus,Pneumocystis carinii, respiratory
syncytial virus, and other respiratory viruses. Also, cultures
of blood, intravascular catheters, urine, protected distal
samples, peritoneal fluid, pleural fluid, and cerebrospinal
fluid were performed as clinically indicated.
Results are reported as medians and quartiles (25th–75th
percentiles) or numbers (%). Patient characteristics were
compared using the w
2
test or Fisher’s exact test, as
appropriate, for categorical variables and the nonpara-
metric Wilcoxon test or the Kruskal–Wallis test for
continuous variables. Vital status at hospital discharge
was available for all patients.
Results
In all, 20 patients (11 men and nine women, median age 50
(20–69) years) fulfilled our inclusion criteria. All patients
experienced acute respiratory failure during G-CSF-in-
duced neutropenia recovery. Patient characteristics are
reported in Table 1. The diagnosis was lymphoma in 10
patients (50%), leukemia in six (30%), myeloma in two
(10%), and solid tumor in two (10%). All patients received
cancer chemotherapy (Table 2) and seven also underwent
radiation therapy (including five patients given total body
irradiation). None of the patients had a diagnosis of
chemotherapy-induced pulmonary toxicity. Before ICU
admission, 8 patients (40%) received peripheral blood stem
cell transplantation after high-dose chemotherapy and two
(10%) received allogeneic hematopoietic stem cells.
ICU admission occurred 16 (4–61) days after the last
chemotherapy course. Median neutropenia duration was
10 (4–22) days and time from neutropenia recovery to
respiratory status deterioration was 1 (0.5 to 2) day.
Leukocyte counts were 300 (100–20 200)/mm
3
on the day
of ICU admission, 1700 (1000–5600)/mm
3
on the day
of neutropenia recovery, and 950 (200–20,000)/mm
3
on
the last day of G-CSF. Median duration of G-CSF was 8
(3–33) days. G-CSF was discontinued in all patients, within
the period ranging from 2 days before to 1 day after
neutropenia recovery.
All patients had acute respiratory failure at ICU
admission. In addition, shock was present in six (30%)
patients, acute renal failure in two (10%), and coma in one
(5%). Median SAPS II score was 47 (29–86) and median
LOD score was six,
1–15
indicating a 65% risk of death.
During neutropenia, prior to ICU admission, pulmonary
infiltrates developed in all 20 patients and was documented
by microbiological tests in 10 patients (Table 3). The
organisms were Aspergillus fumigatus (n¼4), Staphylo-
coccus aureus (n¼2), Escherichia coli,Pseudomonas
aeruginosa,Enterococcus faecalis, Klebsiella pneumoniae,
Pneumocystis carinii, and respiratory syncytial virus. In
all, 3 patients had pre-existing heart disease, but in none of
them was the acute respiratory failure ascribable to cardiac
pulmonary edema. Radiographic changes were present in
all patients at acute respiratory failure onset and consisted
in alveolar infiltrates in 13 patients, interstitial pneumonia
in two, mixed alveolar and interstitial changes in three, and
nodules in two. In 10 patients, hypoxia was considered too
severe to allow bronchoscopy and BAL. Of the 10 patients
who did undergo these investigations, five had tests
showing a pathogen; alveolar cells consisted only in
alveolar macrophages.
ARDS occurred in 14 (70%) patients. Figure 1 shows the
day-to-day changes in PaO
2
/FiO
2
ratio and leukocyte count
within the 5-day period centered on neutropenia recovery.
PaO
2
/FiO
2
was lowest on the day of neutropenia recovery.
Among ARDS patients, 11 received conventional mecha-
nical ventilation (MV) only, two received noninvasive MV
followed by invasive MV, and one required only non-
invasive MV. Among the six patients without ARDS, four
were treated with a high-concentration oxygen mask, one
with noninvasive MV, and one with MV. Duration of
ventilatory support was six (4.5–10.5) days. Patients who
required noninvasive mechanical ventilation only were
ventilated for five (4–7) days, and patients who had
received invasive mechanical ventilation were ventilated
for 5 (5–15) days. The overall ICU mortality rate was 25%;
the five patients who died were among the 14 with ARDS.
Neither neutropenia duration nor G-CSF treatment
duration predicted ARDS. Neutropenia duration, G-CSF
duration, and maximum leukocyte count, were not
significantly different in patients with and without ARDS.
Discussion
Respiratory status deterioration and abnormal lung micro-
vascular permeability during neutropenia recovery without
G-CSF is a well-known entity.
10,11
The possibility that G-
CSF may induce pulmonary toxicity has been investigated,
particularly during neutropenia recovery.
16,18
We describe
20 critically ill cancer patients who experienced noncardiac
acute respiratory failure during G-CSF-induced neutro-
penia recovery. In all patients, pulmonary infiltrates devel-
oped during the neutropenic period and worsened at
neutropenia recovery. These cases support published
evidence that G-CSF-induced neutropenia recovery carries
Neutropenia recovery and acute lung injury
L Karlin et al
246
Bone Marrow Transplantation

Table 1 Characteristics of the 20 patients admitted for acute respiratory failure at the time of neutropenia recovery
Malignancy Time
(months)
since
diagnosis
Status
at ICU
admission
SCT Cancer treatment
a
Time (days)
since last
course
Neutropenia
duration
(days)
Duration of
G-CSF
(days)
Time from
respiratory
symptoms to
NR (days)
Chest radiograph
changes
ARDS Ventilatory
support
Outcome
1 ALL 29 CR No CPP+MTX+VCR 39 8 4 +1 Alveolar infiltrate Yes NIMV+MV Alive
2 CLL 137 PR Auto CPP+VCR+F 20 7 11 1 Interstitial disease No O
2
HCM Alive
3 Myeloma 66 PR Auto CPP+VCR 12 8 8 1 Alveolar infiltrate Yes MV Alive
4 ALL 1 Inaugural No CPP+MTX+VCR 11 10 7 2 Nodules Yes MV Alive
5 AML 37 Relapse Allo CPP+MTX+VCR+ARAC 17 20 11 0 Alveolar infiltrate No O
2
HCM Alive
6 NHL 46 CR Auto CPP+MTX+VCR+ARAC 9 11 3 1 Alveolar infiltrate Yes NIMV+MV Dead
7 NHL 1 Inaugural No CPP+MTX+VCR 9 8 6 1 Alveolar infiltrate Yes MV Dead
8 NHL 121 PR Auto CPP+MTX+VCR 34 13 9 3 Alveolar infiltrate Yes NIMV Alive
9 Solid tumor 9 Relapse Auto CPP+BLEO 8 18 5 2 Alveolar infiltrate Yes MV Dead
10 NHL 1 Inaugural No CPP 11 9 8 0 Alveolar infiltrate Yes MV Alive
11 NHL 2 CR No CPP+VCR 17 10 9 1 Alveolar infiltrate Yes MV Alive
12 NHL 163 CR Auto CPP+BLEO 16 10 12 +1 Alv+interstitial No NIMV Alive
13 NHL 15 CR Allo CPP+VCR 17 14 4 +1 Nodules No MV Alive
14 HL 25 CR Auto BLEO+VCR 61 16 11 3 Interstitial disease No O
2
HCM Alive
15 NHL 2 Inaugural No CPP+MTX+VCR 14 6 5 2 Alveolar infiltrate Yes NIMV Alive
16 Solid tumor 32 Relapse No Gemcitabine 15 4 3 1 Alv+interstitial Yes MV Alive
17 NHL 36 CR Auto CPP 4 22 11 1 Alveolar infiltrate Yes MV Alive
18 NHL 3 CR No CPP 18 5 6 1 Alveolar infiltrate No O
2
HCM Alive
19 AML 1 Inaugural No ARAC 33 7 16 0 Alveolar infiltrate Yes MV Dead
20 AML 2 Inaugural No ARAC 18 22 17 3 Alv+interstitial Yes MV Dead
ALL ¼acute lymphoblastic leukemia; AML ¼acute myeloid leukemia; CLL ¼chronic lymphoid leukemia; NHL ¼non-Hodgkin lymphoma; HL-Hodgkin lymphoma; ARDS ¼acute respiratory distress
syndrome; NR ¼neutropenia recovery; CR ¼complete remission; PR ¼partial remission; SCT ¼stem cell transplantation; CPP ¼cyclophosphamide; MTX ¼methotrexate; VCR ¼vincristine; F ¼fludarabine;
ARAC ¼cytosine arabinoside; BLEO ¼bleomycin.
a
All patients received anthracyclines.
O
2
HCM: high-concentration oxygen mask; NIMV: noninvasive mechanical ventilation; MV: mechanical ventilation.
Neutropenia recovery and acute lung injury
L Karlin et al
247
Bone Marrow Transplantation

a risk of acute respiratory failure in patients with prior lung
disease.
All 20 patients received cancer chemotherapy agents
known to cause pulmonary toxicity. However, none was
considered to have chemotherapy-related pulmonary toxi-
city, and most of the survivors received further cancer
chemotherapy without experiencing recurrent pulmonary
disorders. However, as previously suggested,
16
G-CSF-
related pulmonary toxicity occurs more frequently in
patients who received previously at least three courses of
cancer chemotherapy, suggesting that G-CSF enhances
alveolar inflammation after repeated endothelial damage by
chemotherapy agents.
16,18,22
The first pulmonary event in our patients was pulmonary
infiltrates during neutropenia without a need for ICU
admission. Acute respiratory failure requiring ICU admis-
sion occurred later, during neutropenia recovery. Although
pathogens were recovered in only half our patients,
previous data suggest that G-CSF and neutropenia
recovery merely exacerbate previous lung injury, possibly
via accumulation of neutrophils in the lungs.
23,24
However,
as previously reported in this entity, macrophages, but not
neutrophils, were recovered from BAL fluid, suggesting
that acute lung injury during neutropenia recovery may be
nosologically similar to ARDS during neutropenia.
25,26
In a
lamb model of experimental lung injury, G-CSF-enhanced
alveolar neutrophil functions, increasing both cytokine
production and oxidative burst.
27,28
G-CSF upregulates the production of cytokines that
increase alveolar permeability or neutrophil influx, such as
tumor necrosis factor (TNF) a, interleukin (IL) 1b, and
IL-8.
29,30
In vitro studies also found enhanced secretion of
proinflammatory cytokines by isolated alveolar macro-
phages obtained during neutropenia recovery from rats
that received G-CSF, compared with rats that did not
receive G-CSF, providing a possible explanation for lung
injury exacerbation during G-CSF-induced neutropenia
recovery.
18
Our study has some limitations, however. First, we only
report cases of critically ill patients with acute lung injury
or ARDS during G-CSF-induced neutropenia recovery,
but we do not report the magnitude of the risk. A
prospective observation of the incidence and risk factors
for respiratory symptoms (whatever the severity) during
G-CSF-induced neutropenia recovery is timely. Second,
further study should also seek to evaluate biological
markers reflecting epithelial and endothelial injury that
characterizes the disease, so as to help clinicians easily
diagnose ARDS during G-CSF-induced neutropenia re-
covery. Third, G-CSF has been investigated in large
randomized trials in cancer and noncancer patients without
any report of pulmonary toxicity. However, these studies
were not powered for detecting such pulmonary complica-
tions. Moreover, we believe that noncancer patients
receiving G-CSF are not expecting to present with
pulmonary toxicity since they do not receive cancer
chemotherapy. Indeed, without neutropenia recovery, nor
chemotherapy-related repeated endothelial injuries, the
clinical condition we describe should not occur. Last, we
did not demonstrate that G-CSF withdrawal resulted in
respiratory improvement. However, G-CSF discontinua-
Table 2 Anticancer agents received by the patients
Agents Number of patients
Anthracyclines 20 (100%)
Cyclophosphamide 16 (80%)
Vincristine 12 (60%)
Methotrexate 7 (35%)
Cytosine arabinoside 2 (10%)
Bleomycin 3 (15%)
Gemcitabin 1 (5%)
Fludarabine 1 (5%)
Table 3 Microorganisms recovered from 10 study patients
Patient Microorganism Where recovered When recovered
3S.aureus Protected specimen and blood culture Before ICU admission
4E.faecalis, A.fumigatus Bronchoalveolar lavage ICU
7L.pneumophilia Urine (antigen test) ICU
8E.coli Blood culture Before ICU admission
10 S.aureus Blood culture Before ICU admission
11 A.fumigatus Bronchoalveolar lavage ICU
15 RSV Bronchoalveolar lavage Before ICU admission
16 K.pneumoniae Protected specimen and blood culture ICU
17 P.aeruginosa Protected specimen Before ICU admission
19 P.carinii, A.fumigatus Bronchoalveolar lavage Before ICU admission
Leukocytosis
100
150
200
250
300
350
PaO2 / FiO2 ratio
0
1000
2000
3000
4000
5000
D1 D2D0D -2 D -1
Figure 1 Time course of PaO
2
/FiO
2
ratio (closed circles) and total
leukocyte count (lozenges) during the 5-day period centered on the day of
neutropenia recovery (D0).
Neutropenia recovery and acute lung injury
L Karlin et al
248
Bone Marrow Transplantation

tion is in order after neutropenia recovery, and since G-
CSF-related pulmonary toxicity has been reported, all
nonmandatory drugs potentially harmful for the lung
should be stopped in case of severe respiratory failure.
Survival of cancer patients admitted to the ICU for acute
respiratory failure has improved in recent years. In the
present study, the 25% mortality rate was far lower than
expected in a population of critically ill cancer patients with
severe disease, and a high rate of mechanical ventilation.
This encouraging survival rate may be related mainly to
early G-CSF discontinuation (at acute respiratory failure
onset), early diagnosis, and effective early supportive care.
This study, together with previous data from animals and
humans, strongly suggests the harmful effect of G-CSF in
some cancer patients who experience pulmonary infection
during neutropenia. G-CSF is widely used in cancer
patients and has substantially improved the safety of
cancer chemotherapy and the prognosis of many malig-
nancies. This agent is generally safe. Nevertheless, it may
exacerbate respiratory disorders related to chemotherapy-
associated pulmonary toxicity. The exacerbation occurs
during neutropenia recovery. Physicians should be aware of
this risk and should exercise great caution when using G-
CSF in neutropenic patients with pulmonary involvement.
In summary, in patients with pulmonary infiltrates
during neutropenia, G-CSF-induced neutropenia recovery
carries a risk of respiratory deterioration due to acute lung
injury or ARDS. It must be emphasized that G-CSF is
useful in many patients to reduce the duration of
neutropenia and to allow intensive chemotherapy proto-
cols. However, clinicians must maintain a high index of
suspicion for G-CSF-related acute respiratory failure so
that they can discontinue G-CSF therapy early and
immediately transfer the patient to the ICU for early
noninvasive mechanical ventilation, adequate supportive
care, and appropriate diagnostic investigations.
Acknowledgements
We thank A Wolfe MD for helping with this manuscript.
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