Cancer chemotherapy is administered every day to
numerous cancer patients, with neutropenia mostly a
normally expected event [1,2]. During neutropenia,
bacterial sepsis remains a major threat . Potential
sources of infection include primarily the lungs, the
digestive tract, and the bloodstream [4,5]. Some of the
patients with prolonged neutropenia are more likely to
present with nonbacterial infections, namely acute
leukemia patients and stem cell/bone marrow transplant
recipients . Although neutrophils are believed to have
a pivotal role in the pathophysiology of acute lung injury
(ALI) and acute respiratory distress syndrome (ARDS),
early evidence emerged that neutropenic patients were
not spared from ALI and ARDS . Several hypotheses
have been raised, including alveolar macrophage or
monocyte deactivation  in relation to malignancy,
cancer chemotherapy or sepsis.
Neutropenia recovery occurs silently in the vast
majority of patients. Deterioration of the respiratory
status, however, has been reported during resolution of
leukopenia [9,10] – that is, 2 to 3 days before and after
the neutrophil count reaches 500/mm3 or the leukocyte
count reaches 1,000/mm3 . An aggravating role of
granulocyte colony-stimulating factor (G-CSF) has been
suggested in both clinical and experimental fi ndings
[12,13]. Patients at risk for ALI/ARDS during neutropenia
recovery are those with pulmonary infi ltrates during
neutropenia [10,12,13]. Other risk factors that have been
suggested include delayed or pro longed neutropenia 
and invasive pulmonary aspergillosis .
In the previous issue of Critical Care, Rhee and
coworkers assessed the risk factors for ARDS in 71
critically ill patients with hematologic malignancies and
long-lasting neutropenia . All of the patients received
G-CSF. About one-half of the patients developed ARDS
during neutropenia recovery. Th e authors identifi ed that
patients presenting pneumonia during neutropenia were
at higher risk of ARDS during neutropenia recovery.
Th e present study provides additional evidence that
neutropenic patients presenting clinically or microbio-
logically documented pneumonia should be monitored
carefully at the time of neutropenia recovery. Th e study
also raises the issue of G-CSF-related pulmonary toxicity
in this context . Th ere are, however, three potential
sources of bias in the study that should be highlighted.
First, one-half of the patients had an acute leukemia, all
of them receiving G-CSF. Although the safety of G-CSF
in patients with acute leukemia has been well established
in numerous clinical trials, its potential advantages
remain inconclusive since there is no evidence of a
reduction in the overall frequency of infectious compli-
cations or the duration of hospitalization, nor any benefi t
in terms of disease-free survival or overall survival .
Th e benefi t–risk ratio of G-CSF in these patients should
therefore be carefully addressed in each individual case.
Second, the neutropenia duration was rather long in
the present study (22.5 days), which is in agreement with
the fact that 90% of the patients received chemotherapy
Acute respiratory failure is a life-threatening
complication in cancer patients. During neutropenia,
patients are at high risk for bacterial pneumonia
or invasive fungal infections, when neutropenia is
prolonged. A high proportion of patients in whom
neutropenia had been complicated by pneumonia will
present with substantial respiratory deterioration during
neutropenia recovery. Patients with fungal pneumonia
and those receiving granulocyte colony-stimulating
factor to shorten neutropenia duration may be at
higher risk for this acute lung injury/acute respiratory
distress syndrome during neutropenia recovery. Routine
screening of patient’s risk factors is crucial since fi rst
symptoms of acute respiratory distress syndrome may
occur before biological leukocyte recovery.
© 2010 BioMed Central Ltd
Acute respiratory distress syndrome during
Élie Azoulay* and Michael Darmon
See related research by Rhee et al., http://ccforum.com/content/13/6/R173
AP-HP, Hôpital Saint-Louis, Medical ICU, University Paris-7 Paris-Diderot, UFR de
Médecine, 1 avenue Claude Vellefaux, 75010 Paris, France
Azoulay and Darmon Critical Care 2010, 14:114
© 2010 BioMed Central Ltd
for acute leukemia. Prolonged neutropenia has been
identifi ed as a risk factor for respiratory deterioration
during neutropenia recovery . Th is also indicates that
the 50% incidence and the severity of respiratory
deteriora tion during neutropenia recovery reported in
Rhee and colleagues’ study may not be generalizable to all
patients with hematological malignancies such as diff use
B-cell lymphoma or myeloma, and even less to patients
with solid tumors.
Th ird, the mortality rate reported in the study is in the
higher ranges of recently published data [17,18]. Th is is
probably further proof that patients reported in the
paper by Rhee and coworkers are among the sickest
critically ill leukemic patients. Along this line, the
absence of docu mented invasive aspergillosis in the
study is a surprising fi nding.
Although no sound causal relationship can be estab-
lished from these data between neutropenia recovery and
ARDS, we would like to emphasize the fi ve convincing
arguments supporting the reality of ARDS during
neutropenia that the authors developed in their
discussion section. First, a high proportion of patients in
whom neutropenia had been complicated by pneumonia
will present with substantial respiratory deterioration
during neutropenia recovery. Also, the incidence of ALI/
ARDS in neutropenic patients with pneumonia is far
higher during than before or after neutropenia recovery.
Th ird, several groups from diff erent parts of the world
have described this clinical entity. Further, the experi-
mental models of ALI/ARDS in neutropenic rats have
been able to reproduce this condition with reasonable
pathophysiology hypotheses. Finally, this ARDS situation
is clinically plausible in these frail lung’s patients with
established predisposition to infections , cancer
chemotherapy and G-CSF-induced pulmonary toxicity, and
sometimes to pulmonary infi ltration by the malignancy.
In the future, early recognition of those patients likely
to present ALI/ARDS in this specifi c clinical setting is a
worthwhile endeavor. Th e relevance of routine screening
for each individual patient’s risk factors is made crucial
by the fact that the fi rst symptoms of ARDS may occur
before biological leukocyte recovery, and by the need to
weight the benefi t–risk ratio of G-CSF administration in
every patient with clinically or microbiologically
pneumonia compli cating neutropenia.
ALI = acute lung injury; ARDS = acute respiratory distress syndrome; G-CSF =
granulocyte colony-stimulating factor.
The present work was supported by a grant from the Assistance-Publique
Hôpitaux de Paris (AOM 04139).
The authors declare that they have received grants from Pfi zer and Gilead but
not in relation to this publication.
Published: 10 February 2010
1. Rhee CK, Kang JY, Kim YH, Kim JW, Yoon HK, Kim SC, Kwon SS, Kim YK, Kim KH,
Moon HS, Park SH, Kim HJ, Lee S, Song JS: Risk factors for acute respiratory
distress syndrome during neutropenia recovery in patients with
hematologic malignancies. Crit Care 2009, 13:R173.
2. Coleman MP, Quaresma M, Berrino F, Lutz JM, De Angelis R, Capocaccia R,
Baili P, Rachet B, Gatta G, Hakulinen T, Micheli A, Sant M, Weir HK, Elwood JM,
Tsukuma H, Koifman S, E Silva GA, Francisci S, Santaquilani M, Verdecchia A,
Storm HH, Young JL; CONCORD Working Group: Cancer survival in fi ve
continents: a worldwide population-based study (CONCORD). Lancet Oncol
3. Bodey GP: Infection in cancer patients. A continuing association. Am J Med
4. Cartoni C, Dragoni F, Micozzi A, Pescarmona E, Mecarocci S, Chirletti P, Petti
MC, Meloni G, Mandelli F: Neutropenic enterocolitis in patients with acute
leukemia: prognostic signifi cance of bowel wall thickening detected by
ultrasonography. J Clin Oncol 2001, 19:756-761.
5. Puig N, De La Rubia J, Jarque I, Salavert M, Moscardó F, Sanz J, Lorenzo I,
Montesinos P, Martín G, Martínez J, Sanz G, Blanes M, Sanz M: Characteristics
of and risk factors for pneumonia in patients with hematological
malignancies developing fever after autologous blood stem cell
transplantation. Leuk Lymphoma 2007, 48:2367-2374.
6. Darmon M, Azoulay E, Alberti C, Fieux F, Moreau D, Gall JR, Schlemmer B:
Impact of neutropenia duration on short-term mortality in neutropenic
critically ill cancer patients. Intensive Care Med 2002, 28:1775-1780.
7. Ognibene FP, Martin SE, Parker MM, Schlesinger T, Roach P, Burch C,
Shelhamer JH, Parrillo JE: Adult respiratory distress syndrome in patients
with severe neutropenia. N Engl J Med 1986, 315:547-551.
8. Mokart D, Kipnis E, Guerre-Berthelot P, Vey N, Capo C, Sannini A, Brun JP,
Blache JL, Mege JL, Blaise D, Guery BP: Monocyte deactivation in
neutropenic acute respiratory distress syndrome patients treated with
granulocyte colony-stimulating factor. Crit Care 2008, 12:R17.
9. Rinaldo JE, Borovetz H: Deterioration of oxygenation and abnormal lung
microvascular permeability during resolution of leukopenia in patients
with diff use lung injury. Am Rev Respir Dis 1985, 131:579-583.
10. Azoulay E, Darmon M, Delclaux C, Fieux F, Bornstain C, Moreau D, Attalah H,
Le Gall JR, Schlemmer B: Deterioration of previous acute lung injury during
neutropenia recovery. Crit Care Med 2002, 30:781-786.
11. Azoulay E, Thiéry G, Chevret S, Moreau D, Darmon M, Bergeron A, Yang K,
Meignin V, Ciroldi M, Le Gall JR, Tazi A, Schlemmer B: The prognosis of acute
respiratory failure in critically ill cancer patients. Medicine (Baltimore) 2004,
12. Karlin L, Darmon M, Thiéry G, Ciroldi M, de Miranda S, Lefebvre A, Schlemmer
B, Azoulay E: Respiratory status deterioration during G-CSF-induced
neutropenia recovery. Bone Marrow Transplant 2005, 36:245-250.
13. Azoulay E, Attalah H, Yang K, Herigault S, Jouault H, Brun-Buisson C, Brochard
L, Harf A, Schlemmer B, Delclaux C: Exacerbation with granulocyte colony-
stimulating factor of prior acute lung injury during neutropenia recovery
in rats. Crit Care Med 2003, 31:157-165.
14. Todeschini G, Murari C, Bonesi R, Pizzolo G, Verlato G, Tecchio C, Meneghini V,
Franchini M, Giuff rida C, Perona G, Bellavite P: Invasive aspergillosis in
neutropenic patients: rapid neutrophil recovery is a risk factor for severe
pulmonary complications. Eur J Clin Invest 1999, 29:453-457.
15. Azoulay E, Attalah H, Harf A, Schlemmer B, Delclaux C: Granulocyte colony-
stimulating factor or neutrophil-induced pulmonary toxicity: myth or
reality? Systematic review of clinical case reports and experimental data.
Chest 2001, 120:1695-1701.
16. Ottmann OG, Bug G, Krauter J: Current status of growth factors in the
treatment of acute myeloid and lymphoblastic leukemia. Semin Hematol
17. Azoulay E, Mokart D, Rabbat A, Pene F, Kouatchet A, Bruneel F, Vincent F,
Hamidfar R, Moreau D, Mohammedi I, Epinette G, Beduneau G, Castelain V, de
Lassence A, Gruson D, Lemiale V, Renard B, Chevret S, Schlemmer B:
Diagnostic bronchoscopy in hematology and oncology patients with
acute respiratory failure: prospective multicenter data. Crit Care Med 2008,
18. Soares M, Caruso P, Silva E, Teles JM, Lobo SM, Friedman G, Dal Pizzol F, Mello
PV, Bozza FA, Silva UV, Torelly AP, Knibel MF, Rezende E, Netto JJ, Piras C, Castro
A, Ferreira BS, Réa-Neto A, Olmedo PB, Salluh JI; Brazilian Research in Intensive
Azoulay and Darmon Critical Care 2010, 14:114
Page 2 of 3
Care Network (BRICNet): Characteristics and outcomes of patients with
cancer requiring admission to intensive care units: a prospective
multicenter study. Crit Care Med 2010, 38:9-15.
19. Lehrnbecher T, Koehl U, Wittekindt B, Bochennek K, Tramsen L, Klingebiel T,
Chanock SJ: Changes in host defence induced by malignancies and
antineoplastic treatment: implication for immunotherapeutic strategies.
Lancet Oncol 2008, 9:269-278.
Azoulay and Darmon Critical Care 2010, 14:114
Cite this article as: Azoulay E, Darmon M: Acute respiratory distress syndrome
during neutropenia recovery. Critical Care 2010, 14:114.
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