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(Chest. 2001;120:1695-1701.)
© 2001 American College of Chest Physicians

Granulocyte Colony-Stimulating Factor or Neutrophil-Induced Pulmonary Toxicity: Myth or Reality?*

Systematic Review of Clinical Case Reports and Experimental Data

Elie Azoulay, MD; Habiba Attalah; Alain Harf, MD, PhD; Benoît Schlemmer, MD and Christophe Delclaux, MD, PhD

* From the INSERM U 492, Université Paris XII, Faculté de Médecine de Créteil, France; Service de Physiologie, Explorations Fonctionelles, Hôpital Henri Mondor, Paris, France; Assistance Publique, Hôpitaux de Paris, France; Service de Réanimation Médicale, Hôpital Saint Louis, Paris, France.

Correspondence to: Elie Azoulay, MD, Faculté de Médecine de Créteil, 8, rue du Général Sarrail, 94010 Créteil, France; e-mail: elie.azoulay{at}creteil.inserm.fr

Key Words: antitumoral chemotherapy • ARDS • cancer patients • granulocyte colony-stimulating factor • neutropenia • neutropenia recovery • neutrophils • pneumonia


   Introduction
TOP
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Human granulocyte colony-stimulating factor (G-CSF) is the most important regulatory cytokine that is capable of stimulating the production of neutrophils from committed hematopoietic progenitor cells both in vitro and in vivo.1 2 G-CSF both increases neutrophil counts and enhances and primes many neutrophil functions, suggesting a role for this growth factor in host defenses not only in neutropenic patients but also in many non-neutropenic immunocompromised patients.

G-CSF is widely prescribed in cancer patients to hasten recovery from chemotherapy-induced neutropenia and to mobilize peripheral blood progenitor cells for autologous bone marrow transplantation.3 The prevention or decreased duration of cytotoxic drug-induced neutropenia is ascribable to the quantitative stimulating effect of G-CSF on granulopoiesis.4 G-CSF therapy has considerably improved the safety of myelosuppressive chemotherapy, most notably in patients with lymphoma, in whom decreased treatment-related mortality, higher complete remission rates, and longer disease-free survival times have been reported.5 6 7 In addition to shortening the duration of neutropenia and hospitalization, G-CSF reduces the incidence of infectious episodes in patients with lymphoma, and even in those with leukemia or solid tumors.8 9 10 11 Moreover, as compared to autologous bone-marrow transplantation, autologous G-CSF-mobilized peripheral blood progenitor cell transplantation (with or without cyclophosphamide) was associated with shorter times to platelet and neutrophil recovery and with earlier hospital discharge.3

Treatment with G-CSF is also increasingly used as an adjunct to antibiotic therapy in non-neutropenic patients who have various critical conditions, such as community-acquired pneumonia, complicated diabetes mellitus, brain injury, burns, and even neonatal bacterial sepsis.12 13 14 15 16 17 In these indications, the qualitative effects of G-CSF therapy regulate neutrophil survival, proliferation, differentiation, and activation.18 19 20 21 22

Adverse events have been ascribed to G-CSF in both healthy volunteers and patients. These effects occurred in approximately 30% of cases and consisted mainly of bone pain, headache, and fatigue.23 Pulmonary adverse effects ascribed to G-CSF include cough, dyspnea, and interstitial or alveolar pulmonary infiltrates with mild-to-severe blood gas level deterioration. A few cases of ARDS have been reported.

G-CSF treatment is being more and more widely used in immunocompromised patients with or without neutropenia. Therefore, the number of patients exposed to a high risk of G-CSF-related pulmonary toxicity may be increasing. Underreporting undoubtedly occurs. Because fatal cases of G-CSF-related ARDS have occurred, all cases of G-CSF-related pulmonary toxicity should be reported and risk factors should be identified. We systematically reviewed all published cases of G-CSF-related pulmonary toxicity, with the objective of identifying situations in which G-CSF treatment should be avoided or used only with special precautions.


   Materials and Methods
TOP
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The PUBMED Database (http://www.ncbi.nlm.nih.gov/PubMedOld/medline.html) was searched for letters, case reports, original articles, meta-analyses, or reviews reporting one or more episodes of G-CSF-related pulmonary toxicity. MeSH terms used for the search were G-CSF, granulocyte macrophage colony-stimulating factor, hematopoietic growth factors, pneumonia, lung disease, and ARDS. The search was updated on June 30, 2000.

Each of the publications identified by the search was read independently by two pulmonologists (EA and CD). Cases in which G-CSF-related pulmonary toxicity was highly probable were selected based on the presence of all the following criteria: (1) onset of pneumonia within 10 days after G-CSF therapy initiation; (2) clinical respiratory symptoms with pulmonary infiltrates shown by chest radiograph or CT scan; (3) impairment of gas exchange after G-CSF therapy initiation or PaO2 < 70 mm Hg on room air at diagnosis; (4) no evidence by either fiberoptic bronchoscopy and BAL or open pulmonary biopsy of another cause for the pneumonia (eg, infection, alveolar hemorrhage, tumor, or alveolar proteinosis); (5) no evidence of acute congestive heart failure (by Swan-Ganz catheter or echocardiography); and (6) in nonfatal cases, complete recovery after G-CSF discontinuation, with or without steroid therapy. Cases of engraftment syndrome were excluded.24


   Results
TOP
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Eighty-four cases of G-CSF-related pulmonary toxicity were identified and separated into three groups based on the circumstances of onset. Only one report incriminating G-CSF as the main cause of pneumonia was excluded from our analysis because it failed to meet all of our selection criteria.

Pulmonary Toxicity With G-CSF Used Alone
Two cases of G-CSF-related pulmonary toxicity have been reported in non-neutropenic patients treated with G-CSF alone. Among the 1,801 published cases of G-CSF treatment in healthy volunteers donating granulocytes to neutropenic relatives undergoing marrow transplantation, only one was associated with pulmonary toxicity.25 This subject was a 38-year-old man in whom ARDS developed after 3 days of G-CSF treatment (750 µg) with no other medications. The other patient who experienced pulmonary toxicity after G-CSG treatment alone was a 72-year-old man who was given the growth factor unnecessarily for anemia. After 5 days of treatment (5 µg/kg/d), he developed diffuse bilateral alveolar densities. Despite receiving mechanical ventilation, the patient died from ARDS.26

Pulmonary Toxicity With G-CSF Used in Combination With Other Potentially Toxic Agents
Twenty-one publications have reported 73 cases of G-CSF-related pulmonary toxicity in neutropenic patients (Table 1 ). All these patients recovered from their neutropenic episode before the diagnosis of pulmonary toxicity. The mean (± SD) age was 54 ± 0.5 years, and 36 patients (44.4%) were women. Three patients (3.7%) did not have a malignancy and were given G-CSF for neutropenia that complicated antibiotic therapy, dialysis, or methotrexate therapy for rheumatoid arthritis. Among the 70 cancer patients, most (61; 84%) had non-Hodgkin’s lymphoma, and all had received three or more courses of antitumoral chemotherapy. Forty patients (55%) had received cyclophosphamide, 36 patients (49%) had received bleomycin, and 23 patients (31.5%) had received methotrexate. Thirty-six patients had interstitial pneumonia with mild-to-moderate hypoxemia, 35 patients had ARDS, and 2 patients had isolated pleural effusions. The mortality rate was 24.6% (18 deaths). All the survivors recovered after G-CSF therapy discontinuation with or without steroid therapy.


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  		Table 1.. Cases of G-CSF-Related Pulmonary Toxicity*

 
Pulmonary Toxicity During G-CSF-Enhanced Neutropenia Recovery
As shown in Table 2 , we identified nine cases in which ARDS occurred, not before or after, but during neutropenia recovery, which was defined as the 7-day period centered on the day on which the neutrophil count rose to > 1,000 cells/mm3. In these patients, G-CSF was given to expedite neutropenia recovery and was considered to be effective. These nine patients had either cancer or neutropenia induced by noncytotoxic drugs. Each patient had a history of clinically documented pneumonia before neutropenia recovery, and a causative organism was recovered in most cases, although in a few the cause of the pneumonia remained unknown.


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  		Table 2.. ARDS Occurring at the Time of Neutropenia Recovery*

 

   Discussion
TOP
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The main property of G-CSF is an ability to enhance both neutrophil production and neutrophil functions. Neutrophils are stimulated to produce reactive oxygen species, an effect that increases their bactericidal capabilities. Interestingly, functions are stimulated in both vascular neutrophils and emigrated neutrophils. Discrepancies exist among in vitro studies of the ability of G-CSF to stimulate or inhibit neutrophil chemotaxis. In vivo, however, G-CSF clearly increases neutrophil migration to sites of infection. This has raised concerns that G-CSF may have toxic effects on the lungs, as there is ample evidence that activated neutrophils may be toxic for the alveolar capillary wall. In the 1980s, it was concluded from this evidence that the neutrophil was the main cell responsible for the alveolar capillary wall injury that leads to ARDS.27 Thus, clinicians were alert to the possibility that G-CSF therapy might increase neutrophil-related pulmonary toxicity and promptly reported cases that were consistent with this hypothesis, with most of the reports published between 1991 and 1997. In all the reports of pulmonary toxicity ascribed to G-CSF that had been used to treat neutropenia, the pulmonary symptoms started during or after neutropenia recovery, suggesting that the pulmonary toxicity of G-CSF was mediated by neutrophils. The central issue, therefore, is whether stimulation by G-CSF increases the toxicity of neutrophils for the lungs.

In addition to its effects on neutrophil production and functions, G-CSF may enhance the functions of monocytes, macrophages, and endothelial cells, which carry G-CSF receptors.4 28 By binding to these receptors, G-CSF may regulate cytokine production and feedback. However, the results of this regulation seem to vary with the timing of G-CSF initiation relative to the onset of neutropenia, with the infectious organism, and with the route of G-CSF administration. Thus, paradoxical effects can be seen. A striking example is the protective effect of G-CSF against ARDS that has been reported in at-risk patients.12 29 To date, G-CSF is the only agent known to have this effect.

G-CSF Toxicity in Healthy Animals
Administration to healthy animals of granulocyte macrophage colony-stimulating factor, but not G-CSF, has been reported to cause alveolar cell recruitment and pulmonary edema.30 When administered IV or subcutaneously, G-CSF alone produced neither pulmonary edema nor alveolar neutrophil influx.31 Conversely, both events were early findings after the instillation of G-CSF into the trachea.32

Effect of G-CSF Treatment During Experimental Acute Lung Injury
In vivo studies have found evidence of a role for G-CSF in modulating the inflammatory response to acute lung injury (ALI), with G-CSF pretreatment either exacerbating or improving the condition of patients with ALI. On the one hand, G-CSF therapy seemed to be useful in overcoming the suppressive effects of ethanol on polymorphonuclear neutrophil function in vitro (phagocytic activity) and in vivo (neutrophil recruitment to the lung).33 G-CSF also protected against ALI in granulocytopenic mouse models of Pseudomonas aeruginosa or Candida albicans pneumonia.34 35 On the other hand, G-CSF exacerbated pulmonary edema in {alpha}-napthylthiourea-induced ALI in rats36 and in intratracheal lipopolysaccharide-induced ALI in guinea pigs pretreated with cyclophosphamide,37 but not in IV lipopolysaccharide-induced ALI in healthy guinea pigs or sheep.38

These apparently conflicting results do not allow us to determine whether G-CSF therapy is beneficial or deleterious during ALI and suggest that the role of neutrophils in this setting remains to be elucidated. Several authors have pointed out that G-CSF not only affects neutrophils, but also enhances tumor necrosis factor (TNF)-{alpha} release by alveolar macrophages, an effect that may be beneficial in situations characterized by inadequate TNF-{alpha} release. For instance, alcohol contributes to the inhibition of TNF-{alpha} production by alveolar macrophages and therefore to the suppression of the normal autocrine amplification pathway responsible for G-CSF production in response to an Escherichia coli challenge,39 which may explain the beneficial effect of G-CSF in this setting and was demonstrated both in an experimental study33 and in a human study.40 Similarly, in a granulocytopenic mouse model of P aeruginosa pneumonia, G-CSF exerted beneficial effects by increasing endogenous TNF-{alpha} production, thus enhancing alveolar macrophage functions.34 Support for this mechanism has been provided by an elegant experiment devised by Karzai et al41 in a rat model of E coli or Staphylococcus aureus pneumonia. In this study, the administration of G-CSF was associated with poorer oxygenation and increased bacteremia and mortality in the E coli pneumonia model and with a protective effect in the S aureus pneumonia model. The authors attributed this paradoxical effect of G-CSF to the fact that mean TNF-{alpha} levels were higher after E coli challenge.

G-CSF-Related Toxicity in Humans
Our literature review found 84 published cases of highly probable G-CSF-related pulmonary toxicity, including 2 in patients who received G-CSF alone, 9 in patients who had ARDS during neutropenia recovery enhanced by G-CSF, and 73 in patients who experienced exacerbation by G-CSF of chemotherapy-related pulmonary toxicity. Strikingly, although most patients received G-CSF for neutropenia complicating antitumoral chemotherapy or other drug treatments, they recovered from the neutropenia before the diagnosis of pneumonia. This suggests that pulmonary toxicity of G-CSF may not occur in the absence of neutrophils.

Compared to the huge number of patients who have received G-CSF since the introduction of this agent for clinical use,4 these 84 cases of G-CSF-related pulmonary toxicity may seem to be of limited significance. Furthermore, in the overwhelming majority of these cases, G-CSF was given in combination with drugs known to induce pulmonary toxicity, raising the possibility that G-CSF therapy did not contribute significantly to the pulmonary disease. However, G-CSF-related pulmonary toxicity is probably underreported, and, consequently, an evaluation of its incidence based on published cases can only lead to an underestimation. Moreover, in most published cases, G-CSF exacerbated the pulmonary toxicity known to occur in 1 to 10% of patients receiving antitumor agents (primarily bleomycin, methotrexate, and cyclophosphamide).42 43 44 45 In randomized trials investigating the efficacy of G-CSF in preventing complications of neutropenia in cancer patients receiving antitumoral chemotherapy, no excess pulmonary events occurred in the G-CSF groups.42 Neither was G-CSF therapy associated with excess pulmonary events in studies12 15 16 40 of G-CSF therapy in non-neutropenic patients with community-acquired pneumonia or other infections. However, these important and well-conducted studies were not designed to detect cases of G-CSF-related toxicity and, therefore, probably lacked the statistical power needed to determine whether G-CSF induced excess pulmonary events. A retrospective study46 found an increased incidence of respiratory failure after the introduction of G-CSF therapy. Thus, the 84 cases included in our review may be a warning signal indicating that we must strive to identify risk factors for serious or life-threatening pulmonary side effects of G-CSF.

The 84 cases reported in this review cannot be taken as incontrovertible proof that G-CSF produces toxic effects on the lung. However, the two cases in which ARDS occurred during treatment with G-CSF alone are extremely disturbing because they are strong evidence that G-CSF itself can induce ARDS. Although probably rare, this complication of G-CSF therapy is of great concern because it seems to be difficult to predict and can be fatal.

The nine cases of ARDS during neutropenia recovery enhanced by G-CSF therapy are probably similar to previously reported cases of ARDS during neutropenia recovery without G-CSF therapy.47 Rather than the level of hyperleukocytosis at ARDS onset, pneumonia prior to neutropenia recovery48 49 50 51 and the rate of leukocyte count elevation after neutropenia recovery may be the main risk factors.52

In all the remaining cases, G-CSF seems to have exacerbated the pulmonary toxicity induced by other drugs, primarily bleomycin, methotrexate, and cyclophosphamide. Extensive investigations were performed to rule out other diagnoses (eg, infection, tumor, congestive heart failure, alveolar hemorrhage, or alveolar proteinosis). Strikingly, the doses of the antitumor agents used in these patients were below the toxic cumulative dose in every case. This suggests that G-CSF may lower the dose threshold for pulmonary toxicity of these drugs. Another noteworthy fact is that pulmonary toxicity occurred after three or more chemotherapy courses in every case, suggesting that G-CSF induced the sequestration and adhesion of neutrophils in the lungs, thus increasing the risk of toxicity of neutrophil products (ie, reactive oxygen species and proteases) for endothelial and even epithelial cells previously injured by repeated exposure to antitumor agents.53 54 55 In keeping with this hypothesis, the patients with G-CSF-related pulmonary toxicity already had recovered from neutropenia at the time of the diagnosis of the lung disorder.43 46 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71

In conclusion, whether G-CSF can induce pulmonary toxicity remains an open debate. Only two published cases were clearly caused by G-CSF-related pulmonary toxicity. However, the other cases suggest that G-CSF may increase the pulmonary toxicity of other drugs via its activating effect on neutrophils. They also indicate that neutropenic patients with a recent history of pulmonary infiltrates are at increased risk of ARDS at neutropenia recovery. In these patients, G-CSF treatment should either be avoided or closely monitored and should be discontinued as soon as the leukocyte count rises to > 1,000 cells/µL. Experimental and clinical studies are needed to identify situations in which G-CSF may carry an increased risk of exacerbating endothelial/epithelial lung injury due to toxic or infectious agents in both neutropenic and non-neutropenic patients. This may help clinicians to prevent the rare but sometimes fatal occurrence of ARDS and to further improve the outstanding safety profile of G-CSF therapy, which at present is safe in > 99% of patients.


   Footnotes
 
Abbreviations: ALI = acute lung injury; G-CSF = granulocyte colony-stimulating factor; TNF = tumor necrosis factor

This review was supported by a grant from Aventis Pharma France.

Received for publication February 13, 2001. Accepted for publication April 24, 2001.


   References
TOP
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Relation of G-CSF to Pulmonary Neutrophilia and Severity of Lung Injury in Patients with ARDS
Franz J Wiedermann
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