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A Randomized Controlled Trial of Granulocyte Colony-Stimulating Factor for the Treatment of Severe Sepsis Due to Melioidosis in Thailand

  1. Allen C. Cheng1,
  2. Direk Limmathurotsakul3,
  3. Wirongrong Chierakul3,
  4. Nongluk Getchalarat3,
  5. Vanaporn Wuthiekanun3,
  6. Dianne P. Stephens2,
  7. Nicholas P. J. Day3,5,
  8. Nicholas J. White3,5,
  9. Wipada Chaowagul4,
  10. Bart J. Currie1,2, and
  11. Sharon J. Peacock3,5
  1. 1Menzies School of Health Research, Charles Darwin University, Darwin, Australia
  2. 2Royal Darwin Hospital, Darwin, Australia
  3. 3Faculty of Tropical Medicine, Mahidol University, Bangkok
  4. 4Department of Medicine, Sappasithiprasong Hospital, Ubon Ratchathani, Thailand
  5. 5Centre for Tropical Diseases, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, United Kingdom
  1. Reprints or correspondence: Dr. Allen C. Cheng, Dept. of Medicine, University of Melbourne, 9th floor, Royal Melbourne Hospital, Parkville VIC 3052, Melbourne, Australia (allen.cheng{at}menzies.edu.au).
 
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Abstract

Background. Melioidosis is a tropical infectious disease associated with significant mortality. Most deaths occur early and are caused by fulminant sepsis.

Methods. In this randomized, placebo-controlled trial, we assessed the efficacy of lenograstim (granulocyte colony-stimulating factor [G-CSF], 263 µg per day administered intravenously) in ceftazidime-treated patients with severe sepsis caused by suspected melioidosis in Thailand.

Results. Over a 27-month period, 60 patients were enrolled to receive either G-CSF (30 patients, 18 of whom had culture-confirmed melioidosis) or placebo (30 patients, 23 of whom had culture-confirmed melioidosis). Mortality rates were similar in both groups (G-CSF group, 70%; placebo group, 87%; risk ratio, 0.81; 95% confidence interval, 0.61–1.06; P = .2), including among patients with confirmed melioidosis (83% vs. 96%; P = .3). The duration of survival was longer for patients who received G-CSF than for patients who received placebo (33 h vs. 18.6 h; hazard ratio, 0.56; 95% confidence interval, 0.31–1.00; P = .05).

Conclusions. Receipt of G-CSF is associated with a longer duration of survival but is not associated with a mortality benefit in patients with severe sepsis who are suspected of having melioidosis in Thailand. We hypothesize that G-CSF may “buy time” for severely septic patients, but survival is more likely to be improved by management of associated metabolic abnormalities and organ dysfunction associated with severe sepsis.

Melioidosis, an infection caused by the bacterium Burkholderia pseudomallei, is a major cause of community-acquired septicemia in northeast Thailand. Treatment is difficult; despite improvements in diagnostics and treatment regimens, the mortality rate associated with severe melioidosis remains unacceptably high. In Thailand, the in-hospital mortality rate for patients with culture-confirmed melioidosis who are treated with parenteral ceftazidime, the first-line therapy of choice, is 40%–50% [1].

Most fatalities occur in the subgroup of patients with severe sepsis; although the introduction of ceftazidime substantially improved mortality rates, studies have shown that the choice of antibiotic does not reduce mortality within the first 48 h of hospital admission [2, 3]. Thus, additional interventions are required to reduce early mortality in this group with poor outcomes. One possibility is treatment with granulocyte colony-stimulating factor (G-CSF). G-CSF was adopted for use in patients presenting to the Royal Darwin Hospital (Darwin, Australia) with septic shock caused by melioidosis in December 1998. In a retrospective analysis, mortality rates decreased from 95% to 10% after the introduction of G-CSF [4]. However, these results were potentially confounded by concomitant changes in patient care over the same period.

The findings of clinical trials of treatment with G-CSF in patients without neutropenia, conducted in areas where melioidosis is not endemic, have been less impressive; a systematic review of 5 clinical trials of G-CSF failed to reveal any benefits associated with its use [5]. It was suggested that delays in the administration of G-CSF, because of microbiological confirmation being part of the enrollment criteria, may have contributed to the negative findings of previous studies [6]. In view of the continued uncertainty regarding the effect on mortality of G-CSF administered to patients with severe melioidosis, we undertook a prospective study in a major center in northeast Thailand, where melioidosis is highly endemic.

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Methods

A randomized placebo-controlled trial of G-CSF was performed at Sappasithiprasong Hospital, located in Ubon Ratchathani, in northeast Thailand. Patients were allocated to receive either lenograstim (Granocyte; Chugai Pharmaceutical) administered intravenously at 263 µg per day or placebo (1 mL of normal saline) for 3 days. Patients were identified from active surveillance of daily hospital admission logs; ward rounds of medical, respiratory care, and intensive care wards 3 times daily; and discussion with treating clinicians.

Inclusion and exclusion criteria. Patients were included if they were suspected of having community-acquired melioidosis (onset within 72 h of hospital admission), had severe sepsis by the criteria outlined below, agreed to stay in the hospital for intravenous antibiotic therapy, were adults (age, >14 years), were willing to participate in the study, and provided written, informed consent (if the patient was not able to give consent because of illness, consent was obtained from relatives). Severe sepsis and end-organ perfusion abnormalities were defined by standard criteria and previous studies of septic shock [7,8,9–10]. Renal disease was defined as preexisting renal impairment (serum creatinine level of >2.0 mg/dL or >176 mmol/L) or renal calculi, associated with endemic distal renal tubular acidosis in this region [11].

Sepsis was defined as ⩾2 of the following signs and symptoms clinically ascribed to infection: fever (temperature >38°C or <t;36°C), tachycardia (heart rate >90 beats/min), tachypnea (respiratory rate >20 breaths/min, PaCO2 <t;32 mmHg, or receipt of mechanical ventilation), and/or a WBC count >12,000 cells/mL or <t;4000 cells/mL or >10% band forms. Severe sepsis was defined as the presence of ⩾2 of the following end-organ perfusion abnormalities: shock (systolic blood pressure <t;90 mmHg, a decrease of systolic blood pressure of >40 mmHg from baseline, or requirement for vasopressors or inotropes for >1 h in the absence of other causes of hypotension [e.g., anesthesia or antihypertensive medication] despite adequate fluid challenge sufficient to restore circulating blood volume), metabolic acidosis (pH <t;7.3, base excess lower than -5, or a lactate level of ⩾3 mg/L), respiratory dysfunction (need for mechanical ventilation or PaO2/FIO2 <t;300), renal dysfunction (oliguria <t;500 mL per 24 h, creatinine level >2.0 mg/dL, or renal replacement therapy), altered mental status (Glasgow coma score <t;12 if not sedated), liver dysfunction (bilirubin level of >2.0 mg/dL), and thrombocytopenia (platelet count <t;100,000 cells/mL).

Patients were excluded from the study if the time from the diagnosis of septic shock was >24 h; if they were known to have a hematologic malignancy, myelodysplasia or congenital neutropenia, febrile neutropenia (WBC count of <t;1000 × 106 cells/dL), or hypersensitivity to G-CSF; if they were pregnant or lactating; if they were not expected to remain in the hospital for treatment; if they were known to have an objection to participation in the study; or if they were previously enrolled in the study or had received G-CSF within the past month. Patients with community-acquired sepsis with cultures positive for other organisms or with clinical features suggesting an alternative diagnosis (e.g., presence of eschar) were also excluded.

Randomization. The randomization sequence for the G-CSF trial was generated by Kasia Stepniewska (Mahidol University, Bangkok, Thailand) using the ralloc module for Intercooled Stata 7.0 [12] and was concealed from all investigators during the study. Block randomization using varying block sizes was used to minimize large imbalances between the intervention groups. The study drugs were packaged, numbered, and labeled a priori by a member of staff not associated with the study team and were given to ward nurses with instructions for administration. Treating nurses were asked not to disclose the treatment allocation to patients, treating medical staff, or researchers. Blinding was not tested but was likely to be incomplete because of elevated WBC counts in most patients treated with G-CSF, which was not concealed from clinicians.

Assessment of patients and outcomes. Patients were closely observed by clinicians and the study team for progression of the disease and any adverse effects of any treatment. Treatment with G-CSF was stopped if WBC counts were <t; 75,000 × 106 cells/mL. Apart from the study medications, patients received standard treatment for sepsis and melioidosis, including mechanical ventilation, inotropic support, and fluid management. Renal replacement therapy was not available to patients with acute renal failure. Ceftazidime was administered for at least 10 days or until the patient showed a clear improvement in signs and symptoms, including the clearance of fever for ⩾48 h. Severity of illness was assessed using the APACHE 2 scoring system [13], the sepsis-related organ function assessment (SOFA), and a previously proposed melioidosis scoring system. The SOFA score is a well-validated scoring system measuring the severity of organ dysfunction in 6 domains (CNS, respiratory, cardiovascular, hepatic, clotting, and renal) [8, 9]. Our previously proposed melioidosis scoring system was based on predictors of mortality in Australia and assessed age, presence of pneumonia, acidosis, renal function, bilirubin measurement, and lymphocyte count [14]. Standard oral antibiotic therapy (doxycycline and cotrimoxazole with or without chloramphenicol) was then administered for a minimum of 20 weeks.

The primary outcome measures were 28-day mortality and duration of survival. Secondary outcome measures were fever clearance time; adverse drug reactions; SOFA scores [9] at days 1, 3, 7, and 10; time to resolution of shock; duration of mechanical ventilation; and duration of hospitalization.

Statistical considerations. Previous data had shown that mortality from septic shock caused by melioidosis in Thailand was as high as 80%–95% (data not shown), consistent with mortality rates in Darwin, Australia, before the introduction of G-CSF [4]. We wished to demonstrate a reduction in mortality rate from 80% to 40% with 80% power at the .05 significance level, suggesting that 60 patients would be required for the study.

We analyzed data on an intent-to-treat basis, with an important a priori subgroup being patients with culture-confirmed melioidosis. Other a priori analyses were adjusting for severity of illness using APACHE 2 scores, whether a patient had diabetes mellitus, and a survival analysis. Proportions were compared using Fisher's exact test, medians were compared by the Mann-Whitney nonparametric U test, and the duration of survival was compared by the log rank test and a Cox regression model using Stata/SE, version 9.0 (Stata Corp.)

Ethical considerations. We chose to look for a large reduction in mortality following consultation with local clinicians, because we believed that this level of benefit would have to be present if the use of G-CSF was to be sustainable in Thailand. Ethical permission for this study was obtained from the Ministry of Public Health, Royal Government of Thailand, and the Human Research Ethics Committee of the Menzies School of Health Research, Australia. This trial was registered with the Australian Clinical Trials Registry (ACTR 12605000024640) and International Standard Randomised Controlled Trial Number Register (ISRCTN 26167403).

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Results

From August 2003 through November 2005, 60 patients with suspected melioidosis were enrolled in the study; 30 patients received ceftazidime with G-CSF and 30 received ceftazidime alone. of these patients, 41 had culture-confirmed melioidosis (18 in the G-CSF arm and 23 in the placebo arm) (figure 1). Among the 19 patients who did not have culture-confirmed melioidosis, no microbiological diagnosis was made for 10 patients; among the remaining patients, Klebsiella species (2 patients), Escherichia coli (2 patients), Acinetobacter species (2 patients), and gram-positive organisms (3 patients) were isolated from blood cultures.

Figure 1
Figure 1

Flow of patients in a trial of granulocyte colony-stimulating factor (G-CSF) for the treatment of severe sepsis caused by melioidosis in Thailand.

During this time, ∼4000 patients were screened for eligibility (figure 1), and culture-confirmed melioidosis was diagnosed in 599 patients; of these patients, 202 (33%) died. Among the patients with melioidosis who were excluded, 41 were children, 40 had chronic presentations of melioidosis, 4 had febrile neutropenia, 99 did not have sepsis at presentation, 229 did not have organ dysfunction sufficient to meet eligibility criteria, and 29 did not remain in the hospital for treatment; 116 patients did not have clinical suspicion of melioidosis, and for these patients, the diagnosis was made from culture results >24 h after hospital admission. Among these 116 patients who were eligible for this study but were not enrolled because they did not have clinically suspected melioidosis, the overall mortality rate was 77%, and the median duration of survival was 37 h (interquartile range [IQR], 14–81 h).

Baseline characteristics were similar in both groups with suspected melioidosis (table 1). The severity of illness was similar, reflected in a median APACHE 2 score of 22 in both groups. The median SOFA score (G-CSF group, 9; placebo group, 7) and median melioidosis score (6 in both groups) were also similar at baseline. A higher proportion of patients in the G-CSF group had diabetes mellitus (63% vs. 47%). A higher proportion of patients in the placebo group had pneumonia (67% vs. 53%), and this was also reflected in markers of respiratory dysfunction (the median PaO2/FIO2 was 214 in the placebo group and 310 in the G-CSF group). Renal dysfunction (73% of patients had baseline creatinine levels of >2.0 mg/dL) and acidosis (70% had baseline bicarbonate levels of <t;15 mmol/L) were common at baseline. Similar differences were evident when patients with culture-confirmed melioidosis were considered separately (table 1).

Figure 2
Figure 2

Survival curves for patients receiving granulocyte colony-stimulating factor (G-CSF) and placebo.

Table 1
Table 1

Baseline characteristics of patients in a trial of granulocyte colony-stimulating factor (G-CSF) for the treatment of severe sepsis caused by melioidosis in Thailand.

In an intent-to-treat analysis of all patients suspected of having melioidosis, 78% died at a median of 25.5 h following enrollment (table 2). G-CSF–treated patients had a lower crude mortality than did patients who received placebo (70% vs. 87%; risk ratio [RR], 0.81; 95% CI, 0.61–1.06), but the difference was not statistically significant (P = .2). The median survival of patients who received G-CSF was longer than for those who received placebo (34 h vs. 19 h; hazard ratio [HR], 0.56; 95% CI, 0.31–1.00; P = .05) (Figure 2). In a Cox regression analysis, adjusting for APACHE 2 score, treatment with G-CSF was associated with longer survival (HR, 0.62; 95% CI, 0.34–1.12; P = .117), but this was not statistically significant. APACHE 2 score was associated with shorter duration of survival (HR, 1.02; 95% CI, 1.02–1.11; P = .003)

Table 2
Table 2

Outcomes among patients in a trial of granulocyte colony-stimulating factor (G-CSF) for the treatment of severe sepsis caused by melioidosis in Thailand.

In patients with culture-confirmed melioidosis, similar differences were observed: mortality rate was lower in the G-CSF group (83%) than in the placebo group (96%), but this difference was not statistically significant (RR, 0.87; 95% CI, 0.70–1.1; P = .3). The duration of survival in patients with culture-confirmed melioidosis was longer in G-CSF–treated patients (median survival, 33.5 h) than in placebo-treated patients (median survival, 15 h; HR, 0.51; 95% CI, 0.26–1.0; P = .05). No significant differences in mortality were present in patients with diabetes.

WBC count at enrollment was higher in G-CSF–treated patients (median WBC count, 14,800 cells/mL; IQR, 8100–18,250 cells/mL) than in placebo-treated patients (median WBC count, 10,000 cells/mL; IQR, 3930–17,600 cells/mL). Among the 21 patients who survived to day 3, WBC counts were higher in patients treated with G-CSF (median WBC count, 24,850 cells/mL; IQR, 17,970–33,900 cells/mL) than in those treated with placebo (median WBC count, 9050 cells/mL; IQR, 7290–13,450 cells/mL; P = .002).

Because of the short duration of survival, no meaningful analysis of trends in markers of organ dysfunction or other secondary outcome measures could be performed. The median SOFA score for all 60 patients at baseline was 9.5 (IQR, 7–12). Among patients who survived to day 3, the median SOFA score on day 1 was 7 (IQR, 6–9), and the median SOFA score on day 3 was 7 (IQR, 4–11). No patient had adverse events attributed to treatment, and no patient was withdrawn from the study because of high WBC counts.

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Discussion

Melioidosis has a wide spectrum of severity; this study enrolled patients with severe sepsis, which is associated with the highest mortality. A previous study that compared patients who received G-CSF with historical control subjects in Darwin, Australia, suggested a large mortality benefit associated with G-CSF treatment [4]. However, in the present clinical trial, conducted in Thailand, no significant effect on mortality was demonstrated in association with the use of G-CSF.

G-CSF has been widely used in the treatment of congenital and acquired neutropenias [15, 16]. In animal models, prophylactic treatment with G-CSF reduced sepsis-related mortality among nonneutropenic mice [17, 18]. G-CSF acts to increase the production of neutrophils and also results in an improvement in neutrophil function. Neutrophil function has been shown to be impaired in conditions such as malnutrition [19], diabetes [20], chronic renal failure [21], and hazardous alcohol use [22], all of which are more common in patients with melioidosis [23,24–25]. G-CSF also has immunomodulatory effects, suppressing the proinflammatory cytokines IL-2 and IFN-γ and stimulating the production of the antiinflammatory cytokine receptor antagonists to IL-1, soluble receptors to TNF and IL-10 [26]. In addition, G-CSF may increase the intracellular concentration of antibiotics [27].

No previous studies have demonstrated significant benefits associated with G-CSF in patients with pneumonia. Our previous study in Darwin had potential confounders, including the earlier use of effective antibiotics and the adoption of a closed intensive care model [4]. In Thailand, severely septic patients are managed in a relatively resource-constrained environment: no invasive monitoring was available, ventilatory and inotropic support was limited, and nurse-to-patient ratios were lower than in developed countries. of importance, renal replacement therapy was not available; a high proportion of patients in this study presented with a severe metabolic acidosis associated with acute renal failure.

In view of the limited supportive care, it is remarkable that any effect on survival could be demonstrated. Patients treated with G-CSF survived almost twice as long as did patients treated with placebo (albeit, survival was still measured in hours), and this effect size was similar after adjustment for the severity of illness. The majority of patients in this study had melioidosis, and this effect was also seen for this group. We hypothesize that G-CSF may “buy time” for patients with severe sepsis caused by melioidosis, possibly by reversing functional neutrophil defects associated with risk factors for this disease or possibly through an antiinflammatory effect. However, the ultimate outcome may depend on other factors, particularly on the management of severe acidosis, renal failure, and other organ dysfunction associated with severe sepsis. Limited data also suggest that the high mortality rate seen here may not be limited to patients suspected of having melioidosis; the crude mortality associated with Staphylococcus aureus bacteremia in the same hospital is 48% [28].

Limitations of the study included the difficulty in early identification of patients with melioidosis, which hampered enrollment. The clinical presentation of melioidosis is similar to that of other causes of severe sepsis, including other bacterial disease, leptospirosis, and scrub typhus. Clinical findings are not specific, and the rapid diagnostic tools available, such as direct immunofluorescence, lack sensitivity [29, 30]. Despite this, we believe that we have answered the clinical question of whether G-CSF treatment is associated with sustainable, clinically significant benefit when administered early in patients with suspected melioidosis in Thailand. Furthermore, considering the early and high mortality observed in both groups, we believe it to be unlikely that we would have demonstrated a clinically significant benefit, even if more patients with melioidosis had been enrolled.

Other limitations included some differences between the groups, which were evident at baseline and could be attributed to the small size of the trial. In particular, more patients in the placebo group had pneumonia, which is a known predictor of outcome [14]. However, the severity of illness, measured by the APACHE 2 score and by other scoring systems, was similar across groups. Finally, as discussed, the resource-constrained medical environment limits the generalizability of this trial to other settings; we still advocate the use of G-CSF in severe melioidosis for patients when intensive care is not resource-constrained.

We conclude that the use of G-CSF is not associated with a clinically significant effect on mortality in severely septic patients suspected of having melioidosis in Thailand. A question remains as to whether G-CSF treatment may be of benefit in patients with less severe illness, because the overall mortality rate associated with melioidosis at this center is 40%–50%. However, it is likely that optimal fluid resuscitation and vasopressor therapy, guided by invasive monitoring, and the management of severe acidosis and acute renal failure by renal replacement therapy would be of greater benefit in critically ill patients with melioidosis in this resource-constrained setting.

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Acknowledgments

We thank Premjit Amornchai and Kumpol Wongsuvan for laboratory support and thank the medical and nursing staff at Sappasithiprasong Hospital for clinical support. Dr. Kasia Stepniewska generated the randomization list. Dr. Nick Anstey provided significant early input into the study protocol. James Baker facilitated the drug donation.

Financial support. Merck Australia, the Wellcome Trust of Great Britain, National Health and Medical Research Council of Australia (NHMRC), Murray Will Fellowship for Rural Physicians (Royal Australian College of Physicians), and Flinders University of South Australia. A.C.C. was supported by a NHMRC training scholarship, and S.J.P. was supported by a Wellcome Trust Clinical Fellowship.

Potential conflicts of interest. One-third of the lenograstim required for this study was donated by Merck Australia, the former Australian distributor of lenograstim. No financial support was received from commercial sources.

  • Received February 26, 2007.
  • Accepted April 18, 2007.
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  1. Clin Infect Dis. (2007) 45 (3): 308-314. doi: 10.1086/519261
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