More Help with Sepsis from Biologics

Abstracts & Commentary

Synopsis: rhIL-11 given orally to neutropenic rats experimentally infected with Pseudomonas aeruginosa appears to preserve the integrity of gut epithelia while resulting in fewer pathologic changes, lower levels of endotoxin and numbers of bacteria in the tissues, and longer survival. Recombinant human interleukin 11 (rhIL-11) administration was associated with a reduction in a variety of infectious complications, including bacterium due to Gram-negative bacilli originating from the gut among patients given intensive chemotherapy for hematologic malignancies.

Sources: Ellis M, et al. Recombinant human interleukin-11 and bacterial infection in patients with haemotological malignant disease undergoing chemotherapy. Lancet. 2003;361:275-280; Opal SM, et al. Orally administered recombinant human interleukin-11 is protective in experimental neutropenic sepsis. J Infect Dis. 2003;187:70-76.

Interleukin-11 is a pleiotropic cytokine with several targets in addition to the main one, the megakaryocyte. These include, surprisingly, the enterocyte. For example, rhIL-11 is known to protect hamsters from mucositis induced by 5-fluorouracil and radiation therapy.1 It has other broad immunoprotective capabilities, primarily in downregulating proinflammatory responses. Furthermore, Opal and colleagues showed that rhIL-11 protects rats against experimental sepsis due to Pseudomonas aeruginosa, and when oral human IL-11 is given to the animals, systemic levels of endotoxin were reduced and the animals maintained their mucosal mass. Moreover, in both hamsters and rats, weight loss was reduced by rhIL-11. Interestingly, TNF-alpha and interferon-gamma messenger RNA were also reduced in enterocytes, suggesting that rhIL-11 preserves epithelial cell integrity and providing a rationale for its use as an adjunct to treating or ameliorating sepsis due to enteric bacteria.

Investigators at Tawan Hospital in Al-Ain, United Arab Emirates, in collaboration with Swedish and Welsh colleagues, studied 40 patients undergoing intensive chemotherapy for hematologic malignancies (mainly AML and ALL). Patients were randomly assigned to receive 50 µg/kg rhIL-11 or a matching saline placebo subcutaneously daily from the start of chemotherapy for as long as granulocytes remained below 0.5 × 109/L or for 21 days—whichever was longer. Fever was managed by giving empirical therapy, and G-CSF was given to two-thirds of patients because of severe neutropenia (granulocytes < 0.1 × 109/L for more than 10 days) There were 20 patients in each group, the average age was 36, and the men outnumbered the women 3 to 1.

rhIL-11 was given for an average of 21.5 days and the placebo for an average of 24 days. The main outcome was a reduction in bacteremia, and other outcomes included the time to occurrence of first bacteremia, the distribution of bacteria among patients, febrile events, and mucosal damage. On both counts, rhIL-11 succeeded in outperforming a placebo. Thirteen patients in the placebo group experienced bacteremia involving 20 different species, of which 15 were Gram-negative bacilli compared with only 5 patients in the treatment group involving 6 species, of which 4 were Gram-negative bacilli. Bacteremia also occurred later in the rhIL-11 group. Significantly fewer patients given rhIL-11 developed pneumonia and enterocolitis (10% and 20%, respectively) than in the placebo group (45% and 40%, respectively). Hypotension associated with sepsis also affected only 2 patients given the rhIL-10 compared with 7 given placebo. Logistic regression indicated that treatment with rhIL-11 was the only factor to independently reduce the risk of enteric bacteremia (P = .04) .

The C-reactive protein concentration was higher in rhIL-11 patients before and during neutropenia, but the rate of oral mucositis was significantly reduced. As might be expected, the rhIL-11 group also recovered the platelet count faster. The urinary lactulose-mannitol ratio was used to assess gastrointestinal permeability and was more often normal for patients given rhIL-11 (14/18, or 78%) than for those given the placebo (9/20, or 40%). Two patients died in each group: two in the treatment group secondary to nonbacterial causes and 1 in the treatment group that may have died as a result of Clostridium difficile enterocolitis. Apart from peripheral edema that affected 6 patients given rhrhIL-11 and 2 given the placebo, the side effects were infrequent, mild, and considered manageable.

Comment by J. Peter Donnelly, PhD, and Joseph F. John, Jr., MD

The race continues to bolster the antimicrobial therapy of sepsis. Clinicians in the United States have of late been wrestling with the role that drotrecogin alpha (Xigristm) should play in managing sepsis, and usage does seem to be increasing, particularly in intensive care units. We are currently awaiting more information about its efficacy and toxicity in phase 4 trials.

The approach taken by Ellis and colleagues was motivated by the long-held belief that the gut is the origin of Gram-negative bacillary infection in neutropenic patients and that its integrity is damaged by cytoreductive chemotherapy. Hence, they designed, in essence, a proof-of-concept study to see whether treatment with rhIL-11 would reduce Gram-negative sepsis and , if so, if it was associated with preservation of the mucosal integrity of the gastrointestinal tract.

The study was carried out in a hospital in the UAE in collaboration with Swedish and Welsh scientists. Although the number of patients was small, the outcomes were virtually all polarized in favor of rhIL-11. One might quibble over whether bacteria such as Fusobacterium species and Stenotrophomonas maltophilia are enteric in origin, but the fact remains that if the reduction in bacteremia is shown to be as large as found in this study, then there is an enormous potential benefit for these patients and not just in terms of Gram-negative sepsis. The rates of pneumonia were also significantly lower after treatment with rhIL-11. Hence, the patients benefited from rhIL-11 by experiencing fewer infectious complications all around.

Of particular interest was the apparent preservation of gut integrity, suggesting a strategy of stabilizing enterocyte integrity to reduce transposition of bacteria across the intestinal mucosa. If this is true, then one could extend this to other patients such as those in the ICU because of trauma or surgery. Furthermore, unlike some other biological agents being used in clinical practice like the interferons, the rate of fever in the rhIL-11 group was actually lower than that in the placebo group, although CRP levels were higher.

The side effects of almost 3 weeks of subcutaneous treatment were not considered important, although the occurrence of peripheral edema might well give cause for concern. The fact that that gut mucosa was preserved appears to complete the picture and proves the earlier observations in hamsters were correct.

Just as this clinical paper appeared, Opal et al extended their original observations that rhIL-11 and rhG-CSF improved the outcome of experimentally induced Gram-negative sepsis in neutropenic rats2 by exploring an oral form of rhIL-11 in the same model. This treatment reduced the expression of genes for TNF-a and interferon-g in enterocytes, suggesting that the compound may preserve epithelial cell integrity during chemotherapy. Taken together, it would appear that rhIL-11 acts directly on the gut mucosa. This is very exciting, indeed, since rhIL-11 in an oral form offers an approach to preventing or at least ameliorating the gut toxicity induced by the intensive cytoreductive chemotherapy used to treat hematologic malignancies and to prepare for stem cell transplants. A formal blinded, placebo-controlled trial with sufficient power that showed gut integrity to be maintained and infectious complications to be reduced would make a major contribution to the well-being of thousands of patients by consigning mucositis in its oral and gut manifestations to history, protecting patients against the ravages of Gram-negative sepsis without having to resort to antimicrobial agents for prophylaxis, and helping them maintain their weight and perhaps even continue eating and drinking normally. What more can one ask? 

Dr. Donnelly is Clinical Microbiologist University Hospital Nijmegen, The Netherlands Section Editor, Microbiology.

Dr. John is Chief, Medical Subspecialty Services, Ralph H. Johnson Veterans Administration Medical Center; Professor of Medicine, Medical University of South Carolina, Charleston, SC.

References

1. Sonis S, et al. Leukemia. 1999;13:831-834.

2. Opal S, et al. Blood. 1999;93:3467-3472.