Plasma Angiopoietin 2 Concentrations Are Related to Impaired Lung Function and Organ Failure in a Clinical Cohort Receiving High-Dose Interleukin 2 Therapy
Gores, Kathryn M.; Delsing, Angela S.; Kraus, Sara J.; Powers, Linda; Vaena, Daniel A.; Milhem, Mohammed M.; Monick, Martha; Doerschug, Kevin C.
Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
Received 4 Feb 2014; first review completed 25 Feb 2014; accepted in final form 3 Apr 2014
Address reprint requests to Kathryn M. Gores, MD, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Dr, Iowa City, IA 52242. E-mail: email@example.com.
This work was supported by the National Center for Advancing Translational Science and the National Institutes of Health through 2 UL1 TR000442-06 and R01 HL 092056.
The authors have no financial disclosures and no conflicts of interest to report. All authors have approved the manuscript and its submission to this journal.
The content is solely the responsibility of the authors and does not necessarily represent official views of the NIH.
K.M.G. contributed to acquisition of data, analysis and interpretation of data, drafting the submitted article, and revising it critically for important intellectual content. A.S.D. and S.J.K. contributed to conception and design, acquisition of data, and approval of the final manuscript. L.P. contributed to data analysis and approval of the final manuscript. D.A.V. and M.M.M. contributed to subject recruitment and approval of the final manuscript. M.M. contributed to data analysis and revising the manuscript critically for intellectual content. K.C.D. contributed to study conception and design, acquisition of data, analysis and interpretation of data, drafting the submitted article, and revising it critically for important intellectual content.
ABSTRACT: Introduction: The pathophysiology and therapeutic options in sepsis-induced lung injury remain elusive. High-dose interleukin 2 therapy (HDIL-2) is an important protocol for advanced malignancies but is limited by systemic inflammation and pulmonary edema that is indistinguishable from sepsis. In preclinical models, IL-2 stimulates angiopoietin 2 (AngP-2) secretion, which increases endothelial permeability and causes pulmonary edema. However, these relationships have not been fully elucidated in humans. Furthermore, the relevance of plasma AngP-2 to organ function is not clear. We hypothesized that plasma AngP-2 concentrations increase during HDIL-2 and are relevant to clinical pathophysiology. Methods: We enrolled 13 subjects with metastatic melanoma or renal cell carcinoma admitted to receive HDIL-2 and collected blood and spirometry data daily. The plasma concentrations of AngP-2 and IL-6 were measured with enzyme-linked immunosorbent assay. Results: At baseline, the mean AngP-2 concentration was 2.5 (SD, 1.0) ng/mL. Angiopoietin 2 concentrations increased during treatment: the mean concentration on the penultimate day was 16.0 (SD, 4.5) ng/mL and increased further to 18.6 (SD, 4.9) ng/mL (P < 0.05 vs. penultimate) during the last day of therapy. The forced expiratory volume in 1 s decreased during treatment. Interestingly, plasma AngP-2 concentrations correlated negatively with forced expiratory volume in 1 s (Spearman r = −0.78, P < 0.0001). Plasma AngP-2 concentrations also correlated with plasma IL-6 concentrations (r = 0.61, P < 0.0001) and Sequential Organ Failure Assessment scores (r = 0.68, P < 0.0001). Conclusions: Plasma AngP-2 concentrations increase during HDIL-2 administration and correlate with pulmonary dysfunction. High-dose IL-2 may serve as a clinical model of sepsis and acute lung injury. Further investigation is warranted.
Severe sepsis is a systemic inflammatory response syndrome (SIRS) in the setting of infection that results in acute organ failure (1). Severe sepsis is a major health care concern, killing one in four people who develop the syndrome and continuing to increase in incidence (2, 3). Unfortunately, the mechanisms leading to multiorgan failure are poorly understood, and therapeutic approaches remain limited. Furthermore, heterogeneities in subjects and the timing of interventions introduce challenges to clinical investigations of severe sepsis.
Capillary permeability is tightly regulated in health but fundamentally altered in sepsis. This disruption in endothelial barrier integrity causes a vascular leak syndrome. In the lung, this manifests as acute lung injury (ALI) and is associated with 25% to 35% mortality (4, 5). Angiopoietin 2 (AngP-2) is stored in Weibel-Palade bodies and is released in response to activation of the vascular endothelium in response to inflammation or stress (6). AngP-2 competitively inhibits binding of AngP-1 at the Tie-2 receptor. Preclinical models of ALI demonstrate that AngP-2 causes paracellular endothelial gap formation in vitro and pulmonary leak in murine models (7). Overwhelmingly, clinical models of systemic inflammation have focused on markers present in subjects with clinically manifested ARDS rather than the profile of inflammatory markers leading up to the development of lung injury. In clinical sepsis, plasma AngP-2 concentrations are related to impaired oxygenation (8), the development of ALI (9), and mortality (10). A thorough understanding of the progression of activated pulmonary endothelium and the role of AngP-2 secretion in regulating permeability may help us address the mechanisms of organ injuries in SIRS and sepsis.
High-dose interleukin 2 (IL-2) therapy (HDIL-2), used in treatment of advanced malignancies, induces a vascular leak syndrome (11) that is clinically indistinguishable from sepsis and thus a compelling model of endothelial barrier dysfunction. Sera of HDIL-2–treated human subjects have high concentrations of AngP-2, and these sera induce permeability in lung models (7). The effects of AngP-2 within pulmonary tissue are implied by ex vivo models, tissue cultures, and animal models but have not yet been demonstrated in humans. We therefore chose to investigate whether HDIL-2 leads to an increase in circulating AngP-2 and whether plasma AngP-2 levels are clinically relevant in the evolution of systemic inflammation and lung dysfunction.
We hypothesized that plasma AngP-2 concentrations increase during HDIL-2 and are relevant to clinical physiology. We designed a study to prospectively enroll human subjects receiving HDIL-2 for metastatic melanomas and renal cell carcinomas to study the progression of SIRS and organ dysfunction in a human population.
MATERIALS AND METHODS
We studied 13 subjects admitted to our medical intensive care unit (ICU) for HDIL-2 for metastatic renal cell carcinomas or melanomas. These subjects were identified by oncology clinic staff members as candidates for treatment. High-dose IL-2 is not offered to patients with significant comorbidities including cardiovascular, respiratory, renal, or hepatic dysfunction, and thus no additional inclusion or exclusion criteria were utilized. Informed consent was obtained upon admission to the ICU, before the first dose of HDIL-2. The study was approved by the University of Iowa Institutional Review Board (#201202738).
Clinical administration of HDIL-2
The clinical use of HDIL-2 is not an experimental intervention, but part of a standard clinical protocol that is similar to that used at other institutions (12, 13). High-dose IL-2 is indicated as a standard treatment option for selected patients with metastatic kidney cancer and metastatic melanoma. Patient selection includes excellent cardiopulmonary and other end-organ function as well as extent of metastatic disease, histological subtype, and details of prior therapies (14). A brief overview of the IL-2 protocol is as follows: HDIL-2 was prescribed at 600,000 U/kg intravenously every 8 h for up to 14 doses administered via peripherally inserted central catheter placed upon admission. Patients were assessed for stability by the ICU team before each dose. Decisions to stop or hold HDIL-2 were made by the by the oncologists who were blinded to research measures and generally reflect clinical assessments of overwhelming organ failure. Common indications for stopping include (a) urine output of less than 80 mL in 8 h; (b) serum creatinine of more than 4 mg/dL or abrupt rise from baseline; (c) rapidly progressive shock or high vasopressor needs; (d) requirement for supplemental oxygen; and (e) more than one dose held in 24 h. Fluids and norepinephrine were administered based on clinical evaluation of volume status and presence of hypotension.
Research data collection
We collected clinical data from the medical record throughout treatment, including (a) values necessary to calculate daily Sequential Organ Failure Assessment (SOFA) scores (15), (b) fluid balance, (c) cumulative HDIL-2 doses, and (d) data related to demographics and comorbidities. Acute renal failure was defined a priori as a rise in serum creatinine of more than 0.3 mg/dL in 8 h. Shock was determined to be present if vasopressors were utilized in the preceding 8 h. Before the first dose of HDIL-2 and then daily, we collected blood for research analysis and measured pulmonary function using a portable spirometer (EasyOne Spirometer; NDD Medical Technologies, Andover, Mass). The subjects performed spirometry with a minimum of three attempts in the seated position in an ICU bed for all time points. American Thoracic Society consensus criteria (16) were used to determine adequacy of results. Some subjects refused parts of the study while receiving HDIL-2.
We measured the concentrations of AngP-2 and IL-6 in plasma samples from baseline, penultimate, and last days of HDIL-2 using commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kits (both R&D Systems, Minneapolis, Minn). Because the duration of HDIL-2 is determined by patient tolerance, the penultimate and last days of therapy cannot be identified a priori and do not occur in a set day of therapy (e.g., day 3) for all subjects.
Data were analyzed with GraphPad Prism software version 5.0 (San Diego, Calif). Plasma concentrations were compared throughout treatment using one-way analysis of variance (ANOVA) for repeated measures or Friedman test according to sample distribution. Significant differences (two-sided α < 0.05) were evaluated with Tukey multiple-comparisons test, test for linear trend, or Dunn multiple-comparisons test, as appropriate. Spearman correlation was used for comparison of continuous variables with non-Gaussian distribution.
We enrolled 13 subjects admitted to our ICU for HDIL-2. Subject ages ranged from 33 to 65 years old, and four subjects (31%) were male. Six subjects had metastatic melanoma, whereas the remainder had renal cell carcinoma. While the latter subpopulation had nephrectomies before enrollment, baseline serum creatinine ranged from 0.6 to 1.3 in all subjects.
The median number of HDIL-2 doses was 12 (range, 8–14). High-dose IL-2 initiated systemic inflammation as evidenced by an acute rise in plasma IL-6 concentration. Specifically, the mean concentration of IL-6 in plasma at baseline was 50.7 (SD, 75.7) pg/mL. This value increased to 267.5 (SD, 260) pg/mL on the penultimate day, and 192.5 (SD, 150) pg/mL on the last day of therapy (Friedman test P = 0.002; Dunn multiple comparison P < 0.05 for both penultimate and last days versus baseline, data not shown).
Subjects exhibited signs of organ failure during HDIL-2, as summarized in Table 1. During therapy, 10 subjects (77%) developed acute renal failure. Subjects uniformly had a positive fluid balance during therapy, with a median cumulative fluid balance of 9.5 L (range, 5.6–12.6 L). Despite fluids, seven subjects (54%) developed shock treated with vasopressors. As a whole, multiorgan failure was common as defined by a median SOFA score of 7 (range, 2–9).
The SOFA scoring system utilizes Pao2/Fio2 ratios to measure pulmonary organ failure. As previously stated, supplemental oxygen is a stop criterion for HDIL-2, thus Pao2/Fio2 may not be a sensitive assessment for evolving lung injury during this treatment. At baseline, the mean values for forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were 77% and 90% of predicted values, respectively (Fig. 1), and the FEV1/FVC ratio was 0.66. Both FEV1 and FVC decreased during the first 3 days of HDIL-2 (ANOVA P < 0.0001, with posttesting P < 0.0001 for downward linear trend), when all subjects continued therapy and performed spirometry. The FEV1/FVC ratio did not change during HDIL-2.
We measured the plasma concentration of AngP-2 during HDIL-2. At baseline, the mean AngP-2 concentration was 2.5 (SD, 1.0) ng/mL, a value somewhat higher than the range 0.32 to 1.08 ng/mL reported for control subjects (17, 18). Angiopoietin 2 concentrations increased during treatment, and the mean concentration on the penultimate day was 16 (SD, 4.5) ng/mL (Fig. 2). For most subjects, AngP-2 concentrations continued to rise up to the last day of HDIL-2, ranging from 3.8 to 28.7 ng/mL (interquartile range, 14.0–21.1 ng/mL). The mean AngP-2 concentration was 17.4 ng/mL on the last day of HDIL-2 (SD, 6.2 ng/mL; repeated-measures ANOVA P < 0.0001, Tukey multiple-comparisons test P < 0.05 vs. baseline). These values are in the range described in clinical investigations of sepsis-induced ALI (19).
We investigated relationships between plasma AngP-2 concentrations and subject physiology. Notably, plasma AngP-2 concentrations correlated with plasma IL-6 concentrations (r = 0.61, P < 0.0001; Fig. 3). During the last 2 days of therapy, the mean concentration of AngP-2 was not significantly higher in subjects who developed shock (18.6 [SD, 5.0] ng/mL) than in those subjects without shock (15.5 [SD, 4.1] ng/mL, single outlier excluded, P = 0.10). However, we found that plasma AngP-2 correlated with multiple organ failure as measured with SOFA scores (r = 0.68, P < 0.0001; Fig. 4).
Given the effects of AngP-2 upon lung endothelial tissue models, we evaluated relationships between plasma AngP-2 and evolving pulmonary pathophysiology as measured by spirometry. Notably, FEV1, expressed as percent predicted normal, correlated inversely and strongly with plasma AngP-2 concentrations (Spearman r = −0.78, P < 0.0001; Fig. 5). To further assess the relationships between AngP-2 and FEV1, we performed separate correlation analyses for each time point. We found that AngP-2 correlated inversely with FEV1 at baseline (Spearman r = −0. 72, P = 0.006) and penultimate (r = −0.61, P = 0.05) time points. We note that five subjects refused spirometry on the last day of HDIL-2, and thus their data were not available for this analysis. In the remaining subjects with last-day values, the correlation between AngP-2 and FEV1 fell short of significance (r = −0.43, P = 0.35). The mean plasma concentration of AngP-2 on the last day of HDIL-2 was higher in subjects who refused spirometry (22.0 [SD, 5.9]) ng/mL than in subjects who completed spirometry (14.6 [SD, 4.8 ng/mL]; P = 0.03, data not shown), suggesting that missing spirometry data are from the sickest subjects.
In this cohort of human subjects, we demonstrate that plasma AngP-2 concentrations increase throughout HDIL-2. More so, levels of AngP-2 correlate with systemic illness including inflammation, shock, and multiorgan failure. Our most interesting finding is that rising plasma AngP-2 concentrations correlate with the evolution of pulmonary pathophysiology.
Previous in vitro studies identified a relationship between HDIL-2 and AngP-2. Plasma from subjects receiving HDIL-2 induces increased permeability in endothelial cultures, whereas this effect is blocked by inhibition of AngP-2 (7, 20). Our data demonstrate that circulating AngP-2 is relevant to evolving pathophysiology. Specifically, our data are the first to demonstrate a direct correlation between plasma AngP-2 and progressive pulmonary dysfunction during HDIL-2.
Our findings have implications well beyond that of cancer therapy. Many aspects of HDIL-2 are indistinguishable from sepsis. The incidence of shock and acute renal failure in our subjects resembles reports of severe sepsis and early lung injury (3, 21). Our study provides further biochemical evidence of similar systemic inflammation during both HDIL-2 and sepsis. Specifically, both plasma IL-6 (22, 23) and AngP-2 (8, 24) concentrations during HDIL-2 are comparable to clinical studies of sepsis and ALI. Previous studies have demonstrated that AngP-2 levels were elevated in children with septic shock (25), as well as surgical patients with ARDS (26). The same study additionally demonstrated a correlation between mortality and the plasma AngP-2 concentration on the day clinical criteria for ARDS were met. More recently, studies showed that early increases in plasma AngP-2 in septic subjects predicted (a) the subsequent development of ALI subjects without lung injury present on admission (9) and (b) mortality (10). These studies enrolled subjects in the emergency room, arguably as early as possible during clinical sepsis. Thus, we know little regarding the events that led up to a rise in AngP-2 during clinical systemic inflammation. Our study provides the first clinical data to demonstrate the initiation of systemic inflammation that leads to simultaneous expression of AngP-2 and progressive organ injury.
Myriad preclinical models of sepsis demonstrate efficacy of innovative therapies that subsequently fail to improve patient outcomes, suggesting that such models do not fully recapitulate the clinical syndrome (27). In fact, a recent study demonstrated that acute inflammatory stresses from different etiologies result in highly similar responses in humans, while corresponding mouse model responses correlate poorly with the human conditions. This urges a higher priority for studies of complex human conditions rather than murine models (28). However, clinical investigations of sepsis are also challenged as heterogeneity of both subject populations, and timings of interventions make it difficult to find a signal and to identify appropriate and comparable time points for evaluation. Furthermore, unlike preclinical models, clinical investigations of sepsis are unable to capture a time 0 of systemic inflammation and thus may not be able to fully elucidate pathways that occur before organ injury occurs. Accordingly, both preclinical models and clinical investigations of sepsis face significant challenges to further our understanding of the pathogenesis of acute organ failure during sepsis.
Our results suggest that HDIL-2 may provide an important system in which to investigate the early pathogenesis of organ failure. Subjects who underwent HDIL-2 constitute a clinical population that (a) limits comorbidities that confound clinical investigations of sepsis, (b) progresses from time 0 to fulminant SIRS, and (c) demonstrates significant organ injury with direct relevance to clinical sepsis. Thus, HDIL-2 provides a unique model to detect the evolving relationships between effector molecules of systemic inflammation, such as AngP-2, and their roles in the pathogenesis of organ failure during clinical SIRS.
Previously, authors have proposed AngP-2 as a therapeutic target to prevent organ failure (29). Clinical investigations of HDIL-2 offer the potential to identify biochemical processes before secretion of AngP-2 is increased and thus identify additional targets to decrease AngP-2. Interleukin 2 directly stimulates endothelial cell secretion of AngP-2 without the circulating immune cells responsible for antitumor effects (20, 30). Because the therapeutic and injury pathways are likely distinct, studies aimed at decreasing AngP-2 may benefit treatment for renal cell carcinoma and melanoma. Such studies, performed during clinical SIRS from HDIL-2, may also serve to improve the outcomes of clinical sepsis.
Our study does have limitations. First we enrolled only a small number of subjects, as a limited number of patients are eligible for HDIL-2, given its indications and potential for toxicity (31). Next, cancer patients may display different responses to inflammation. This seems unlikely given the aforementioned similarities between our measures of AngP-2 and previous studies. Another limitation is that we elected to measure AngP-2 at only three time points. These were carefully selected in an attempt to provide the most informative evaluation of the progression of lung injury. In so doing, we demonstrated that AngP-2 continued to rise in the last 2 days of HDIL-2. This finding is also supported clinically, as most of our subjects had escalating multiorgan failure on their last day of HDIL-2 administration, consistent with systemic vascular leak syndrome.
We note that none of our subjects required supplemental oxygen, thus would not meet clinical definitions of mild acute respiratory distress syndrome (ARDS). However, noncardiogenic pulmonary edema during HDIL-2 is well documented and noted to be sudden and at times lethal, leading to a change in practice patterns to prevent fulminant ARDS (31). Furthermore, animal models demonstrate significant progression of lung injury even before gas exchange abnormalities (32). Thus, it seems likely that our subjects experienced the precursors of the clinical phenotype of ARDS.
An important limitation is that we did not directly measure lung injury; rather, we assume that decreasing FEV1 represents noncardiogenic pulmonary edema. Chest radiographs are not routinely ordered during HDIL-2. When chest radiographs are ordered, pulmonary edema is commonly found late in HDIL-2 (33), yet this imaging modality may not be sufficiently sensitive to detect the early phases of lung injury (34). Because IL-2 causes inflammation, acute bronchoconstriction is a possibility. However, FEV1 and FVC decreased in parallel with an unchanged FEV1/FVC ratio, consistent with an evolving restrictive process. This supports our belief that decreasing FEV1 in HDIL-2 patients is secondary to pulmonary edema. Certainly, the utility of FEV1 as a surrogate marker of lung injury in this population as well as further studies looking into the physiology underlying the decrease in FEV1 seen in HDIL-2 could be explored.
Plasma AngP-2 concentrations increase during HDIL-2 administration and correlate with clinical evolution of organ failure. High-dose IL-2 may serve as a clinical model of early sepsis and evolving ALI. Further investigations of the events and mechanisms leading to AngP-2 secretion may be beneficial to HDIL-2 as well as patients with sepsis.
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Acute respiratory distress syndrome; acute lung injury; systemic inflammatory response syndrome; interleukin 2
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