Serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF)-alpha were frequently measured during the first 30 days after allogeneic bone marrow transplantation (BMT) in 84 consecutive adult patients. Major transplant-related complications (MTCs) occurred in 33% of cases and included veno-occlusive liver disease, idiopathic pneumonia syndrome, severe endothelial leakage syndrome and >grade II acute graft-versus-host disease. Compared with patients having minor complications, those with MTCs developed higher levels at times of maximal clinical signs (all cytokines, P<0.001), between days 0–5 post-BMT (IL-6 and IL-8, P<0.05) and days 6–10 (L-6, P<0.001; IL-8 and TNF, P<0.01) post-BMT. We could not discriminate patterns of cytokine release that were specific for any subtype of MTC. Higher levels of IL-8 during days 0–5 were associated (P=0.044) with early (<40 days) death. Multivariate analysis including patient and transplant characteristics as well as post-BMT levels of C-reactive protein showed that high average levels of one or more of the cytokines within the first 10 days post-BMT were independently associated with MTC (Odd's ratio: 2.3 [1.2–4.5], P=0.011). This study shows that systemic release of proinflammatory cytokines contributes to the development of MTC and provides a rationale for pre-emptive anti-inflammatory treatment in selected patients.
Despite improvements in supportive care, the practice of allogeneic bone marrow transplantation (BMT) remains limited by its toxicity. Overall transplant-related mortality (TRM) varies between 10 and 50% and is mainly because of infections and noninfectious complications during the first months after BMT, including: acute graft-versus-host disease (AGVHD), hepatic veno-occlusive disease (VOD), pneumonitis and severe endothelial leakage syndrome (ELS). Severe AGVHD (>stage II) has a major impact on survival after BMT because of a high mortality rate either directly or because of secondary infections. In a recent prospective cohort study including more than 1500 patients, VOD occurred in 8.9% of allogeneic marrow recipients.1 VOD generally occurs within the first 20 days after BMT and can be mild, moderate or severe with a variable mortality rate, ranging between 3 and 67%.2 The idiopathic pneumonia syndrome (IPS) occurs in between 7 and 8% within the first 4 months and with a median onset of 3 weeks after allogeneic BMT. The mortality rate is close to 80%.3 ELS is an ill-defined syndrome characterized by fluid retention as the result of increased capillary permeability, often in the context of multiorgan dysfunction.4 We have previously shown that high levels of C-reactive protein (CRP) are associated with the occurrence of major transplant-related complications (MTCs), including severe AGVHD, VOD, ELS and pneumonitis.5 CRP is an acute-phase protein produced by hepatocytes and is a reliable marker of systemic inflammation.6 The inflammatory response in humans is characterized by the systemic release of proinflammatory cytokines including interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF)-alpha. These cytokines have been shown to play a role in the pathogenesis of AGVHD,7 but their role in the development of other major complications is still debated. High levels of TNF were found to precede and occasionally to coincide with severe VOD.8,9,10 High peak levels of IL-6 were seen during maximal symptoms in patients with VOD10 or a VOD-like syndrome following AGVHD.11 Also, short and very high IL-8 peaks were observed a few days after the clinical diagnosis of VOD.10 However, it remains unclear whether these cytokines play a direct role in the initiation of VOD or rather act in a later phase, contributing to the status of multiorgan failure into which many patients with this complications evolve.12 Increased levels of several cytokines, including IL-6 and TNF have been detected in the bronchoalveolar lavage fluid of patients with IPS.13 Based on similarities of ELS with the clinical manifestations of toxicity because of interleukin-2 therapy, it has been hypothesized that complement activation and endothelial injury contribute to its pathogenesis.14,15
In this study, we show that the systemic release of proin-flammatory cytokines is a common factor in the pathogenesis of all types of MTC. Our data also provide information about the relevance of measuring or monitoring cytokine levels after BMT.
Patients and methods
Patients and transplant conditions
A total of 96 consecutive allogeneic marrow transplants were performed in adult patients (age ≥15 years) in our unit between 1991 and 1999. Of these, 12 were excluded from analysis because the number of serum samples that could be evaluated was insufficient. Four patients who received a second transplant from the same donor after a second myeloablative conditioning were analyzed twice as separate patients. The median age of the 84 patients thus included was 36 years (range 15–50) and 59 (70%) were male. Diagnosis at the time of BMT was: chronic myeloid leukemia (n=31), acute leukemia (n=30), aplastic anemia (n=6), myelodysplasia (n=6), second transplant (m=4), lymphoma (n=4), myeloma (n=2), and solid tumor second tumor plant (m=4), (n=1). Patients with acute leukemia or myelodysplasia in first complete remission and chronic myeloid leukemia in first chronic phase were considered to be in a good-risk category, representing 64% of cases. Marrow was the source of stem cells in all patients and donors were HLA-identical siblings (n=73), volunteer-unrelated donors (n=10) or a haploidentical brother (n=1). From the start of the conditioning regimen until the end of neutropenia and stabilization of clinical condition, patients were hospitalized in an isolation unit with laminar air flow protection. At the same time they received norfloxacin (400 mg 3qd PO), itraconazole (200 mg 2qd PO) or fluconazole (200–400 mg qd PO or IV, adapted to renal function) and started mouthwashes with povidon-iodine solution (4qd) and liquid nystatine (100 000 IU 4qd). The conditioning regimen was always myeloablative and included total body irradiation (TBI) in 82% of cases. GVHD prevention consisted of either cyclosporin in combination with methotrexate (56%) or partial T-cell depletion by E-rosetting (44%). T-cell depletion was preferred for patients older than 40 years. Granulocyte colony-stimulating factor (G-CSF) was administered in 50% of cases after marrow infusion until stable neutrophil recovery, defined as the achievement of stable neutrophil levels above 0.2 × 109/l. Cytomegalovirus (CMV) infection was diagnosed by PCR analysis and/or antigenemia in a few cases.
Definition of major complications
Fever was defined as a recorded body temperature between 38 and 38.5°C measured on two occasions with at least 4 h interval or one measurement above 38.5°C, without concomitant transfusion of packed cells or platelets. Fluid balance and body weight as well as blood levels of bilirubine were prospectively monitored in all patients. Fluid retention was rigorously treated with fluid and salt restriction and diuretics with addition of dopamine in severe cases. All patients received a continuous infusion of heparin 100 U/kg. VOD was defined according to the modified Seattle criteria12 as the occurrence, within the first 20 days after BMT, of fluid retention of at least 2% body weight in combination with a direct bilirubinemia above 2 mg/100 ml. Hepatomegaly, right upper quadrant pain and ascites were considered additional criteria. No other explanation for these signs and symptoms could be present at the time of diagnosis. As MTCs, other than VOD, were considered: >grade II AGVHD, severe ELS and pneumonitis, all occurring within the first 40 days after BMT. AGVHD was diagnosed and staged according to the Seattle criteria.16 Severe ELS was defined as the occurrence of fever, fluid retention and weight gain of >3% without hyperbilirubinemia and in the absence of cardiac failure with insufficient response to diuretics, requiring fluid restriction and dopamine therapy. Pneumonitis was defined as the presence of fever and respiratory symptoms that could not be related to cardiac failure or generalized fluid retention and with clear demonstration of pulmonary infiltrates on chest X-ray. Early bacteremia was defined as the finding, within 30 days after BMT, of at least two positive blood cultures in a patient with fever, with identification of the bacterial species having the same antimicrobial susceptibility pattern and taken at two different time points during the same episode of fever. TRM was defined as death owing to any reason in a patient without evidence of relapse. As reason for TRM the primary cause was taken into account, for example, AGVHD when a patient died of infection in the context of AGVHD.
Serum samples were collected every 2 days or daily at times of fever from the day of BMT until stable neutrophil recovery and discharge from the BMT-Unit and stored at −20°C. Serum cytokine levels were measured on these collected samples with the aim to have at least one level of each cytokine per patient available for each 5-day episode during the first 30 days after BMT. If more samples were available during the same 5-day period, the mean value was taken into consideration, so that every 5-day period contributed equally to the statistical analysis. Daily samples were taken during episodes of fever. The average cytokine level during the first 10 days after BMT was calculated as follows: [mean d0-5+mean d6–10]/2. The average IL-6, IL-8 or TNF level for each patient was considered increased if it was above the median of the averages of the whole group. The total cytokine release score for each patient during d0–10 (TCRSd10) was calculated as the number of cytokines for which the average exceeded the median. The TCRSd10 can thus be 0,1, 2 or 3. For example: a patient with average IL-6 and IL-8 levels above the median, but an average TNF level below the median had a TCRSd10 of 2.
The cytokine levels were determined by enzyme amplified sensitivity immunoassays (Biosource, Nijvel, Belgium). The sensitivities of IL-6, IL-8 and TNF-alpha were 2, 0.7 and 3 pg/ml, respectively.
All statistical tests were carried out two tailed, at the 5% level of significance, using the Prism 3.0 or the SPSS (version 11) statistical software. For comparison of continuous variables, the Mann–Whitney test was used. The association between categorical variables was investigated by the χ2 or Fisher's exact test. Time to TRM was estimated by the Kaplan–Meier method and for comparison between groups the log-rank test was used. Sensitivity and specificity of variables were based on ROC curve analysis. For multivariate analysis, logistic regression was performed using a forward stepwise model.
Based on the study of the clinical records, all 84 post-BMT episodes were divided into three distinct categories: absence of any clinical complication except for fever without documented infection (fever only) (n=23), fever in association with documented bacteremia or mucositis or some degree of fluid retention but no criteria for MTC (minorTC) (n=33) and one or more MTC (n=28). The fever only and minorTC subgroups taken together constitute the MTC− (67%) as opposed to the MTC+ (33%) group. None of the patients with fever only or minorTC died of toxicity within the first 100 days after BMT. The 1-year probability of TRM in patients developing MTC was 61% as compared to 14% for those without MTC (P<0.001) (Figure 1). In Table 1, several relevant pre- and post-transplant variables are compared among the several subgroups of patients. As compared to the minorTC subgroup, patients with fever only were older, had more frequently T-cell depletion as GVH prophylaxis and all received marrow from a HLA-identical sibling donor. There was no significant difference in terms of pretransplant variables between the minorTC and MTC subgroups, although patients with MTC tended to have more frequently bad-risk category and less T-cell depletion. Bacteremia occurred in 27% of all patients and with comparable frequency in patients with minor or major complications. Bacteremia was caused by coagulase-negative staphylococci in 61% of the cases. Significantly more patients in the MTC+ group developed renal and hepatic dysfunction. As summarized in Table 2, a total of 38 MTC occurred in 28 patients and in 20 (71.5%) cases, only one type of MTC could be observed. VOD developed in 12 of the 81 evaluable patients and the median times to reach maximal bilirubinemia (median 5.1 mg/100 ml, range 2.6–18.1 mg/100 ml) and fluid retention (median 4%, range 2.3–8%) were 13 and 14 days, respectively. One patient developed severe hyperbilirubinemia, but was not fully evaluable for VOD. He died as the result of hepatorenal failure and was also classified as MTC. ELS occurred in eight patients and the median time to maximal fluid retention (median 5%, range 3–12%) was 13 days. Pneumonitis occurred in eight patients and was generally characterized by the appearance of bilateral infiltrates in association with progressive respiratory failure. In no case could an infectious etiology be documented (cultures of sputum or bronchoalveolar lavage) or suspected as based on response to anti-infectious therapy. Therefore, these patients were classified as having idiopathic pneumonitis syndrome. Median time to appearance of pulmonary infiltrates on X-ray was 15 days. Only three of the eight patients with pneumonitis died, which may be because of our policy of early corticosteroid treatment of this syndrome leading to the resolution of the infiltrates in the majority of cases. Nine patients had grade >II AGVHD, mostly as a secondary event and occurring later, at a median of 22 days after transplant. CMV infection was documented in 14 of the 80 (17.5%) evaluable cases and occurred at a median of 44 days (range 28–60) post-BMT. Death before day 40 post-BMT occurred in eight (9.5%) patients and the primary causes were pneumonitis (n=3), ELS (n=2), VOD (n=1), hepatorenal failure (n=1) and AGVHD>II (n=1).
Figure 2 shows the comparison of the cytokine patterns obtained in the three clinical subgroups. In this figure, we also added the pattern of patients who developed one or more MTC without AGVHD (n=17), showing that these patterns were very similar to those in the whole MTC+ group. Levels of cytokines were generally higher in the minorTC as opposed to the fever only subgroups, but the differences were small and only significant for IL-6 (days 6–15) and IL-8 (days 6–10). In contrast and in comparison with the minorTC group, levels were significantly higher in patients with MTC for IL-6 and IL-8 (days 0–20) and TNF (days 6–20 and days 26–30). Maximal levels of three cytokines were observed at times of maximal clinical signs of VOD, ELS and pneumonitis, but generally preceded the occurrence of AGVHD>II by roughly 1 week. Increases of IL-6 and IL-8 were already seen within the first days after BMT and clearly preceded clinical events, whereas TNF levels were higher in the later phase of the aplastic episode, coinciding with the time of neutrophil recovery. We could not detect significant differences between the patterns observed for the MTC, taken separately (data not shown). We also compared cytokine patterns of patients with lethal (n=8) as compared to nonlethal MTCs (n=20) and found that high levels of IL-6 (P=0.075) and especially IL-8 (P=0.044) (Figure 3) were associated with early (<d40 post-BMT) TRM.
We further focused on the first 10 days after BMT. Considering the average levels of cytokines for all patients during this period, the medians (range) of these average values were (in pg/ml): 69 (8–2934) (IL-6), 13 (2–474) (L-8) and 10 (3–75) (TNF). The TCRSd10 was not influenced by the use of TBI (P=0.16) or G-CSF (P=0.52). We found a clear relation between the TCRSd10 and the occurrence of MTC. The incidence of MTC was 68, 33, 21 and 4% for patients with scores of 3, 2, 1 and 0, respectively (P<0.001). The TCRSd10 was included in a multivariate analysis with other variables known at the time of transplant or measured in the early post-BMT episode, which could have an impact on the incidence of MTC (Table 3). It appeared that TCRSd10 was most strongly and independently associated with MTC. A TCRSd10 of one was already highly significant (Odd's ratio: 2.3; P=0.011). In addition to TCRSd10, only the average CRP levels d0–10 were significant (P=0.035), but improved the model very marginally (Odd's ratio: 1.01). Including the same variables, we also found that TCRSd10 was independently associated with the TRM at 1 year after BMT (Odd's ratio: 3.3; P<0.001). The sensitivity and specificity of some cytokine levels during the d0–5 and d6–10 levels to predict for the occurrence of MTC are summarized in Table 4.
In this study, we frequently measured IL-6, IL-8 and TNF serum levels during the first 30 days after BMT in 84 consecutive adult patients. The patterns obtained were then correlated with clinical events. Our definition of MTC was based on similar definitions used in other reports9 as well as on our own observation that patients with such complications had a 61% risk of TRM within the first year after BMT. In contrast, none of the patients without MTC died within the first 100 days after BMT and the 1-year TRM in this subgroup was only 14%. In our series, CMV infection and other serious complications such as fungal infections occurred several weeks later as compared to the types of early MTC that we defined, and it is thus very unlikely that they contributed to cytokine release within the early post-BMT phase. Bacteremia within 30 days post-BMT occurred in 27% of all cases and was mainly because of coagulase-negative staphylococci. Such infections usually have a relatively benign course but may contribute to the inflammatory response.17 Therefore, we compared patients with MTC with a subgroup developing minor complications only, including bacteremia in a similar proportion of cases.
The major finding of our study is that proinflammatory cytokine release is a factor essential and common to all types of MTC and that no particular pattern was specific for either VOD, ELS, IPS or AGVHD. AGVHD is generally accepted to be a cytokine-mediated proces. Our results strongly suggest that also VOD, ELS and IPS can be considered as the clinical correlates or end points of an exaggerated systemic inflammatory reaction with massive cytokine release. The cytokines are likely to be produced by host macrophages and endothelial cells. L-6 is released in response to tissue injury and is a key cytokine regulating the acute-phase response. L-6 induces CRP production by hepatocytes18 and CRP can amplify complement activation by T cells, leading to endothelial damage.19 L-8 can be released by activated endothelial cells in response to TNF-alpha20 and is a potent activator of neutrophils which can further contribute to tissue damage. TNF-alpha is a key mediator in inflammation, also activating endothelial cells and leading to increased vascular permeability. The trigger for cytokine release is most probably cellular damage because of the conditioning regimen, although alloreactive mechanisms occurring at a subclinical level may also play a role.
A second important finding is that significant increases of cytokines, in particular IL-6 and IL-8, could be detected within the first days after BMT. Moreover, multivariate analysis showed that early cytokine release was most strongly associated with the later development of MTC, independently from several patient (age, disease status) and transplant characteristics (T-cell depletion), known to be risk factors for MTC and TRM. Our data also suggest that increases of two or three proinflammatory cytokines may be more predictive of MTC as compared to single cytokine increases. This may be a simple reflection of the severity of the inflammatory response or it may indicate a synergistic deleterious effect of these cytokines with respect to tissue damage. This may be particularly true for IL-8 which was associated with fatal outcome of MTC. These observations strongly suggest that cytokine release is part of the initiating mechanisms in the pathogenesis of MTC. However, it is clear that other factors are also involved. VOD is characterized by a systemic hypercoagulability state as evidenced by a decrease in naturally occurring anticoagulants including protein C and antithrombin III.21,22 Also, high plasma levels of factors associated with fibrinogenesis such as N-terminal propeptide for type III procollagen23,24 and hyaluronic acid25 have been observed in VOD. Our findings are consistent with both processes involved in the pathogenesis of VOD, since it is known that a hypercoagulable status can be induced and maintained by proinflammatory cytokines. TNF-alpha can induce a procoagulant environment with increased levels of plasminogen activator inhibitor-1.26 Highly significant increases of this protein have been observed concomitantly with the onset of bilirubin elevation in five of seven VOD patients.27 The secondary processes involved in ELS and IPS remain unclear, although an increased vascular permeability resulting in systemic and/or pulmonary edema is likely to play an important role in both syndromes. Local cytokine production is involved in IPS, since increased levels of interleukin-1, interleukin-2, IL-6 and TNF have been found in the bronchoalveolar fluid of patients this syndrome.13 We add to these data that a systemic cytokine release including IL-6 and IL-8 is also involved. Since L-8 is involved in the pathogenesis of the adult respiratory distress syndrome,28 our data suggest that IPS may be closely related to this syndrome. Consistent with the current hypothesis about the pathogenesis of AGVHD,29 we found that AGVHD generally occurred in a later phase post-BMT as a result of alloreactive processes, likely to be triggered by cytokine release.
Since we identified early cytokine release to be independently associated with the occurrence of MTC, we determined sensitivities and specificities of some cytokine levels within the first 5 or 10 days after transplant. This may be useful for the clinical management of BMT patients because it allows for the identification of patients at risk of MTC and TRM, also providing a clue and a rationale for early or pre-emptive anti-inflammatory treatment. Several treatment options may be considered. Early treatment with high-dose methylprednisolone has been shown to be beneficial to the majority of patients with regimen-related hepatotoxicity, of which many had VOD.30 Defibrotide has antithrombotic but also anti-inflammatory properties and leads to a complete response in around 50% of VOD cases. Results were better when treatment was applied earlier.31 Recombinant human-activated protein C or dotregocin-alpha has anti-thrombotic, anti-inflammatory and profibrinolytic properties and reduces mortality in patients with sepsis.32 Anti-T-cell antibodies such as antithymocyte globulins have been used for pre-emptive treatment of AGVHD in high-risk patients.33 Monoclonal antibodies directed against activated T cells such as visilizumab34 or ABX-CBL35 have been used successfully to treat steroid-refractory AGVHD. The use of anticytokines in AGVHD has thus far been disappointing, mainly because of initiating therapy at advanced stages and recurrence of AGVHD after stopping the treatment.36,37,38 Pre-emptive therapy and use of combinations of several anticytokines, anticytokine receptor or of anticytokines with other forms of immunotherapy may be more effective. Possible candidates include infliximab (chimeric human/mouse anti-TNF antibody)39 and daclizumab (humanized anti-interleukin-2 receptor antibody).40 A novel candidate therapeutic agent may be anti-CD14 which has led to a reduction of lipopolysaccharide-induced symptoms and inflammatory reactions in humans.41 In murine models, lipopolysaccharide has been shown to trigger TNF-alpha release by macrophages which in turn primed the GVH reaction.42
In summary, this study clarifies the role of proinflammatory cytokines in the pathogenesis of MTC. Systemic release of IL-6, IL-8 and TNF is part of the initiating events as well as an essential factor at times of maximal clinical signs of these complications. Our data provide a rationale for anti-inflammatory strategies as well as tools to select for patients in whom the benefit of such therapies is more likely to be demonstrated.
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Schots, R., Kaufman, L., Van Riet, I. et al. Proinflammatory cytokines and their role in the development of major transplant-related complications in the early phase after allogeneic bone marrow transplantation. Leukemia 17, 1150–1156 (2003) doi:10.1038/sj.leu.2402946
- tumor necrosis factor-alpha
- major complications
- allogeneic marrow transplantation
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