Anti-endotoxin Properties of Polymyxin B-immobilized Fibers
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Polymyxin B is an antibiotic that shows strong bactericidal activity against Gram-negative bacteria, by binding to and inactivating endotoxin. Systemic administration of polymyxin B in humans is restricted because of its nephrotoxicity and neurotoxicity, and this compound was therefore considered a strong candidate ligand for the extracorporeal selective adsorption of circulating endotoxin in the blood. Toraymyxin® is a direct hemoperfusion column that uses polymyxin B attached to an insoluble carrier to bind endotoxin in the blood. In 1994, the Japanese National Health Insurance system approved the use of Toraymyxin for the treatment of endotoxemia and septic shock.
In this chapter, we will review the development, clinical use, and efficacy of Toraymyxin, examine the structure of the Toraymyxin column, and comment on the current position of Toraymyxin in the treatment of severe sepsis and septic shock. We will also highlight some potential new applications of Toraymyxin for pulmonary diseases.
KeywordsPolymyxin Lipopolysaccharide Endotoxemia Septic shock Toraymyxin
Endotoxin is one of major constituents of the cell wall in Gram-negative bacteria. Endotoxin is recognized through toll-like receptor-4 as a pathogen-associated molecular component that activates macrophages and other leukocytes to produce various inflammatory mediators. Endotoxin plays a major role in the development of toxic symptoms in Gram-negative bacterial infections. A recent review showed that co-detection of Gram-negative bacteria and endotoxemia is strongly predictive of increased risk of mortality compared to detection of neither . It is therefore a reasonable therapeutic approach to evaluate and remove circulating endotoxin in the blood of patients with Gram-negative bacterial infections.
Polymyxin B is a polycationic antibiotic that binds to and inactivates endotoxin, thereby neutralizing endotoxin-associated toxicity in humans . Systemic administration of polymyxin B in humans is restricted because of its nephrotoxicity and neurotoxicity, and this compound was considered a strong candidate ligand for the extracorporeal selective adsorption of circulating endotoxin in the blood.
The selective removal of endotoxin from blood has been discussed since the 1970s, when Nolan and Ali first demonstrated the adsorption of endotoxin via the ion-exchange resin cholestyramine . Various non-selective adsorbents such as charcoal or ion-exchange resins have since been considered, but a new selective adsorbent was needed for the specific and efficient removal of circulating endotoxin from blood. Sepharose 4B beads to which polymyxin B was covalently immobilized were shown to be effective adsorbents for the removal of endotoxin in a rat model and in human hemodialysis systems [4, 5]. Polyethylenimine  and albumin , rather than polymyxin B, have also been used as ligands for the selective adsorption of endotoxin.
In 1983, we began in vitro and in vivo experimental studies. A pre-clinical study showed that selective removal of endotoxin from the blood by extracorporeal direct hemoperfusion with polymyxin B-immobilized fibers resulted in improved survival in an endotoxemia canine model . Survival also improved in a Gram-negative bacterium (Escherichia coli) intravenous administration canine model after extracorporeal hemoperfusion with polymyxin B-immobilized fibers, indicating the potential for use thereof in humans .
The polymyxin B-immobilized fibers blood purification column, Toraymyxin®, was developed as a medical device to be used in conjunction with direct hemoperfusion to remove circulating endotoxin from the blood in humans. A phase I clinical study was initiated in 1989, and in 1994 the first clinical report of 16 patients with septic multiple organ failure treated with direct hemoperfusion with Toraymyxin (PMX) was published . PMX for 2 h significantly decreased the level of circulating endotoxin from 76 to 21 pg/mL. Furthermore, the patients’ hyperdynamic state (in terms of cardiac index), which is characteristic of endotoxic shock, returned to normal after treatment . Regarding the technical term for Toraymyxin, we have suggested defining “PMX” as “direct hemoperfusion with the polymyxin B-immobilized fiber column (Toraymyxin)”.
In 1994, Toraymyxin was adopted by the Japanese National Health Insurance system for the treatment of endotoxemia and septic shock . Since then, Toraymyxin has been used safely in more than 100,000 cases in emergency and intensive care units in Japan. Three different columns are currently available for clinical use in Japan: PMX-20R for use in adults, PMX-05R for use in children, and PMX-01R for use in babies (Fig. 19.1).
In 1998, Toraymyxin received CE mark approval in Europe. In 2005, the results of the first randomized controlled trial (RCT) in Europe were published, showing that treatment with Toraymyxin is safe, and improves cardiac and renal dysfunction due to sepsis or septic shock . In 2007, the findings of a meta-analysis demonstrated the favorable effects of PMX . In 2009, the results of the second RCT in Europe, the EUPHAS study (Early Use of Polymyxin B Hemoperfusion in Abdominal Sepsis), which was conducted in Italy, were published, showing that Toraymyxin treatment results in a significant reduction in sepsis-associated mortality . A large RCT, the ABDO-MIX trial in France, has failed to show survival benefit and improvement in organ failure with Toraymyxin treatment compared to conventional treatment of peritonitis-induced septic shock . Recruitment into another large RCT, the EUPHRATES trial in the USA, is now closed and the results showed that polymyxin B hemoperfusion plus conventional medical therapy did not reduce mortality at 28 days in patients with septic shock and high endotoxin activity (Fig. 19.1, ClinicalTrials.gov Identifier: NCT01046669). Toraymyxin is currently available for use in clinical settings in Italy, Spain, Russia, India, Switzerland, Austria, Korea, Taiwan, Saudi Arabia, Slovenia, Thailand, and Turkey.
In this chapter, we will review the development, clinical use, and efficacy of Toraymyxin, examine the structure of the Toraymyxin column, and comment on the current position of Toraymyxin in the treatment of severe sepsis and septic shock. We will also highlight some potential new applications for Toraymyxin.
19.2 Development of Polymyxin B-immobilized Fibers
19.2.1 Polymyxin B and Endotoxin
Polymyxin B has strong bactericidal activity against Gram-negative bacteria. The bactericidal properties of polymyxin B are discussed in more detail in other chapters. Polymyxin B also neutralizes the lethal toxicity, limulus gelation activity, and hemodynamic effects of endotoxin, a major component of the outer membrane of Gram-negative bacteria, by binding to the lipid A domain, which is the active center of the endotoxin molecule . The protective effects of polymyxin B against endotoxemia and septicemia have been demonstrated in various animal models [17, 18, 19].
Electron microscopy imaging has revealed that when endotoxin is exposed to polymyxin B, its usual ribbon-like structure partially or fully disaggregates . The detergent-like activity of polymyxin B arises from its ability to prompt the dissociation of endotoxin’s micellar structure . Polymyxin B has been shown to bind to the lipopolysaccharide of Salmonella typhimurium at the negatively charged 2-keto-3-deoxyoctulosonate lipid A region of the lipopolysaccharide molecule. This is achieved via electrostatic, and possibly hydrophobic, interactions at a stoichiometric ratio of one polymyxin B molecule to one lipopolysaccharide monomer unit . Furthermore, Vesentini et al. demonstrated that short-range interactions between polymyxin B and endotoxin are mediated mainly via hydrophobic forces, whereas long-term complex formation is mediated via ionic forces. The interaction energy occurring in each molecular complex was calculated at different intermolecular distances, and the binding forces were estimated by fitting interaction energy data. Maximum binding forces calculated via molecular mechanics for the polymyxin B–endotoxin complex range from 1.39 to 3.79 nN .
Together, these studies have clarified that polymyxin B binds to and detoxifies endotoxin, and that it is through this binding that polymyxin B exerts its anti-microbial activity.
19.2.2 Polymyxin B-immobilized Fibers
19.2.3 Endotoxin Adsorption Capacity and Bactericidal Activity of Polymyxin B-immobilized Fibers In Vitro
Polymyxin B-immobilized fibers also show bactericidal activity. Polymyxin B-immobilized fibers were added to a phosphate buffer solution containing Pseudomonas aeruginosa , and changes in bacterial cell count were assessed under continual stirring for 9 h. Bacterial cell counts decreased sharply from approximately 107 to 103 CFU/mL (Fig. 19.6c) .
Together, these results clearly demonstrate that immobilized polymyxin B retains the endotoxin binding and bactericidal properties of free polymyxin B .
19.2.4 Endotoxin Adsorption Capacity of Polymyxin B-immobilized Fibers In Vivo
19.3 Toraymyxin, a Polymyxin B-immobilized Fiber Column for Human Use
19.3.1 Physical Structure of Toraymyxin Cartridge
The endotoxin adsorption capacity of the Toraymyxin column was evaluated in a bovine serum perfusion model. An endotoxin-containing bovine serum solution (10 ng/mL of endotoxin, total 1.5 L) was perfused through the Toraymyxin cartridge at a flow rate of 100 mL/min, and the change in endotoxin level was monitored using an LAL assay. Endotoxin concentration reached equilibrium after 2 h of perfusion (Fig. 19.9b) .
19.3.2 Toraymyxin as a Medical Device
19.3.3 Use of the Toraymyxin Column in Hemoperfusion
Prior to use, Toraymyxin columns must be rinsed with physiological saline and then primed. For example, a PMX-20R column must be washed out with 4 L of physiological saline and then primed with 1 L of physiological saline containing 20 mg of nafamostat mesilate or 1000 U of unfractionated heparin. For patients in an extremely critical condition or with an extremely low blood pressure, an albumin solution containing anticoagulation agents may be used as the final priming solution.
Vascular access for hemoperfusion is usually via a central vein (internal cervical vein, subclavian vein, or femoral vein). The standard blood flow rate through the Toraymyxin column depends on the size of the column: 80–120 mL/min for PMX-20R, 20–40 mL/min for PMX-05R, and 8–12 mL/min for PMX-01R. An anticoagulant (20–30 mg/h nafamostat mesilate or bolus 40–60 U/kg and 40–60 U/kg/h unfractionated heparin, depends on patients’ coagulation condition) should also be administered to prevent coagulation within the blood circuit (Fig. 19.10b). Since coagulation dysfunction is common in patients with septic shock, the short half-lives of these regional anticoagulants in the blood mean that they are safe for use during hemoperfusion. Nafamostat mesilate is the most commonly used anticoagulant for this purpose in Japan.
Since 1994, Toraymyxin has been used in more than 100,000 cases in Japan. Despite adverse effects such as thrombocytopenia or hypotension being reported, their incidence is rare, and there have been no reports of any serious adverse effects .
19.4 Mechanism of Action of PMX Therapy
19.4.1 Removal of Endotoxin
The Toraymyxin column was originally designed to specifically adsorb endotoxin. Plasma endotoxin levels significantly decrease immediately after PMX treatment compared with pre-treatment levels . By using data from a multicenter study, Tani reported that PMX treatment significantly reduced plasma endotoxin concentrations from 83.7 ± 26.7 pg/mL to 56.4 ± 27.9 pg/mL after 2 h of direct hemoperfusion with a Toraymyxin column . Although almost all of the studies conducted so far have demonstrated a significant decrease in plasma endotoxin levels following PMX treatment, a recent RCT failed to show such an effect . However, this could be due to the use of the LAL assay, which is prone to contamination and lacks precision and accuracy resulting in both false positive and false negative results . Indeed, our previous study showed that sensitivity for the detection of endotoxin in the turbidimetric LAL assay was very low (26.9%; 14 of 52 patients) in patients with severe sepsis and septic shock who required PMX treatment . A new method for the detection and quantitation of endotoxin is therefore immediately needed.
Recently, Romaschin developed a rapid assay, called the endotoxin activity assay (EAA), that detects endotoxin in whole blood by using autologous neutrophil-dependent chemiluminescence . The EEA has been approved by the United States Food and Drug Administration as a clinical method for the diagnosis of endotoxemia, and was used in the EUPHRATES trial (see Sect. 19.5.1) .
A rapid LAL assay for detecting endotoxin by using a laser light-scattering particle-counting method called endotoxin scattering photometry (ESP) has also been developed. Endotoxin binds to and activates factor C, a clotting enzyme, early in the LAL cascade, which ultimately results in the production of the insoluble protein coagulin. Coagulin spontaneously forms a polymer, and it is this polymer formation that is detected in the turbidimetric LAL assay. Obata et al. reported that by using ESP they were able to detect coagulin particles formed under agitation of the LAL cascade, and that the transferring period of the LAL cascade after endotoxin stimulation depends on the concentration of endotoxin before gelation . The ESP method allows for more rapid and sensitive detection of endotoxin compared with the turbidimetric LAL method.
Furthermore, ESP is able to discriminate between patients with sepsis and those with septic shock undergoing gastrointestinal emergency surgery compared with the standard turbidimetric LAL assay . After undergoing PMX therapy for a longer-duration (> 2 h), the hemodynamic condition of patients with septic shock due to intra-abdominal infection improved, and the reduction in plasma endotoxin concentration could be detected via ESP but not through the standard turbidimetric method. We have demonstrated the ability of endotoxin adsorption in longer-duration PMX treatment . Using the ESP method, we observed a reduction in endotoxin after passing through the Toraymyxin column even when PMX duration was greater than 2 h. Therefore, ESP appears to be sensitive enough to detect circulating endotoxin in the plasma of patients with septic shock who require PMX therapy.
19.4.2 Other Potential Mechanism of Action of PMX Therapy
Although Toraymyxin was originally developed for the adsorption of circulating endotoxin from the blood, recent studies have shown other potential applications. Jaber reported that it may be possible to use Toraymyxin to remove lipoteichoic acid (LTA) from peripheral blood . In an in vitro study, polymyxin B significantly suppressed LTA-induced tumor necrosis factor (TNF)-α production by peripheral blood mononuclear cells, suggesting that LTA may also be removed during direct hemoperfusion with PMX and that this removal may be due to binding of LTA to polymyxin B.
Other recent studies have reported a possible relationship between immune cells and the reduction in inflammatory mediators. Ono demonstrated that the expression levels of HLA-DR, a major histocompatibility complex class II cell surface receptor on monocytes, and CD16 on granulocytes, markedly decrease in patients with septic shock. However, PMX treatment had beneficial effects by increasing leukocyte expression of these surface antigens . The number of CD16+CD14+ monocytes and the expression level of monocytic toll-like receptor 4 dramatically increase in patients with severe infection, and recent studies have shown that PMX treatment is effective in reducing both of these in patients with septic shock . Moreover, Ono demonstrated that the removal of surplus circulating CD4+CD25+Foxp3+ regulatory T cells in patients with septic shock via hemoperfusion with Toraymyxin might represent a novel strategy for inducing recovery from sepsis-associated immunosuppression . Tsuzuki have demonstrated immediate inhibition of NF-κB binding activity and suppression of TNF-α secretion after endotoxin neutralization with polymyxin B regardless of whether the peripheral blood mononuclear cells were already producing TNF-α or not . Reducing the number of circulating monocytes or modulating their function may contribute to improving pro-inflammatory responses following PMX treatment.
Anandamide and 2-arachidonyl glyceride are endogenous cannabinoids that are released by activated macrophages and platelets during endotoxic shock, and play a crucial role in the induction of shock-related hypotension . Wang showed that anandamide was efficiently adsorbed by a polymyxin B-immobilized bead column in vitro . Therefore, the adsorption of cannabinoids by polymyxin B may be an important mechanism for improving hemodynamic dysfunction following PMX treatment.
Macrophage migration inhibitory factor (MIF) is constitutively expressed by monocytes, macrophages, T cells, B cells, endocrine cells, and epithelial cells. Microbial toxins and cytokines are powerful inducers of MIF release by immune cells, and up-regulation of MIF expression during the course of inflammatory and infectious diseases plays an important role in the pathogenesis of sepsis and septic shock . In a recent study, we demonstrated that Toraymyxin directly adsorbed MIF in vitro (unpublished data).
High-mobility group box 1 protein (HMGB1), which is a protein previously known only as a nuclear transcription factor, is now implicated as a mediator of delayed endotoxin lethality and systemic inflammation . An experimental study demonstrated that serum levels of HMGB1 were lower in PMX-treated patients than in controls . The reduction in circulating HMGB1 level may also contribute to the beneficial effects of PMX treatment in patients with sepsis [46, 47, 48].
Further studies are required to investigate the clinical efficacy of PMX treatment and elucidate the precise mechanism. Nevertheless, in Japan, PMX treatment is a widely accepted method to improve the condition of patients with septic shock, and this useful clinical device is gaining acceptance as its use becomes more widespread.
19.5 Clinical Use of PMX Therapy
19.5.1 PMX Therapy for the Treatment of Sepsis
The results of the first prospective, multicenter, observational clinical trial of Toraymyxin for the treatment of patients with sepsis in Japan were published in 1998 . The survival rate was significantly higher in the treatment (PMX) group (54.0%) compared with the control group who received standard therapies (36.4%). In the treatment group, the mean plasma endotoxin concentration was significantly lowered from 83.7 pg/mL before treatment to 56.4 pg/mL immediately after treatment. The day after treatment, the mean plasma endotoxin concentration was found to be 28.5 pg/mL. Post treatment, the mean plasma endotoxin concentration was lower in those who survived (18.8 pg/mL) compared with those who died (88 pg/mL). Other cardiac function parameters also improved after treatment.
Nemoto demonstrated that the rate of overall survival in patients with sepsis significantly improved after PMX treatment compared with standard therapies without PMX (41% vs. 11%) in a RCT of 98 patients with sepsis in Japan . PMX improved the rate of survival in patients with an APACHE II (Acute Physiology and Chronic Health Evaluation II) score <30, but not in those with scores >30, demonstrating that Toraymyxin treatment is most effective at improving patient outcome when applied during the early stages of sepsis .
In 1998, Toraymyxin received CE mark approval in Europe. In 2005, Vincent et al. published the results of a multicenter, open-label, pilot, randomized controlled study conducted in the intensive care units of six academic medical centers in Europe, which was the first RCT of Toraymyxin conducted outside of Japan . Thirty-six postoperative patients with severe sepsis or septic shock secondary to intra-abdominal infection were randomized to either PMX treatment for 2 h (n = 17) or standard therapy (n = 19). PMX treatment was well tolerated and no significant adverse effects were observed. Patients treated with PMX showed significant increases in cardiac index (P = 0.012 and 0.032 at days 1 and 2, respectively), left ventricular stroke work index (P = 0.015 at day 2), and oxygen delivery index (P = 0.007 at day 2) compared with controls. Furthermore, the need for continuous renal replacement therapy after study entry was significantly reduced in the PMX group (P = 0.043). There were no statistically significant differences in endotoxin and interleukin six levels, and organ dysfunction as assessed by the Sequential Organ Failure Assessment (SOFA) score, or 28-day mortality. Note that sepsis in the patients enrolled in this study was likely too severe to find statistical significance in the mortality outcome. Together, these results show that PMX treatment is safe and that it improves cardiac and renal dysfunction due to sepsis or septic shock.
Cruz et al. have also published the results of the EUPHAS (Early Use of Polymyxin B Hemoperfusion in Abdominal Sepsis) trial, which was a prospective, multicenter, RCT conducted at the intensive care units of ten Italian tertiary care hospitals in 2009 . Sixty-four patients with severe sepsis or septic shock who had undergone emergency surgery for intra-abdominal infection were enrolled in this study. Patients were randomized within 6 h after open abdominal surgery to either conventional therapy (n = 30) or conventional therapy plus two sessions of 2 h PMX with an interval of 24 h between sessions (n = 34). Twenty-eight-day mortality was significantly improved in the PMX group (32%; 11/ 34 patients) compared with that in the conventional therapy group (53%; 16/30 patients). In the PMX group, mean arterial pressure significantly increased from 76 mmHg (before treatment) to 84 mmHg (72 h after treatment; P = 0.001) and vasopressor requirement (measured as inotropic score) significantly decreased from 29.9 (before treatment) to 6.8 (72 h after treatment; P < 0.001). In contrast, in the conventional therapy group, mean arterial pressure (before, 74 mmHg; 72 h after, 77 mmHg; P = 0.37) and inotropic score (before, 28.6; after, 22.4; P = 0.37) did not change significantly with treatment. Ratio of partial pressure arterial oxygen and fraction of inspired oxygen (PaO2/FIO2 ratio) significantly increased (before, 235; after, 264; P = 0.049) in the PMX group but not in the conventional therapy group (before, 217; after, 228; P = 0.79). Moreover, SOFA score, which is an indicator of the severity of organ dysfunction, improved in the PMX group compared with the conventional therapy group (change in SOFA score, −3.4 vs. −0.1; P < 0.001).
Although the goal was planned to enroll 120 patients in this study, the interim analysis revealed that the risk of mortality in the conventional treatment group was significantly higher than that in the PMX group; thus, the study was terminated midway. Despite the high mortality rate in the conventional treatment group and the lack of evaluation of circulating endotoxin levels, this was the first report showing an improved rate of survival in a RCT conducted outside of Japan.
A multicenter randomized controlled trial, The ABDOMIX trial (Effects of Hemoperfusion with a Polymyxin B Membrane in Peritonitis with Septic Shock), was conducted in France . A total of 243 patients with peritonitis-induced septic shock from abdominal infections were enrolled and the primary end point of the study was 28-day mortality. This multicenter randomized controlled study demonstrated a non-significant increase in mortality and no improvement in organ failure with PMX treatment compared to conventional treatment of peritonitis-induced septic shock. However, Antonelli et al. pointed out that major differences in mortality and completion rates of two scheduled sessions of PMX compared to the EUPHAS study may jeopardize their comparability, suggesting that any definitive conclusion be put on hold . The 28-day mortality rate recorded in both groups was significantly lower than that reported in larger studies (between 32.7% and 53% for similar patient cohorts) [51, 52, 53]. Furthermore, only 81 of the 119 treated patients completed the two scheduled sessions of PMX. In the previously published EUPHAS study, all patients enrolled had completed the two planned sessions of PMX, and a significantly higher mortality rate was recorded in the control group .
The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized Controlled Trial of Adults Treated for Endotoxemia and Septic Shock) , which is ongoing in the USA and Canada , is a trial designed to address the criticisms of previous studies. Circulating endotoxin levels in patients with septic shock were evaluated by using a novel endotoxin detection method called the endotoxin activity assay (EAA). A total of 432 patients with septic shock and high EAA activity (> 0.6) were enrolled and randomized to either PMX or conventional treatment. Dellinger et al. reported that the primary endpoint for mortality rate (44.3% in placebo group and 43.75% in PMX group) was not met in the full intention-to-treat population. Their interim results showed that the mortality rate in the per protocol population (36.9% in placebo group and 31.9% in PMX group) was 5% in favor of PMX treatment (P = 0.407). Interestingly, the final results of the EUPHRATES trial did not show reduced mortality at 28 days in patients with PMX treatment (ClinicalTrials.gov Identifier: NCT01046669).
Direct hemoperfusion sessions with Toraymyxin column usually last 2 h; however, the obvious clinical efficacy of longer-duration PMX (> 6 h) in such cases has been reported [36, 54, 55, 56]. No adverse effects, such as thrombocytopenia, have been reported with longer duration Toraymyxin treatment [36, 54]. Further studies to clarify the suitability of longer-duration Toraymyxin treatment are expected.
19.5.2 PMX Therapy for the Treatment of Acute Exacerbation of Idiopathic Pulmonary Fibrosis and Acute Respiratory Distress Syndrome
Idiopathic pulmonary fibrosis (IPF) is one of a heterogeneous group of diffuse parenchymal lung disorders of unknown etiology. Acute exacerbation of IPF is characterized by severe worsening dyspnea and high mortality. IPF is one of the most common presentations of idiopathic interstitial pneumonia. Previous reports have suggested that PMX treatment improves oxygenation in patients with acute lung injury or acute respiratory distress syndrome (ARDS) due to severe sepsis [60, 61]. The potential benefit of PMX therapy for the treatment of acute exacerbation of IPF has also been reported . A multicenter retrospective analysis of 160 patients showed that PMX therapy improves oxygenation and survival in patients experiencing acute exacerbation of IPF . A large-scale, prospective, RCT in patients experiencing acute exacerbation of IPF will be conducted in the near future.
The successful treatment of severe ARDS due to influenza virus infection with PMX has been reported recently. Yokoyama et al. reported a case of severe ARDS caused by novel swine-origin influenza virus (A/H1N1pdm) . The patient underwent PMX, after which her hypoxemia improved and she survived. This is the first report of severe, life-threatening ARDS due to a novel influenza virus in which PMX was beneficial. Yatera et al. reported a case of ARDS due to influenza A infection that was successfully treated with PMX . Kudo et al. has reported cases of severe pneumonia due to highly pathogenic avian influenza A (H5N1) in Vietnam successfully treated with CHDF coupled with Toraymyxin hemoperfusion, suggesting that it is an effective candidate treatment for ARDS due to the H5N1 virus if applied early in the disease .
These data show that new indications for PMX treatment in the field of pulmonary medicine will likely be available in the near future.
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