Thoracic empyema continues to be a significant cause of morbidity, especially in developing countries. Pulmonary infections, including community-acquired pneumonia, bronchiectasis, and lung abscess, are the most prevalent cause of thoracic empyema in developed countries, followed by surgical trauma [1]. In contrast, studies from India have revealed that tuberculosis accounts for a large number of empyema cases (38.6%) [2].

In empyema and complicated parapneumonic effusions (CPE), leucocytes sequestrate into the infected pleural space and secrete several permeable factors causing spillage of fibrinogen into the pleural space. Fibrinogen is then converted to fibrin, which adheres to the tissue surface, which traps the pathogenic microorganism. However, this entrapment prevents host defence mechanisms and antibiotics from reaching the site of infection. Infected pleural fluid has been shown to have low fibrinolytic activity and increased concentrations of plasminogen activator inhibitors [1-3].

Tillet and Sherry [4] first demonstrated the use of fibrinolytic therapy in 1949 as a treatment for empyema [3,4]. Fibrinolytic therapy was reintroduced by Bergh et al. [5] in 1977, and they used a more refined form of streptokinase (STK) [6,7]. Many trials and reports have shown the effectiveness of fibrinolytic agents for the treatment of empyema/CPE [6,8]. However, these were small trials and case series with success rates ranging from 38% to 100% [6,7,9].

Intrapleural fibrinolytic therapy (IPFT) is frequently administered to patients with CPE or empyema in whom antibiotic therapy and initial drainage fail [10-12]. It is also a suitable option for patients who are not candidates for or do not want to undergo surgery [13]. The rationale for this approach is that this strategy reduces the need for surgery and shortens the duration of hospitalization [3,11].

Urokinase (UK) was effective in a randomized trial of patients with multiloculated pleural effusions [14,15]. Patients in the intervention group with UK showed significantly more drainage volume of pleural fluid, required less surgical referral, and required fewer days in the hospital. Intrapleural recombinant tissue plasminogen activator (rt-PA) has been successfully administered in patients with complicated parapneumonic pleural effusion and empyema.

The landmark multicenter intrapleural sepsis trial (MIST2) published in 2011 included a comparison with intrapleural recombinant human DNase, a potential treatment for pleural infection that may help prevent septate formation and decreased viscosity by destroying extracellular DNA [11]. The blinded 2-by-2 factorial trial randomly assigned 210 patients with pleural disease to receive a 3-day study treatment using double placebo, rt-PA and placebo, DNase and placebo, or rt-PA and DNase. The combined intrapleural rt-PA and DNase therapy reduced the hospital stay length, decreased the need for thoracic surgery, and produced a more considerable improvement in pleural opacity on day seven relative to double placebo [16].

After the MIST2 study, no other randomized trial has been performed in this field. In our study, we aimed to compare the efficacy of UK versus rt-PA (alteplase) as intrapleural fibrinolytic agents for the management of complicated pleural effusion.

To evaluate the efficacy of UK versus rt-PA (alteplase) as intrapleural fibrinolytic agents for the management of complicated pleural effusion.

A total of 50 patients were enrolled into the study. Among them, 84% (n=42) were males and 16% (n=08) were females. The majority of the patients belonged to the young age group (between 20 and 30 years), which led to skewing of the age distribution graph to the right. However, this was an expected phenomenon as the majority of the clientele in our hospital are young individuals.

The causes of empyema included tuberculous (60%) and bacterial empyema (40%). Among them, 30 (60%) patients received UK, and 20 (40%) patients received alteplase as IPFT agents. The baseline demography, radiological, and biochemical parameters are summarized in Table 1.

Parameters, such as pre-intervention radiological features, initial volume of the pleural fluid, and pleural fluid LDH, were similar in both groups. The median value of age and interval of symptoms to the intervention were comparable.

Tillet and Sherry [4] first demonstrated the use of fibrinolytic therapy in 1949 as a treatment for empyema. A group of 23 patients with loculated empyema or hemothorax received intrapleural instillation of STK and streptodornase through an intercostal drain. Several reports emerged thereafter, showing the effectiveness of fibrinolytic agents in the management of loculated pleural effusion [4]. However, the initial enthusiasm waned due to severe systemic side effects, such as fever and leucocytosis caused by various impurities in the enzyme mixture. The success rates of fibrinolytic agents still range from 38% to 100% [3,14,15].

The patients with CPE or empyema in whom antibiotic therapy and initial drainage fail are generally administered IPFT [10,11]. It is also a suitable option for patients who are not candidates for or do not want to undergo surgery. The rationale for this approach is that this strategy reduces the need for surgery and shortens the duration of hospitalization [3].

UK was effective in a randomized trial of patients with multiloculated pleural effusions [14,15]. Patients in the intervention group with UK showed significantly more drainage volume of pleural fluid, required less surgical referral, and required fewer days in the hospital. However, a randomized controlled trial (RCT) by Bouros et al. [17] in 1997 showed that UK had more fluid drainage after 24 hours than STK. The drainage volume in the first 24 hours was 380±99 mL in the STK group (p<0.001) and 420.8±110 mL in the UK group (p<0.001). but the total drainage volume at the end of the therapy was not statistically significant. The total volume of fluid drained after treatment was 1,596±68 mL in the STK group, and 1,510±55 mL in the UK group (p>0.05). An odds ratio (OR) of death or referral for surgery for STK versus UK was not significantly different (OR, 1.00; 95% confidence interval [CI], 0.13 to 7.72). A severe adverse reaction in terms of fever and an allergic reaction was significantly more frequent in the STK group. The author concluded that intrapleural STK or UK is an equally effective adjunct for managing CPE and it may reduce the need for referral for surgery in some cases. Despite the comparable efficacy, UK could be the thrombolytic agent of choice due to the potentially dangerous allergic reactions to STK and a relatively little higher cost of UK [17].

Intrapleural rt-PA in patients with complicated parapneumonic pleural effusion and empyema has shown a significant response [18]. The landmark MIST2 study evaluated the efficacy of rt-PA, DNase, rt-PA plus DNase, and placebo in the treatment of CPEs [19]. Two hundred and ten patients were randomized to one of the above four regimens. The interventions were given twice daily for 3 days (rt-PA 10 mg, DNase 5 mg). The primary outcome measure was the absolute change in the pleural opacity on the chest radiograph from the day of randomization until 7 days post-randomization [19]. The administration of the combination of rt-PA and DNase resulted in a more significant reduction in the pleural opacity (-29.5%) than did the administration of rt-PA (-17.2%), DNase (-14.7%), or placebo (-17.2%) [19]. There were no significant differences between rt-PA, DNase, and placebo [19]. When the secondary endpoints were examined, the patients who received the combination showed a significant decrease in surgical referrals and a significantly shorter hospital stay than did the patients who received placebo [19]. rt-PA alone did not differ significantly from placebo in terms of either of these secondary endpoints, while DNase alone was associated with more surgical referrals than placebo [19].

Both UK and rt-PA have been used as IPFT agents and have proven efficacy against placebo, which has been shown in several previous trials [18-20]. However, data related to the comparative effectiveness of UK and alteplase are not abundant. Aleman et al. [15] conducted a double blinded RCT in 2015 and compared UK and alteplase’s efficacy and adverse effect profile. A total of 99 patients were recruited, of whom 51 received alteplase and 48 received UK. Success rates for UK and alteplase at 3 and 6 days were not significantly different, but when only the subgroup of CPE was considered, UK resulted in a high proportion of cures. There were no differences in mortality or surgical need (overall, 3%). The OR of death comparing alteplase (combining 10 mg and 20 mg groups) with UK at 1 year was 0.94 (95% CI, 0.18 to 4.89) [21]. Five (28%) patients receiving 20 mg of alteplase and four (12%) patients receiving 10 mg presented with severe bleeding events. The author recommended that if intrapleural fibrinolytic agents are required, UK may be a more effective and safer agent than alteplase in patients with CPE [15].

Unlike the trial by Altmann et al. [21], our trial demonstrated that as compared to UK, newer fibrinolytic agents, such as alteplase, improved the drainage of infected pleural fluid and could lead to significant X-ray clearance (approximately 42% of the initial X-ray opacity compared to 33% in the UK group) (Table 2).

Bleeding was the most severe adverse effect noticed by Altmann et al. [21]. This study was at high risk of bias as several adverse events were identified in the 20 mg alteplase arm, which led to breaking of the blind after an interim analysis by the drug safety and monitoring committee. The protocol was altered, and the dose of alteplase was reduced to 10 mg daily [21].

Similar to the 2015 RCT, our trials also showed severe adverse reactions, such as bleeding, with the newer fibrinolytic agent, i.e., alteplase group, which was not observed in the patients treated with UK. Two of our patients in the alteplase group developed bleeding in the affected hemithorax after the initial dose of alteplase, which caused us to terminate the therapy after one cycle. However, alteplase was associated with comparable side effect profiles when common side effects were taken into consideration. The odds of fever (20.0% vs. 26.7%) and pain (40% vs. 60%) was low in the alteplase group, but this difference in the incidence was not statistically significant between the groups (Table 3). There was no incidence of life-threatening adverse reactions, such as severe bleeding and hypovolemic shock, requiring blood transfusion or severe anaphylactic reaction in any intervention group. This again highlights that both the drugs are safe when used as IPFT agents.

Our study also demonstrated that the early initiation of fibrinolytic therapy before the development of extensive pleural adhesion might lead to a favorable outcome and more pleural fluid drainage. A 5-year observational study from India reported that more than 75% of the non-responders presented at more than 6 weeks after initiation of symptoms [3]. On subgroup analysis, our study showed that 100% of the patients (n=40), who had received IPFT within 6 weeks of initiation of symptoms, had shown an excellent radiological clearance, compared to only 60% patients (n=6) among those who presented late, i.e., 6 weeks after initiation of symptoms. This difference was also statistically significant (p=0.001) (Table 4).

Our trial indicates that newer fibrinolytic agents, such as alteplase, may have greater efficacy than UK, as they improve pleural fluid drainage and produce significant radiological clearance. Alteplase has marginally fewer side effects than UK, but the difference is not statistically significant. However, unlike the UK group, a severe adverse reaction, such as bleeding, was seen in the alteplase group. Both the drugs have an excellent safety profile, as none of them were associated with a life-threatening adverse reaction.

Our study has few limitations. One of the limitations of our study was the age group. The majority of the patients belonged to the young age group (between 20 and 30 years), which led to skewing of the age distribution graph to the right. However, this was an expected phenomenon as the majority of the clientele in our hospital are young individuals. We administered only a fixed number (two cycles) and dose of the drugs (UK 1,00,000 IU and alteplase 10 mg) to all the patients, irrespective of the extent and duration of the disease. Patients with extensive disease and those presenting late may require different doses and more cycles to show significant responses. Our study was a small single center trial, and further multicentric trials are necessary to determine the association of varying drug doses with the severity of the disease.

In conclusion, our trial showed that rt-PA (alteplase) has greater efficacy and it improves drainage and chest clearance when compared with UK. Although alteplase is associated with a higher incidence of bleeding, both the drugs were not associated with any life-threatening adverse event. Early initiation of fibrinolytic therapy before the development of severe loculation leads to better drainage and superior radiological clearance than in those who present late. From the previous studies and our trials, it may be concluded that IPFT is a safe and effective option for managing complicated pleural effusion or empyema, and newer agents, such as alteplase, have greater efficacy and a similar adverse effects effect profile when compared with conventional agents, such as UK.