Streptokinase

Background: Streptokinase is widely used IV for the treatment of myocardial infarction and intrapleurally for the treatment of loculated pleural effusions. IV administration of streptokinase is known to cause the production of antistreptokinase antibodies.

Objective: The aim of this study was to evaluate whether the intrapleural administration of streptokinase results in a similar elevation of the serum antistreptokinase antibody level.

Methods: During 1 year, venous blood samples were taken from 16 consecutive patients (10 men and 6 women; age range, 22 to 60 years) requiring intrapleural streptokinase administration (250,000 IU once a day, for 2 to 6 days). Blood samples were taken before treatment, on day 5, and day 14. Antistreptokinase antibodies were measured using enzyme-linked immunosorbent assay (ELISA) and were expressed in arbitrary ELISA units. Four patients with myocardial infarction treated with IV streptokinase (1,500,000 IU) were included as control subjects for the method.

Results: Before treatment, the median antistreptokinase antibody level in patients with loculated pleural effusions was 729 ELISA units (range, 196 to 13,529 ELISA units) and increased to 9,240 ELISA units (range, 1,456 to 77,389 ELISA units) by day 14 (p < 0.0001). In the control group, the median pretreatment level was 119 ELISA units, and by day 14 it had increased to 20,495 ELISA units. Four patients who developed an elevated body temperature after intrapleural administration of streptokinase had a significantly higher pretreatment antistreptokinase antibody level compared to other patients.

Conclusions: The intrapleural administration of streptokinase results in the elevation of the serum antistreptokinase antibody level, which is similar to the case with IV administration. An increased pretreatment antistreptokinase antibody level does not influence the result of intrapleural fibrinolysis but can cause an elevation of body temperature after the administration of streptokinase.

Key words: antistreptokinase antibodies; pleural effusion; streptokinase

Abbreviation: ELISA = enzyme-linked immunosorbent assay

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Intravenous thrombolytic therapy with streptokinase is widely used for the treatment of patients with myocardial infarctions. A disadvantage of streptokinase is its antigenicity. That is, it provokes an immune response leading to the production of specific antistreptokinase antibodies, mainly of IgG class, and an elevation of neutralization titers. (1-5) Several studies (1,3,4) have reported that the level of antistreptokinase antibodies and also of neutralization titers remain high for years. It is not uniformly clear whether these findings are clinically relevant, but there is strong evidence that antistreptokinase antibodies inhibit streptokinase activity in vivo (6,7) and may cause adverse events. (8) Most studies from the 1990s conclude that patients who have previously received streptokinase, for whom repeated thrombolytic therapy is required, should be treated with nonimmunogenic thrombolytic drugs. (1-8)

Intrapleural streptokinase administration is indicated for the treatment of loculated pleural effusions and in particular, for the treatment of early empyemas. (9) Streptokinase breaks down loculations in the pleural cavity and allows the evacuation of the exudate. Despite local administration, up to 40% of patients experience some adverse effects (most frequently, the elevation of body temperature), which usually do not cause interruption of the therapy. (10)

The aim of this study was to evaluate whether the intrapleural administration of streptokinase results in the production of antistreptokinase antibodies. The presence of antistreptokinase antibodies in these patients may have clinical importance if later in life those patients develop myocardial infarctions that could be treated with streptokinase. Second, we assessed the relationship between the increased pretreatment antistreptokinase antibody levels and the adverse effects of intrapleural streptokinase therapy.

MATERIALS AND METHODS

Patients and Collection of Samples

The study was performed in the Tartu University Lung Hospital. The institutional ethics committee approved the study protocol.

Over a period of 1 year, 16 consecutive patients (10 men and 6 women; age range, 22 to 60 years) with loculated pleural effusions were included in the study. Thirteen patients had frank pleural empyemas, 2 patients had complicated parapneumonic effusions, and 1 patient had a tuberculous pleural effusion. In three cases, Streptococcus spp were isolated either from pleural fluid or sputum. Venous blood samples were taken before the intrapleural administration of streptokinase and subsequently on day 5 and day 14, or on the day of hospital discharge if that occurred first (one patient). Serum samples were stored at -20[degrees]C until evaluation. None of the patients had received streptokinase therapy before.

Four patients with myocardial infarctions who had been treated with IV streptokinase were included as positive control subjects for the comparison of the antistreptokinase antibody levels. Their serum samples were collected and stored under the same conditions.

Measurement of Antistreptokinase Antibody Level

Antistreptokinase antibody concentrations were measured using enzyme-linked immunosorbent assay (ELISA) as previously described. (11) Briefly, the microtiter plates were incubated overnight with 100 [micro]L streptokinase solution (10 IU/mL) [Streptokinase Braun; B. Braun Melsungen AG; Melsungen, Germany], the remaining unspecific binding sites were blocked with 0.1% bovine serum albumin, and the test serum samples were incubated in three-step dilutions (starting from 1:100) at room temperature for 2 h. Bound antistreptokinase antibodies were detected by adding peroxidase-conjugated, rabbit, antihuman IgG (1:5000; DAKO; Glostrup, Denmark) for 1 h and were visualized using 100 [micro]L chromogen 1,2-phenylenediamine dihydrochloride (DAKO) supplemented with 0.04% of a 30% hydrogen peroxide solution. The enzymatic reaction was stopped by 0.5 M [H.sub.2]S[O.sub.4], and the absorbance level was read at 490 nm using a spectrophotometer. The data are presented as arbitrary ELISA units derived by blotting the dilution curves of test sera against a standard curve of the reference serum.

Data Analysis

The data are shown as medians with ranges. Due to the naturally occurring large variance in antibody levels, the antistreptokinase antibody data were normalized by log transformation. For the evaluation of the change in antistreptokinase antibody levels following streptokinase administration, a paired t test was applied to these normalized data. For a comparison of the pretreatment antibody levels between patients with or without subsequent temperature elevation, a Student t test was used. A p value of < 0.05 was considered to indicate statistical significance.

RESULTS

The pretreatment median antistreptokinase antibody level was 729 ELISA units (range, 196 to 13,529 ELISA units) [Fig 1]. On day 5, the respective antibody level was 1,036 ELISA units (range, 100 to 28,126 ELISA units), and on day 14 it rose to 9,240 ELISA units (range, 1,456 to 77,389 ELISA units). The difference between pretreatment and day 14 values was statistically significant (p < 0.0001 [paired t test]). In the control group of myocardial infarction patients, the median antistreptokinase antibody levels were 119 ELISA units (range, 70 to 265 ELISA units), 195 ELISA units (range, 107 to 266 ELISA units), and 20,495 ELISA units (range, 6,887 to 55,848 ELISA units), respectively.

[FIGURE 1 OMITTED]

Four patients with loculated pleural effusions developed body temperatures of > 38[degrees]C or an elevation of at least 1[degrees]C over the pretreatment body temperature after the intrapleural administration of streptokinase (Fig 2). Their pretreatment antistreptokinase antibody values (median, 3,466 ELISA units; range, 573 to 13,529 ELISA units) were statistically higher (p = 0.03 [Student t test]) from other patients' values (median, 523 ELISA units; range, 196 to 4,206 ELISA units).

[FIGURE 2 OMITTED]

In only two patients, a Streptococcus sp was identified as causative microorganism of pleural empyema. In one case, a Streptococcus sp was isolated from sputum. No difference in pretreatment or posttreatment antibody levels or treatment efficacy was observed among these patients compared to the others. Also, we did not find a correlation between the total dose of intrapleurally administered streptokinase and the degree of elevation of the antistreptokinase antibody level.

DISCUSSION

Streptokinase is a drug that is widely used in the treatment of patients with acute myocardial infarctions and acute peripheral vascular occlusions. Intrapleural administration was first described by Tillet et al (12) in 1949 but has become widely accepted for the treatment of loculated pleural effusions during the last decade only. (9) As streptokinase is much less expensive than other thrombolytic agents, it is often the drug of choice. The clinical results of intrapleural streptokinase therapy in our patients were published earlier. (10) The success rate of 72% is comparable to the 44 to 100% that has been reported by other investigators . (9)

Streptokinase is produced by streptococci, and when it is administered IV it reacts with already existing antistreptokinase antibodies in the human organism that have been produced in response to previous streptococcal infections in most patients. However, pretreatment antistreptokinase antibody levels are usually low (1,3,7) and clinically unimportant if the standard dose of 1.5 million units streptokinase was used.

After the IV administration of streptokinase, the specific antistreptokinase antibody level and neutralization capacity rises markedly, reaching a peak at about 2 weeks. (2,3) Our study confirms that, like IV streptokinase administration, intrapleural administration also leads to a significant elevation of the serum antistreptokinase antibody level. Statistically significant elevation developed 2 weeks after the first intrapleural instillation of streptokinase. The total dose of streptokinase did not influence the degree of the antibody level elevation. However, IV administration seemed to result in a more pronounced production of antistreptokinase antibodies.

The recurrent use of streptokinase in the presence of high levels of antistreptokinase antibodies has been demonstrated to cause allergic-type adverse reactions (8,13) or the neutralization of streptokinase, leading to treatment failure. (6) The significant elevation of streptokinase neutralization titers and antistreptokinase antibody levels may persist for up to 54 months. (1,4,5)

Gemmill et al (7) evaluated the influence of the pretreatment concentration of specific IgG antibodies to streptokinase and the streptokinase resistance titer on the efficacy of IV thrombolytic agents among patients previously unexposed to streptokinase. A higher pretreatment resistance titer was demonstrated to have a small, but significant, negative influence on the efficacy of IV thrombolysis with streptokinase. On the contrary, it has been found in other studies that pretreatment antistreptokinase antibody levels do not correlate with the thrombolytic effect or adverse effects. (14,15) Also, in our study no correlation was found between treatment efficacy (ie, intrapleural fibrinolysis) and the pretreatment antistreptokinase antibody level. However, four of our patients experienced body temperature elevations as an adverse effect of intrapleural streptokinase administration. Among this small group of patients, statistically higher pretreatment antistreptokinase antibody levels were demonstrated compared to the rest of study group (Fig 2). In one study by White et al (13) transient fever has also been demonstrated to develop after the early IV readministration of streptokinase, but in that study antibody levels were not measured.

In our study, we measured only the antistreptokinase antibody levels and not the streptokinase neutralization titers, as several previous studies (1,2,4,7,16,17) have shown a positive correlation between these two assays. This significant correlation is particularly evident during the initial phase of antibody production (ie, during the time period that we followed in the present study). (2,3) However, for long-term follow-up the measurement of antistreptokinase antibodies has been suggested to be more sensitive than evaluating neutralization titers. (2)

In conclusion, we have shown that the intrapleural administration of streptokinase results in an elevation of the serum antistreptokinase antibody level after 2 weeks, which is similar to the case with IV administration. As the exact role of a high serum antistreptokinase antibody level in a patient remains unclear, one should avoid agents containing streptokinase in such patients when IV thrombolytic therapy is required.

The elevated pretreatment antistreptokinase antibody level does not influence the result of intrapleural fibrinolysis treatment but can cause the elevation of body temperature after streptokinase administration.

ACKNOWLEDGMENT: We thank Dr. Tiina Toruvere for her help in collecting blood samples from patients with myocardial infarction.

REFERENCES

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(2) Fears R, Ferres H, Glasgow E, et al. Monitoring of streptokinase resistance titre in acute myocardial infarction patients up to 30 months after giving streptokinase or antistreplase and related studies to measure specific antistreptokinase IgG. Br Heart J 1992; 68:167-170

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(4) Lee HS, Cross S, Davidson R, et al. Raised levels of antistreptokinase antibody and neutralization titres from 4 days to 54 months after administration of streptokinase or anistreplase. Eur Heart J 1993; 14:84-89

(5) Patel S, Jalihal S, Dutka DP, et al. Streptokinase neutralisation titres up to 866 days after intravenous streptokinase for acute myocardial infarction. Br Heart J 1993; 70:119-121

(6) Brugemann J, van der Meer J, Bom VJJ, et al. Anti-streptokinase antibodies inhibit fibrinolytic effects of anistreplase in acute myocardial infarction. Am J Cardiol 1993; 72:462-464

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(8) Lee HS, Yule S, McKenzie A, et al. Hypersensitivity reactions to streptokinase in patients with high pre-treatment antistreptokinase antibody and neutralisation titres. Eur Heart J 1993; 14:1640-1643

(9) Sahn SA. Use of fibrinolytic agents in the management of complicated parapneumonic effusions and empyemas. Thorax 1998; 53(suppl):S65-S72

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(12) Tillet WS, Sherry S, Read CT. The use of streptokinase-streptodornase in the treatment of postpneumonic empyema. J Thorac Surg 1951; 21:275-297

(13) White HD, Cross DB, Williams BF, et al. Safety and efficacy of repeat thrombolytic treatment after acute myocardial infarction. Br Heart J 1990; 64:177-181

(14) Fears R, Hearn J, Standring R, et al. Lack of influence of pretreatment antistreptokinase antibody on efficacy in a multicenter patency comparison of intravenous streptokinase and anistreplase in acute myocardial infarction. Am Heart J 1992; 124:305-314

(15) Lynch M, Pentecost BL, Littler WA, et al. Why do patients develop reactions to streptokinase? Clin Exp Immunol 1993; 94:279-285

(16) Moran DM, Standring R, Lavender EA, et al. Assessment of anti-streptokinase antibody levels in human sera using a microradioimmunoassay procedure. Thromb Haemost 1984; 52:281-287

(17) Squire IB, Lawley W, Fletcher S, et al. Humoral and cellular immune responses up to 7.5 years after administration of streptokinase for acute myocardial infarction. Eur Heart J 1999; 20:1245-1252

* From the Department of Thoracic and Cardiovascular Surgery (Dr. Laisaar), Tartu University, Tartu, Estonia; and the Lung Pharmacology Group (Dr. Pullerits), Goteborg University, Goteborg, Sweden.

Manuscript received January 14, 2002; revision accepted June 28, 2002.

Correspondence to: Tanel Laisaar, MD, PhD, Tedre 7, 50404 Tartu, Estonia; e-mail: tanel.laisaar@kliinikum.ee

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