Does Serratiopeptidase prevent thoracic surgery in patients of hydropneumothorax of tubercular aetiology?

ABSTRACT

Background:

Tubercular hydropneumothorax is commonly seen in Indian hospitals. Anti-tuberculosis drugs and intercostal drainage tube (ICD) insertion are the mainstays of treatment. But many patients have to be referred to thoracic surgery for surgical management. This study aims to evaluate the role of serratiopeptidase in successful resolution of tubercular hydropneumothorax and avoidance of thoracic surgery.

Methods:

We conducted a retrospective observational cohort study on 28 patients that were admitted to extrapulmonary TB ward of our hospital. All patients were given anti-TB drugs according to national guidelines and underwent ICD tube insertion. Out of 28 patients recruited, 19 suffering severe chest pain received serratiopeptidase containing analgesic tablets and nine patients of the control group not having severe chest pain received non-serratiopeptidase containing analgesic tablets. Both groups were compared on the basis of successful ICD tube removal. The results were analysed using Chi-square statistic with Yates correction.

Results:

Of the 19 patients in the intervention group who received serratiopeptidase, 16 had successful recovery while three had to undergo thoracic surgery. Of the nine patients in the comparison group, only one had a successful recovery while the other eight had to be referred to thoracic surgery with ICD tube in situ. The outcome showed a statistically significant difference between the two groups, in terms of ICD tube removal and avoidance of thoracic surgery, with a P value of < 0.001.

Conclusion:

We conclude that the addition of serratiopeptidase to anti-tubercular drugs regimen can lead to better clinical outcomes and avoidance of thoracic surgery, in patients of tubercular hydropneumothorax.

INTRODUCTION

Hydropneumothorax is defined as the collection of abnormal amount of fluid and air in the pleural cavity. The most common cause of hydropneumothorax in India is tuberculosis (TB). Intercostal drainage (ICD) tube insertion and anti-tuberculosis drugs in accordance of the well-established DOTS strategy, under the National Tuberculosis Elimination Program (NTEP), are the mainstay of treatment.

Serratiopeptidase is a proteolytic enzyme that has been used for reducing inflammation.[1] It has analgesic,[2] fibrinolytic[3] and anti-inflammatory properties.[4,5] It is used to treat various conditions like osteoarthritis, acne vulgaris and for the management of post-operative pain.[6] Previous animal and human studies have shown that serratiopeptidase also increases the tissue penetration of antibiotics.[7,8]

This study aims to analyse the hypothesis that adding serratiopeptidase to anti-tuberculosis drug regimen may contribute in the successful resolution of hydropneumothorax of tubercular aetiology and avoidance of thoracic surgery.

METHODS AND MATERIALS

Study design and population

This retrospective observational cohort study included 28 patients (21 males and seven females) admitted in extrapulmonary TB ward of our large tertiary care hospital in Northern India, with confirmed diagnosis of tubercular hydropneumothorax. Initially, 32 patients were presented with the chief complaints of fever, cough, breathlessness, loss of appetite and chest pain during a period of 6 months, that is from 1 April to 30 September 2022. They were diagnosed as cases of hydropneumothorax on the basis of a chest radiograph (posteroanterior view). ICD was done in all of them. Two patients with diabetes mellitus and one patient found seropositive for HIV were excluded from the present study. Diagnosis of tubercular aetiology of hydropneumothorax was made on the basis of history and pleural fluid analysis, which included biochemical, cytological and microbiological tests, including the genotypic test of cartridge-based nucleic acid amplification test (CB-NAAT). One patient found rifampicin-resistant was excluded, while the remaining 28 patients found rifampicin-sensitive were included in the study. Patients with thoracic co-morbidities like lung destruction, bronchiectasis, interstitial lung disease and drug-resistant TB were not considered for inclusion to avoid bias. The sample size of only 28 patients was finalised, after subjecting all the patients who presented with the concerned diagnosis of tubercular hydropneumothorax in the study period mentioned above, to the exclusion and inclusion criteria. Ethical committee approval was obtained on 09/12/2022.

All patients underwent ICD tube insertion, with appropriate water seal, along with anti-TB treatment regimen, according to body weight band, under the National TB Elimination Program of India.[9] Out of total 28 patients, 19 patients (15 males and four females), who complained of severe chest pain were given serratiopeptidase containing NSAID analgesic combination tablets (Aceclofenac 100 mg, Paracetamol 325 mg and Serratiopeptidase 15 mg) twice daily, were taken in the intervention arm of the study. However, nine patients (six males and three females), who did not complain of severe chest pain, were given alternative analgesic combination tablets without having serratiopeptidase (Aceclofenac 100 mg and Paracetamol 325 mg) twice daily and were taken in the comparison arm of the study. All patients in both groups were matched for age and sex. In both groups, the ICD tube remained inserted till the criteria for its removal were satisfied, which included lung expansion, no broncho-pleural fistula, drainage of less than 10 ml in 24 h, along with clinical improvement in fever and anorexia. Removal of the ICD tube was taken as an end point indicator of a successful outcome and avoidance of thoracic surgery [Figure 1].

Figure 1.

Flow chart

Statistical analysis

Quantitative variables for both groups included age, duration of ICD being inserted and duration of analgesic combination tablets administered. Mean was taken for all after dividing into intervention and comparison groups. The outcome of both groups was compared and analysed, using Chi-square statistic with Yates correction. For matching of age, Student-t unpaired two-sided test was used and for matching of sex Chi-square with Yates correction was used.

RESULTS

All 32 potentially eligible patients were examined for eligibility, and only 28 (21 males and seven females) were confirmed to be eligible for inclusion in the study. The remaining four patients were excluded on the basis of exclusion criteria of being diabetic, seropositive for HIV and rifampicin-resistant. In the intervention group of 19 patients (mean age 40.63 SD 16.88 years) (CI 33.04–48.22) which received serratiopeptidase containing analgesic tablets, for a mean duration of 14.37 SD 13.25 days (CI 8.412–20.33), we saw that 16 (84.2%) had a successful recovery, with clinical and radiological improvement along with ICD tube removal, while three (15.8%) had to undergo thoracic surgery. The mean duration of the ICD tube remaining inserted, in this group of patients, was 14.25 SD 15.01 days (CI 7.499–21.001). However, we saw that in the comparison group of nine patients (mean age 34.22 SD 14.97) (CI 24.440–44.000) who did not receive serratiopeptidase-containing tablets, only one (11.1%) had successful recovery and ICD tube removal after 15 days, while eight (88.9%) remaining patients were referred to a thoracic surgeon, with ICD tube inserted, for thoracotomy and decortication. No untoward adverse effects were found in any patient of the study. Comparability of both groups, in terms of age, was established by using Student-t unpaired two-sided test, where we found that the t-value was 0.9706 and the P value was 0.3407. Comparability of both groups, in terms of sex, was established using Chi-square with Yates correction, where the P value was 0.8152.

The outcome of both groups in terms of ICD tube removal was compared, and on analysing the data, it was found that the Chi-square statistic with Yates correction was 10.7886, and the P value was 0.001. Hence, it could be said that group of patients given serratiopeptidase showed better outcomes in terms of ICD tube removal and avoidance of thoracic surgery, and this difference was statistically significant.

DISCUSSION

Hydropneumothorax of tubercular aetiology resulting from rupture of the tubercular lung cavity[10] is frequently seen in chest wards of Indian hospitals. Our patients were presented with the chief complaints of breathlessness and cough due to the mass effect of air and fluid in pleural space, along with mediastinal shift. Other studies have also found breathlessness to be the most common symptom of hydropneumothorax[10] and pneumothorax.[11] Fever, chest pain and weight loss are other major complaints in patients of hydropneumothorax due to tubercular aetiology[12] and were also found in our patients. National guidelines for diagnosis and treatment[9] should be used, in all cases of pleural effusion of tubercular aetiology, including microbiological confirmation and universal drug sensitivity testing by genotypic method of pleural fluid for CB-NAAT. Exudative pleural fluid, according to Light’s criteria, along with lymphocytic predominance, and high levels of adenosine deaminase (ADA), is taken as highly suggestive of tubercular aetiology in a high-burden country like India.[13,14]

Serratiopeptidase is a proteolytic enzyme that has long since been used for its anti-inflammatory properties,[1] in the fields of surgery (post-op and traumatic inflammation)[15] otorhinolaryngology (rhinitis, sinusitis),[2] orthopaedics (arthritis, carpal tunnel syndrome[16]), gynaecology and dentistry. Researches conducted in Europe and Japan showed that it is the most effective enzymatic anti-inflammatory agent.[17] It works in three possible ways:

• Anti-inflammatory: It acts by decreasing the amount of fluid and facilitating its drainage by thinning it. It also dissolves dead tissue in the area to fasten the healing process.[4,5]

• Analgesic: It may help as an analgesic by inhibiting the release of bradykinin, a pain-inducing amine from inflamed tissues.[2]

• Fibrinolytic/caseinolytic: It breaks down fibrin and other dead tissue without harming living tissue.[3]

Some animal studies show that serratiopeptidase has a role in increasing antibiotic concentration in tissues[7] and is also supported by its similar use in human study.[8]

In our study, patients were given serratiopeptidase in combination with other NSAIDs, for indication of severe pain alleviation, but it was found that in addition to pain alleviation, it also helped in the faster resolution of tubercular disease, which may be due to increased penetration and concentration of anti-TB drugs in fluids and tissues. In our study, we found that all patients except three, who received serratiopeptidase, underwent successful ICD removal, while all the patients, except one who did not receive it, had to be referred for thoracic surgical intervention. Facilities of thoracic surgery are not widely available in developing countries,[18,19] which face the highest burden of tuberculosis. Hence, it could be said that the addition of serratiopeptidase to anti-TB treatment regimen, leading to avoidance of thoracic surgery, in patients of tubercular hydropneumothorax, could be an important step in the judicious use of this meagre resource of thoracic surgery.

CONCLUSION

We can conclude that the addition of serratiopeptidase to anti-TB drugs regimen could have an important role in avoiding thoracic surgery, among patients of tubercular hydropneumothorax, a type of extrapulmonary tuberculosis. The biggest limitation of our study was its small sample size, and a larger study is required to arrive at a robust and final conclusion.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.