|
 
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| ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 12
| Issue : 2 | Page : 53-60 |
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Early intervention with anti-fibrotic pirfenidone is effective than corticosteroids in preventing pulmonary fibrosis in severe COVID pneumonia patients
Masood Tanvir1, Imran Wagay2, Sobia Nisar1, Rabia Nazir Ahmed1, Muzaffar Maqbool1, Ozaifa Kareem3, Umar Muzaffer1
1 Department of General Medicine, Government Medical College, Karanagar, Srinagar, Jammu and Kashmir, India
2 Department of Radiology, Government Medical College, Karanagar, Srinagar, Jammu and Kashmir, India
3 Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir, India
| Date of Submission | 08-Nov-2021 |
| Date of Decision | 02-Jan-2022 |
| Date of Acceptance | 19-Jan-2022 |
| Date of Web Publication | 26-Apr-2022 |
Correspondence Address:
Dr. Sobia Nisar
Assistant Professor, Department of General Medicine, Government Medical College, Srinagar, Jammu and Kashmir - 190010
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/cmrp.cmrp_110_21
Background: The COVID-19 pandemic caused by SARS-CoV-2 has made nearly 120 million people sick with more than 2 million dead. Many survivors of severe COVID-19 are experiencing post-COVID complications beyond 4 weeks from the disease onset. The decrease in lung function and pulmonary fibrosis are the serious manifestations of COVID-19. The burden of even a relatively mild fibrotic change could have considerable morbidity and mortality, especially in the elderly and those with comorbidities.
Aim: To evaluate the effect of early intervention with anti-fibrotic pirfenidone and corticosteroids in preventing pulmonary fibrosis in severe COVID pneumonia patients.
Methods: This randomised open-label pilot trial was conducted was conducted at Government Medical College, Srinagar for evaluating the role of anti-fibrotic drugs in preventing post-COVID pulmonary fibrosis. In this study, 60 patients with severe COVID-19 infection were screened and randomised into two groups, one receiving anti-fibrotic drug– pirfenidone (n = 17) and other receiving corticosteroids (n = 19). The study participants were evaluated at the baseline and after 6 ± 1 week using 6-min walk test, spirometry and high-resolution computed tomography (HRCT).
Results: The mean (±standard deviation [SD]) age of the pirfenidone and steroid group was 64.16 ± 11.36 and 67.19 ± 13.32 (P = 0.929), respectively. There were no significant differences in clinically relevant baseline characteristics at the time of enrolment in the two treatment groups. The initial CT severity score was 14.84 ± 4.031 and 14.81 ± 4.722 (P = 0.400) in pirfenidone and corticosteroids groups. The mean (±SD) baseline forced expiratory volume in the first second (FEV1) in pirfenidone and corticosteroid was 73.32 ± 18.10 and 71.71 ± 17.92 (P = 0.670), while FEV1/forced vital capacity was 95.89 ± 23.40 and 90.00 ± 21.09 (P = 0.920), respectively, between the two groups. The final fibrosis score was 115.52 ± 12.32 and 138.22 ± 43.90 (P = 0.004) in the pirfenidone and corticosteroids groups, respectively. At the 6th week, the proportion of patients who had died was less in the pirfenidone group as compared in the corticosteroid group (02 patients [11.76%] in the pirfenidone group vs. 08 patients [42.10%] P < 0.001).
Conclusion: Pirfenidone, an anti-fibrotic agent, has a better outcome than corticosteroids in preventing post-COVID pulmonary fibrosis without serious adverse effects. Our study concludes that early initiation of pirfenidone therapy in patients with severe COVID-19 infection, especially those at higher risk like the elderly and those with co-morbidities has a better treatment and survival outcome compared to corticosteroids.
Keywords: Corticosteroids, COVID-19, pirfenidone, pulmonary fibrosis, SARS-CoV-2
How to cite this article:
Tanvir M, Wagay I, Nisar S, Ahmed RN, Maqbool M, Kareem O, Muzaffer U. Early intervention with anti-fibrotic pirfenidone is effective than corticosteroids in preventing pulmonary fibrosis in severe COVID pneumonia patients. Curr Med Res Pract 2022;12:53-60 |
How to cite this URL:
Tanvir M, Wagay I, Nisar S, Ahmed RN, Maqbool M, Kareem O, Muzaffer U. Early intervention with anti-fibrotic pirfenidone is effective than corticosteroids in preventing pulmonary fibrosis in severe COVID pneumonia patients. Curr Med Res Pract [serial online] 2022 [cited 2022 May 19];12:53-60. Available from: http://www.cmrpjournal.org/text.asp?2022/12/2/53/343929 |
| Introduction | |  |
The outbreak of new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) driven coronavirus disease 2019 (COVID-19) in December 2019 rapidly escalated to pandemic and lead to the collapse of health-care systems throughout the world. As of 17 March, 2021, there are more than 121 million confirmed cases and 2.67 million deaths worldwide.[1] SARS-CoV-2 primarily affects the respiratory system and particularly the lungs which is similar to other etiological agents in previous coronavirus outbreaks like SARS and the Middle East respiratory syndrome (MERS).[2] The clinical spectrum of COVID-19 ranges from mild respiratory tract illness to severe interstitial pneumonia with acute respiratory distress syndrome, pulmonary fibrosis, multi-organ dysfunction and death.[3],[4],[5]
In severe COVID-19, the inflammatory changes in the lungs lead to diffuse alveolar damage, type-II pneumocyte hyperplasia along with disruption of the basement membrane and thickening of the alveolar walls.[6] This further deteriorates the lung function leading to the collapse of alveoli, oedema and inflammation progressing to potentially fatal dyspnoea.[7] This initial phase of lung injury is followed by an attempt to repair and restore the normal pulmonary architecture. If imbalanced or prolonged, this process may lead to pulmonary fibrosis with distortion of lung architecture and irreversible lung damage and dysfunction.[8] Recent data suggest that up to 17% of severe COVID-19 patients develop pulmonary fibrosis[7] while more than a third of recovered patients develop fibrotic changes.[9] Pulmonary fibrosis, as a pathological consequence of COVID-19, is characterised by the inability of the lungs to repair the damaged alveolar epithelium, persistence of fibroblasts, and deposition of collagen and other extracellular matrix components.[10] This causes an alteration and destruction of normal lung parenchyma and thus damage to capillaries leading to respiratory failure.[11] These changes are manifested as various patterns on high-resolution computed tomography (HRCT) scans which include interstitial thickening, ground-glass opacities, irregular interfaces, coarse reticular pattern and parenchymal band.[12],[13]
Recent evidence suggests that advanced age represents the most specific predictor for developing severe COVID-19 with rapidly progressive clinical deterioration.[14] This is because in the elderly, co-morbid conditions coupled with immuno-senescence promote viral-induced cytokine storm and decrease systemic anti-inflammatory cytokines resulting in life-threatening respiratory distress with multi-system involvement.[15] As co-morbidities often increase with advancing age, the elderly population, in turn, experiences a more severe form of COVID-19. In presence of loss of resources, the burden of even a mild fibrotic change could be huge in such a population and can result in great functional decline.[16] It has been reported previously that the population with severe SARS-CoV-2 infection is highly representative of patients suffering from idiopathic pulmonary fibrosis (IPF).[17],[18] IPF is a progressive disease in which lung function declines significantly and eventually causes respiratory failure and death.[19] The major risk factors such as advancing age, male sex, co-morbidities including diabetes and hypertension are shared between IPF and COVID-19.[20]
Considering the quantum of the population affected by severe COVID-19, the burden of sequela of the COVID-19 would be huge. Pulmonary fibrosis is an emerging complication of COVID-19 and the data regarding the role of anti-fibrotic therapy in its prevention is scanty. Anti-fibrotic therapy might have a beneficial role in mitigating the development of pulmonary fibrosis following COVID-19 infection.[20] Pirfenidone, an anti-fibrotic medication has anti-oxidant, anti-fibrotic, and anti-inflammatory properties and can decrease the proliferation of fibroblasts and the production of cytokines and proteins associated with fibrosis.[21],[22],[23] Pirfenidone has a pleiotropic effect in attenuating the rate of lung function decline by about 50% in IPF[24] and by inhibiting the synthesis of pro-fibrotic and inflammatory mediators.[25] Thus, the therapeutic potential of initiating early anti-fibrotic therapy in the prevention of pulmonary fibrosis caused by COVID-19 needs to be explored. Being an emerging disease, no data were available to determine the long-term pulmonary sequelae of COVID-19. The pathophysiological similarity between COVID-19 and IPF point towards similar pathogenesis in the two diseases; therefore randomised trials of anti-fibrotic medication in COVID-19 are warranted.
Considering the quantum of the population affected by severe COVID-19, the burden of sequela of the COVID-19 would be huge. Pulmonary fibrosis is an emerging complication of COVID-19 and the data regarding the role of anti-fibrotic therapy in its prevention is scanty. Anti-fibrotic therapy might have a beneficial role in mitigating the development of pulmonary fibrosis following COVID-19 infection.[20] Pirfenidone, an anti-fibrotic medication has anti-oxidant, anti-fibrotic, and anti-inflammatory properties and can decrease the proliferation of fibroblasts and production of cytokines and proteins associated with fibrosis.[26] Pirfenidone has a pleiotropic effect in attenuating the rate of lung function decline by about 50% in IPF[27] and by inhibiting the synthesis of pro-fibrotic and inflammatory mediators.[28] Thus, the therapeutic potential of initiating early anti-fibrotic therapy in the prevention of pulmonary fibrosis caused by COVID-19 needs to be explored. Being an emerging disease, no data was available to determine the long-term pulmonary sequelae of COVID-19. The pathophysiological similarity between COVID-19 and IPF point towards similar pathogenesis in the two diseases; therefore randomized trials of anti-fibrotic medication in COVID-19 are warranted.
| Materials and Methods | | |
This randomised, open-label pilot trial was conducted at Government Medical College and associated SMHS hospitals Srinagar from October 2020 to February 2021. Consecutive subjects satisfying the inclusion and exclusion criteria were allocated two arms. The allocation was done with open-label randomisation according to the random number table sequence and informed consent was obtained before the enrolment. The study was conducted according to the Helsinki Declaration of 1975 and was duly approved by the Institutional Ethics Committee (No: ECR/1422/Inst./JK/2020).
Subject selection
All the consecutive patients admitted with bilateral pneumonia whose initial HRCT was showing 50% lung involvement were informed about the study. Those who gave informed consent and also fitted inclusion/exclusion criteria were enrolled in the study.[29] The patients were randomly assigned to receive either oral pirfenidone or corticosteroid for 6 weeks; however, corticosteroids were given in both groups till hospital discharge. The study participants in the corticosteroid group received oral 60 mg OD corticosteroid for the first week followed by 50 mg in the 2nd week, 40 mg in the 3rd week, 30 mg in the 4th week, 20 mg in the 5th week, and 10 mg in 6th week. The study participants in the pirfenidone group received one tablet of 267 mg of pirfenidone three times a day (TID) orally for 1 week, followed by 2 tablets TID for the second week and 3 tablets TID for the 3rd to 6th week. The primary endpoint was measured by HRCT fibrosis score as employed by others.[30],[31],[32] The fibrosis score using HRCT findings was graded on a scale of 1–5 based on the classification system: (1) normal attenuation; (2) Ground-glass opacification; (3) Interlobular septal thickening; (4) Traction bronchiectasis; and (5) Sub-pleural fibrosis.[33] The presence of each of the above five HRCT findings was assessed independently in three (upper, middle, and lower) zones of each lung. The extent of each HRCT finding was determined by visually estimating the percentage of parenchymal involvement in each zone. The score for each zone was calculated by multiplying the percentage of the area by the grading scale score.[1],[2],[3],[4],[5] The six-zone scores were averaged to determine the total score for each patient. The highest fibrosis score was 500 points and the lowest score (i.e. normal CT) was 100 points using this calculation method. Secondary endpoints were measured by a 6-min walk distance and spirometry. Patients were followed each week and the spirometry (forced expiratory volume in the first second [FEV1] and FEV1/forced vital capacity [FVC]) and 6-min walk test (6MWT) were performed at the first and last follow-up. At the end of 6 weeks, HRCT was repeated and further treatment decision was made.
Statistical analysis
The sample size was not calculated, as the trial was a pilot attempt. Data analysis was performed using IBM SPSS version 22. The data were described as mean ± standard deviation (SD) with comparison done using Student's t-test and Chi-square test for quantitative and qualitative variables. The data normality was checked using Kolmogorov–Smirnoff test and appropriate nonparametric tests was applied in case data was not normally distributed. A P = 0.05 was taken as significant.
| Results | | |
Out of a total of 60 patients that were screened, 56 patients were enrolled and randomised to receive either pirfenidone (n = 28) or corticosteroids (n = 28). Out of 36 patients (64.2%) who completed the study 19 (52.7%) were in the pirfenidone group and 17 patients (47.2%) in the corticosteroid group. Study treatment was discontinued prematurely in 02 patients (10%) in the pirfenidone group because one was diagnosed with adenocarcinoma and another had elevated creatinine levels [Figure 1]. There were no significant differences in clinically relevant baseline characteristics at the time of enrolment between the two study groups including the mean (±SD) age (64.16 ± 11.36 vs. 67.19 ± 13.32).Baseline characteristics are summarised in [Table 1]. The mean (±SD) baseline FEV1 in pirfenidone and corticosteroid was 73.32 ± 18.10 and 71.71 ± 17.92 (P = 0.670) while FEV1/FVC was 95.89 ± 23.40 and 90.00 ± 21.09 (P = 0.920), respectively, between the two groups. In the pirfenidone group, the change in FEV1/FVC from baseline to 6-week follow-up was 95.89 ± 23.40 and 102.94 ± 16.10, respectively [Table 2]. The 6MWT at first follow-up showed that oxygen saturation (SpO2) at the start of the test was 90.36 ± 6.29 and 89.60 ± 7.23 (P = 0.419), while the HR was 97.60 ± 12.86 and 82.50 ± 7.77 beats per minute (P = 0.441) in pirfenidone and corticosteroid group, respectively. At the end of the test, SpO2 was 88.10 ± 7.57 and 97.50 ± 0.70 (P = 0.090) and HR was 106.40 ± 7.63 and 88.00 ± 26.87 (P = 0.001) in pirfenidone and corticosteroid group, respectively. The 6MWT done at the last follow-up revealed that SpO2 at the start of the test was 94.31 ± 3.54 and 93.33 ± 5.50 (P = 0.287) and HR was 98.54 ± 8.88 and 70.50 ± 12.02 (P = 0.650) between pirfenidone and corticosteroid group, respectively. At the end of the test, SpO2 was 90.92 ± 4.57 and 90.67 ± 7.57 (P = 0.202) and HR was 104.54 ± 10.15 and 76.50 ± 21.92 (P = 0.121) between pirfenidone and corticosteroid group, respectively. There is no significant difference between the two treatment groups in the change from baseline to week 6th in the 6-min walk distance [Table 2]. The initial HRCT severity score was 14.84 ± 4.031 and 14.81 ± 4.722 (P = 0.400) in the pirfenidone and corticosteroids groups. | Table 2: Baseline and follow-up clinical characteristics of study population
Click here to view |
 | Figure 2: Computed tomography scans of the lungs of a patient with COVID-19 initially at the disease outset and at the end of the pirfenidone therapy
Click here to view |
Treatment with pirfenidone resulted in a significant difference in the primary end point [Figure 2], the change from initial HRCT score (P = 0.400) to the final fibrosis score (P = 0.004), between treatment groups. At the 6th week, the proportion of patients who had died was reduced in the pirfenidone group as compared in the corticosteroid group (02 patients [11.76%] in the pirfenidone group vs. 08 patients [42.10%] P < 0.001) [Figure 3]. The final fibrosis score was 115.52 ± 12.32 and 138.22 ± 43.90 (P = 0.004) in pirfenidone and corticosteroids groups respectively [Table 2]. | Figure 3: Computed tomography scans of the lungs of a patient with COVID-19 initially at the disease outset and at the end of the corticosteroid therapy
Click here to view |
| Discussion | | |
The COVID-19 infection chiefly causes acute respiratory symptoms including fever, cough, breathing difficulties, asthenia and anosmia.[34] In more severe cases, the infection may cause lung injury, pneumonia, septic shock and respiratory failure.[35] In high-risk population like the elderly and those with co-morbidities, the disease may lead to severe interstitial pneumonia and multiple-organ failure.[35],[36] Many patients who develop severe COVID-19 pneumonia survive the acute phase of illness however, a large proportion may develop fibro-proliferative changes leading to pulmonary fibrosis.[37]
This pilot trial was conducted to determine the effective treatment regimen for preventing post-COVID pulmonary fibrosis. In this trial, the patients with severe COVID-19 received either pirfenidone or corticosteroid therapy, started during hospitalisation, for 6 weeks and a significant benefit of early initiation of anti-fibrotic therapy over corticosteroids was noted. The corticosteroids were given in both groups till hospital discharge. The treatment groups had comparable baseline characteristics and severity of COVID-19 infection at the time of enrolment of the study population. The primary end-point of fibrosis score, as measured by HRCT, was significantly different between the two treatment groups while the secondary end-point, i. e. spirometry and 6-minute walk test did not show any significant difference. This significant difference in primary end-point was supported by less mortality in the pirfenidone group compared to the corticosteroid group. The less mortality in the pirfenidone group could be attributed to its pleiotropic mechanism of action in reducing the fibrotic and inflammatory state of lung tissue[26] or extended corticosteroid use could have detrimental effect.[38] Thus our study supports the role of early initiation of anti-fibrotic therapy in preventing pulmonary fibrosis in the post-COVID phase.
The treatment group that received pirfenidone had a generally safe side-effect profile. These findings are in consonance with those in previous studies.[39],[40] Pirfenidone was discontinued in only two patients due to rise in creatinine levels and detection of adenocarcinoma. The secondary end-points in our study, i.e., spirometry and 6-minute walk test are both reliable, valid, and responsive measures of disease status.[41]
The baseline CT severity score was comparable between the two treatment groups indicating similar disease severity. The follow-up fibrosis score, as measured by HRCT, was 115.52 ± 12.32 in the pirfenidone group and 138.22 ± 43.90 in the steroid group (P = 0.004). In the steroid group, the follow-up CT scan at 6 weeks shows reticulation, traction bronchiectasis and sub-pleural fibrotic bands which was suggestive of post-COVID pulmonary fibrosis. In the pirfenidone group, the follow-up CT scan at 6-weeks showed regression of ground glassing, and consolidation. Among 17 patients in the pirfenidone group, final HRCT showed reticulation in 4 patients, bronchiectasis in none, and sub-pleural fibrotic bands in three patients. The average lung involvement with reticulation was 3.30 ± 1.38% while 1.08 ± 0.44% showed subpleural fibrotic bands. In the steroid group among 11 patients, reticulation was noted in five patients, traction bronchiectasis in five, and sub-pleural fibrotic bands in five patients. In this group, the average lung involvement with reticulation was 7.57 ± 3.71% followed by traction bronchiectasis in 5.47 ± 7.20%, and sub-pleural fibrotic bands in 2.65 ± 3.23% of lungs. These observations point towards the potential benefit of pirfenidone in preventing post-inflammatory pulmonary fibrosis in COVID-19-infected patients. In consonance with this, a recent case report showed the absorption of the interstitial abnormalities including reticulation, GGO and patchy consolidation with the use of pirfenidone in COVID-19 patients.[42]
The study is very important, though preliminary indicator of the role of early interventions to prevent long-term pulmonary sequel of COVID-19 pneumonia. While acknowledging the limitations of the small sample size and double-blind randomised strategy, the data paves way for large, well-designed studies to address the issue of efficacy and safety of pirfenidone in the prevention of pulmonary fibrosis.
| Conclusion | | |
This preliminary observation suggests that early introduction of pirfenidone in preventing post-COVID pulmonary fibrosis scores over corticosteroids in efficacy and safety profile. The findings need to be validated by well-designed study using a robust sample size.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Ethical approval
Ethical approval for this study was provided by the Institutional Ethical Committee Government Medical College, Srinagar under No: ECR/1422/Inst./JK/2020.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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