March20, 2023

Abstract Volume: 1 Issue: 4 ISSN:

Post COVID 19 Lung fibrosis: “Jumping out of the fire in to the frying pan” How to avert the crisis?

Anand Agrawal, MD*, Dr.Kamaljeet Singh, MD1, Shikha Goel,MD2

1.Assistant Professor, Department of Respiratory Medicine, BPSGMC(W) Khanpur Sonepat, Haryana India.

2.Tutor, Department of Pathology, NC Medical College & Hospital, Panipat, Haryana.

*Corresponding Author: Dr. Anand Agrawal *, Professor & Head, Department of Respiratory Medicine, BPSGMC(W) Khanpur Sonepat, Haryana India.


Received Date:  November 13, 2020

Publication Date: December 01, 2020

Post COVID 19 Lung fibrosis: “Jumping out of the fire in to the frying pan” How to avert the crisis?

When entire world rejoicing on Eve of the new year 2020, an acute atypical respiratory ailment known as the severe acute respiratory syndrome caused by the novel coronavirus, flared up in Wuhan, China in weird circumstances, later rapidly spread to other part of the world like a firestorm due to its unacquainted behavior in the human body & fluctuating management guideline.

A SARS disease usually spread through the micro droplet, typically consists of three phases when virus entered the body: viral multiplication, hyperactivity of immune system, and  destruction of lung parenchyma,(1) forbye  pathology of the lung is associated with diffuse alveolar damage, which is characterized by an initial acute inflammatory exudative phase associated with edema, hyaline membranes, and interstitial acute inflammation, followed by an organizing phase with loose organizing fibrosis mostly within the alveolar septa, besides this  lymphopenia, hemophagocytosis in the lung, and white-pulp atrophy of the spleen  is also manifested in SARS patients which supports cytokine deregulation and in  severe cases, may bring about tissue hyper inflammation, fibrosis, lung collapse, multi-organ dysfunction, and patient death .(2,3)

Thille et al. published the report of 159 autopsies from patients with ARDS, reveal that the probability of fibrosis gets exponentially increased from 4% to 61 % with the severity and duration of diseases in follow-up from 1st week to 3rd week. Additionally, 47% of patients had impaired Diffusing Capacity of the lungs for carbon monoxide (DLCO) as well as 25% had reduced total lung capacity (TLC).(4) Similarly in another study conducted by Polak et al. highlighted diffuse alveolar damage (DAD) in 85% as well as fibrotic pattern in 22% with honeycombing in 7% of biopsy and autopsy report of 131 study subjects.(5)

Studies have shown that bilateral interstitial pneumonia is associated with the presence of fibrotic tissue caused by excess collagen in the pulmonary interstitium with hyper-inflammation. (6) Patients with severe diseases showed lymphopenia with the reduction in peripheral blood T-cells as well as increased plasma concentrations of pro-inflammatory cytokines, including interleukin (IL)-6, IL-10, granulocyte-colony stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein (MIP)1α, and tumor necrosis factor (TNF)-α  .(7,8) Similarly hyperactive inflammatory state in the most severe stages of COVID-19 infection, caused by the cytokine storm, is probably the major culprit of pulmonary fibrosis within the lungs, more over injury occurs to the lung endothelium, epithelial cells, and bronchoalveolar capillaries leading to elevated vascular permeability, disseminated intravascular coagulation, focal demarcation of hemorrhages, and proteinaceous exudates within alveolar spaces responsible for severe and in some cases fatal lung lesions which gives the lungs an appearance of bi-lateral ground-glass opacity during computed tomography (CT) scans.(1,9)

The pathophysiological analogy between IPF and COVID-19 suggests a similar pathogenetic mechanism of pulmonary fibrosis; therefore, it is hypothesized that drugs useful for the treatment of IPF could also be useful for patients with COVID-19.(10,11) In fact, existing data indicate that pirfenidone has both antifibrotic as well as anti-inflammatory properties which mitigate the proliferation of fibroblasts as well as accumulation of extracellular matrix in response to cytokine growth factors such as TGF-β and PDGF.(12) Recently it has been cited that pirfenidone signi?cantly inhibits TGF- β 1-induced ?bronectin synthesis. Down-regulation of pro?brotic gene expression and collagen secretion as well as reduction of over expression of TGF-β in in?ammatory conditions plays a crucial role in the anti?brotic activity of pirfenidone, besides this, it also inhibits collagen I ?bril formation lead to a reduction in collagen ?bril bundles. It has been shown that pirfenidone has pleiotropic actions on both the immune system and extracellular matrices (ECM), such as hyaluronan, a major component of the ECM that regulates tissue injury and repair. (13) Recently, the up-regulation of RGS2 has been suggested as a novel mechanism of amelioration of pulmonary ?brosis with pirfenidone treatment. Surprisingly, it has been shown that pirfenidone inhibits the AT1R/p38 MAPK pathway, decreased angiotensin-converting enzyme (ACE), angiotensin II, and angiotensin II type 1 receptor expression, and strongly enhanced liver X receptor-α expression. This will not only protect cells from developing ?brosis but also decrease the entrance of the COVID-19-SARS virus into cells by decreasing the ACE receptor expression.(14)

Although the therapeutic efficacy of pirfenidone in pulmonary fibrosis induced by SARS-CoV-2 is still being demonstrated, few recent studies proposing to use the FDA-approved anti-?brotic therapies (nintedanib NCT04338802 and pirfenidone NCT04282902) for idiopathic pulmonary ?brosis (IPF) in COVID-19 patients.(5,15,16) Pirfenidone and Nintedanib are available only in oral form hence cannot be used in intubated patients, therefore, an inhaled formulation of pirfenidone is under evaluation in patients with COVID-19 (NCT04282902).(17-19) The current literature proposed that antifibrotic intervention can be used in combination with anti-inflammatory drugs to limit the damage produced by the cytokine storm and avoid the death of the patient, however in the chronic phase, when the patient is saved and cured of the infection, pirfenidone can be used to eliminate residual complications, such as fibrotic tissue in the lungs.(20-22)

Therefore early measures to cease the progression of fibrotic changes in the COVID 19 case may help prevent permanent disability among the affected population also mitigate the global burden of DALY loss in the future. Although before incorporating anti-fibrotic medication in the standard guideline of COVID 19 management, need more clinical trials globally in different strata to evaluate its risk-benefit criteria’s among SARS Cov2 infected population to validate its use by the eminent scientific societies as well as the World health organization.


1. Polak SB, Van Gool IC, Cohen D, von der Thüsen JH, van Paassen J. “A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression”. Mod Pathol. 2020;33(11):2128-2138. doi:10.1038/s41379-020-0603-3.

2. Borensztajn K, Crestani B, Kolb M. “Idiopathic pulmonary fibrosis: from epithelial injury to biomarkers – insights from the bench side”. Respiration 2013; 86: 441–452.

3. Kelly M, Kolb M, Bonniaud P, et al. . “Re-evaluation of fibrogenic cytokines in lung fibrosis.” Curr Pharm Des 2003; 9: 39–49.

4. Vasarmidi E, Tsitoura E, Spandidos DA, Tzanakis N, Antoniou KM. “Pulmonary fibrosis in the aftermath of the COVID-19 era (Review)”. ExpTher Med. 2020;20(3):2557-2560. doi:10.3892/etm.2020.8980.

5. Chaudhary S, Natt B, Bime C, Knox KS, Glassberg MK. “Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused”. Front Med (Lausanne). 2020 Sep 9;7:539. doi: 10.3389/fmed.2020.00539. PMID: 33072773; PMCID: PMC7531602.

6. Simler NR, Brenchley PE, Horrocks AW, et al. . “Angiogenic cytokines in patients with idiopathic interstitial pneumonia”. Thorax 2004; 59: 581–585.

7. Bonner JC. “Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor” Rev 2004; 15: 255–273.

8. Vaillant P, Menard O, Vignaud JM, et al. . “The role of cytokines in human lung fibrosis”. Monaldi Arch Chest Dis 1996; 51: 145–152.

9. De Wever W, Meersschaert J, Coolen J, Verbeken E, Verschakelen JA. “The crazy-paving pattern: a radiological-pathological correlation”. Insights Imaging. 2011;2(2):117-132. doi:10.1007/s13244-010-0060-5

10. Torrisi SE, Kahn N, Wälscher J, Sarmand N, Polke M, Lars K, Eichinger M, Heussel CP, Palmucci S, Sambataro FM, Sambataro G, Sambataro D, Vancheri C, Kreuter M. “Possible value of antifibrotic drugs in patients with progressive fibrosing non-IPF interstitial lung diseases”. BMC Pulm Med. 2019 Nov 12;19(1):213. doi: 10.1186/s12890-019-0937-0. PMID: 31718637; PMCID: PMC6852748.

11. George PM, Wells AU, Jenkins RG. “Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy”. Lancet Respir Med. 2020;8(8):807-815. doi:10.1016/S2213-2600(20)30225-3.

12. Lechowicz K, Dro?d?al S, Machaj F, Rosik J, Szostak B, Zegan-Bara?ska M, Biernawska J, Dabrowski W, Rotter I, Kotfis K. “COVID-19: The Potential Treatment of Pulmonary Fibrosis Associated with SARS-CoV-2 Infection”. J Clin Med. 2020 Jun 19;9(6):1917. doi: 10.3390/jcm9061917. PMID: 32575380; PMCID: PMC7356800.

13. Ferrara F, Granata G, Pelliccia C, La Porta R, Vitiello A. “The added value of pirfenidone to fight inflammation and fibrotic state induced by SARS-CoV-2 : Anti-inflammatory and anti-fibrotic therapy could solve the lung complications of the infection?”. Eur J ClinPharmacol. 2020;76(11):1615-1618. doi:10.1007/s00228-020-02947-4.

14. Seifirad S. Pirfenidone: “A novel hypothetical treatment for COVID-19”. Med Hypotheses. 2020 Jun 17;144:110005. doi: 10.1016/j.mehy.2020.110005. Epub ahead of print. PMID: 32575019; PMCID: PMC7297676.

15. Hostettler KE, Zhong J, Papakonstantinou E, et al. . “Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis”. Respir Res 2014; 15: 157.

16. Wollin L, Distler JHW, Redente EF, et al. “Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases”. EurRespir J. 2019;54(3):1900161. Published 2019 Sep 19. doi:10.1183/13993003.00161-2019.

17. Richeldi L, Fletcher S, Adamali H, et al. “No relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone”. EurRespir J. 2019;53:1801060. doi:10.1183/13993003.01060-2018.

18. Hilberg O, Simonsen U, du Bois R, et al.”Pirfenidone: significant treatment effects in idiopathic pulmonary fibrosis.” ClinRespir J 2012;6:131–43. 10.1111/j.1752-699X.2012.00302.x

19. George PM, Wells AU, Jenkins RG. “Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy”. Lancet Respir Med. 2020 Aug;8(8):807-815. doi: 10.1016/S2213-2600(20)30225-3. Epub 2020 May 15. PMID: 32422178; PMCID: PMC7228727.

20. Perelas A, Glennie J, van Kerkhove K, Li M, Scheraga RG, Olman MA, Culver DA. “Choice of antifibrotic medication and disease severity predict weight loss in idiopathic pulmonary fibrosis”. PulmPharmacolTher. 2019 Dec;59:101839. doi: 10.1016/j.pupt.2019.101839. Epub 2019 Sep 10. PMID: 31518649; PMCID: PMC6889056.

21. Wollin L, Wex E, Pautsch A, et al. “Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis”. EurRespir J. 2015;45:1434-1445. doi:10.1183/09031936.00174914.

22. Vitiello A, Pelliccia C, Ferrara F. “COVID-19 Patients with Pulmonary Fibrotic Tissue: Clinical Pharmacological Rational of Antifibrotic Therapy”.[published online ahead of print, 2020 Aug 27]. SN ComprClin Med. 2020;1-4. doi:10.1007/s42399-020-00487-7.




Volume 1 Issue 4 December 2020

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